Duvelisib (Copiktra) inhibits phosphatidylinositol 3-kinase (PI3K). It is available as oral capsules and is indicated for the treatment of refractory CLL, SLL, and Follicular lymphoma.

Duvelisib (Copiktra) Uses:

• Chronic lymphocytic leukemia/small lymphocytic lymphoma relapsed or refractory:

  • Duvelisib is used in the management of relapsed or recurrent chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in adult patients after  2 prior therapies.

• Follicular lymphoma, relapsed or refractory:

  • It can also be used in the treatment of relapsed or refractory follicular lymphoma (FL) in adult patients after at least 2 prior systemic therapies.

Read: Fludarabine (Fludara), Venetoclax (Venclexta), Chlorambucil, Obinutuzumab (Gazyva), Ofatumumab (Arzerra), and Fostamatinib (Tavalisse)

Duvelisib (Copiktra) Dose in Adults

Note:

• Prophylaxis for Pneumocystis pneumonia should be given during the treatment.
• After completion of therapy, continue PCP prophylaxis until the absolute CD4+ count is >200 cells/microliter.
• Consider providing prophylactic antivirals during Duvelisib treatment to prevent cytomegalovirus (CMV) infection or reactivation.

Duvelisib (Copiktra) Dose in the treatment of relapsed or refractory Chronic lymphocytic leukemia and small lymphocytic lymphoma:

• Oral: 25 mg twice a day.

Duvelisib (Copiktra) Dose in the treatment of relapsed or refractory Follicular lymphoma:

• Oral: 25 mg twice a day.

• Dosage modification for concomitant CYP3A4 inhibitor use:

  • Decrease the dose to 15 mg twice daily if administered with potent CYP3A4 inhibitors (eg, ketoconazole).

• Missed doses:

  • If a dose is missed by fewer than 6 hours, administer right then and give the next dose as usual.
  • If a dose is missed by more than 6 hours, wait and administer the next dose at the next appropriate time.

Dose in children:

Not indicated.

Pregnancy Risk Category: N

• It was found that this medication can cause fetal harm if given to pregnant animals. It should be avoided.
• Before starting treatment, it is important to get rid of any pregnancy.
• Both male and female partners should use effective contraception for at least one month after receiving the last doses of Duvelisib.
• Duvelisib base can affect male fertility.

Use Duvelisib while you breastfeed

• It is unknown whether the drug is secreted into breast milk.
• Breastfeeding infants may have adverse reactions, so it is not recommended for use during therapy or at least one month after the last dose.

Renal dose:

Duvelisib (Copiktra) Dose in Kidney disease:

• CrCl 23 to 80 mL/minute:

  • There are no dosage adjustments provided in the manufacturer’s labeling.
  • However, this level of renal impairment had no clinically significant effect on the drug exposure.

• CrCl <23 mL/minute:

  • There are no dosage adjustments provided in the manufacturer’s labeling.

Duvelisib (Copiktra) Dose in Liver disease:

• Hepatic impairment prior to treatment initiation:

  • Child-Pugh class A, B, or C:
    • There are no dosage adjustments provided in the manufacturer’s labeling.
    • However, hepatic impairment had no clinically significant effect on the drug's systemic availability.

• Hepatotoxicity during treatment (ALT, AST elevation):

  • Grade 2 (3 to 5 times the upper limit of normal [ULN]):
    • Maintain the dose and monitor at least weekly until return to <3 times ULN.
  • Grade 3 (>5 to 20 times ULN):
    • Withhold treatment and monitor at least weekly until return to <3 times ULN.
    • Resume treatment at the same dose (first occurrence) or at a reduced dose (subsequent occurrence).
  • Grade 4 (>20 times ULN):
    • Discontinue treatment.

Side effects:

Common Side Effects of Duvelisib (Copiktra):

• Cardiovascular:

  • Edema

• Central Nervous System:

  • Fatigue
  • Headache

• Dermatologic:

  • Skin Rash

• Endocrine & Metabolic:

  • Hypophosphatemia
  • Hyponatremia
  • Hyperkalemia
  • Hypoalbuminemia
  • Hypocalcemia
  • Hypokalemia
  • Weight Loss

• Gastrointestinal:

  • Colitis
  • Diarrhea
  • Increased Serum Lipase
  • Increased Serum Amylase
  • Nausea
  • Abdominal Pain
  • Constipation
  • Vomiting
  • Mucositis
  • Decreased Appetite

• Hematologic & Oncologic:

  • Neutropenia
  • Anemia
  • Thrombocytopenia
  • Lymphocytosis
  • Leukopenia
  • Lymphocytopenia

• Hepatic:

  • Increased Serum Alanine Aminotransferase
  • Increased Serum Aspartate Aminotransferase
  • Decreased Serum Alkaline Phosphatase
  • Increased Serum Alkaline Phosphatase
  • Increased Serum Transaminases

• Infection:

  • Sepsis
  • Serious Infection

• Neuromuscular & Skeletal:

  • Musculoskeletal Pain

• Renal:

  • Renal Insufficiency
  • Increased Serum Creatinine

• Respiratory:

  • Upper Respiratory Tract Infection
  • Pneumonia
  • Cough
  • Lower Respiratory Tract Infection
  • Dyspnea

• Miscellaneous:

  • Fever

Less Common Side Effects Of Duvelisib (Copiktra):

• Dermatologic:

  • Dermatological Reaction

• Infection:

  • Cytomegalovirus Disease

• Neuromuscular & Skeletal:

  • Arthralgia

• Respiratory:

  • Pneumonitis
  • Pneumonia Due To Pneumocystis Jiroveci

Contraindications to Duvelisib (Copiktra):

The literature supplied by the manufacturer does not contain any contraindications.

Warnings and precautions

• Suppression of bone marrow

  • Anemia, low TLC and thrombocytopenia can all be observed.
  • Grade 3 and 4 neutropenia have a median onset time of 2 months. This ranges from 3 days to 31, with the majority occurring in 4 months.
  • For the first two months, monitor ANC at least once every 2 weeks and at most once per week for patients with grade 3 or 4.
  • Stop treatment for grade 4 neutropenia, monitor until ANC >500/mm3, then resume the treatment at the same dose (first occurrence), or at a lower dose (subsequent occurrence).

• Dermatologic toxicities: [US Boxed Warning]

  • In 5% of patients who received duvelisib, there were severe and/or fatal cutaneous reactions.If you have a severe reaction to the skin, stop treatment.
  • There are fatal drug reactions such as DRESS or Toxic Epidermal Necrolysis (TENS).
  • The median time it took for cutaneous reactions to occur (any grade) was 3 to 5 months. This ranged from 1 to 29 months to 1 to 39 months.
  • The median duration was 1 to 3 months. This range is 1 to 37 months.
  • Severe dermatologic events typically presented with pruritic or erythematous features, but cases also included exanthem, skin exfoliation and erythroderma.
  • Any new or worsening cutaneous reactions should be reported to the doctor immediately.
  • Examine all medications and discontinue any that may be contributing to the condition.
  • Patients with mild to moderate (grades 1 and 2) cutaneous reactions should continue with current treatment.
  • If necessary, initiate supportive management with topical corticosteroids or antihistamines for pruritus.
  • You should not continue treatment for severe (grade 3) cutaneous reactions until they are resolved. 
  • Supportive management should be initiated with topical or systemic corticosteroids or antihistamines for pruritus.
  • Keep your condition under observation at least once per week until it is resolved. Once the problem has been resolved, you can resume treatment with a lower dose.
  • If severe cutaneous reactions persist, get worse, or recur, or if they are life-threatening, discontinue treatment.

• Gastrointestinal toxicities: [US Boxed Warning]

  • 18% of patients who received duvelisib were diagnosed with severe and/or fatal diarrhea, or colitis.
  • You should be on the lookout for signs of colitis or severe diarrhea.If colitis develops, you should withhold treatment.
  • The median time it took for diarrhea or colitis to develop (any grade) was four months.
  • This ranges from 1 day to 33 years, with the majority of cases happening within eight months.
  • The median length was 0.5 months, with a range of 1 day to 29.
  • Any new or worsening symptoms of diarrhea should be reported to the doctor immediately.
  • Non-infectious diarrhea and colitis can require supportive management, such as antidiarrheals or enteric corticosteroids or systemic corticosteroids.
  • Treatment interruption, additional monitoring or dose reduction may be required. Diagnostic work-up may also be necessary (e.g. colonoscopy) in order to determine the etiology.

• Hepatotoxicity

  • Patients treated with duvelisib have been found to exhibit Grades 3 and 4, ALT, and/or AS elevations.
  • Patients had ALT or AS >3 times the ULN, and total bilirubin >2x the upper normal limit.
  • The median time it took for transaminase elevation to occur (any grade) was 2 years (range: 3 to 26 months), and the median duration was 1 month (range, 1 to 16 months).
  • During treatment, monitor your liver function.
  • Hepatotoxicity can require frequent monitoring, treatment interruptions, dose reduction and/or discontinuation.

• Infection: [US Boxed Warning]

  • Duvelisib patients were treated for serious and fatal infections.
  • Be on the lookout for symptoms and signs of infection.
  • If you suspect that there is an infection, stop taking the medication.
  • Most serious infections are pneumonia, sepsis and lower respiratory infections.
  • The median time it took for infection to develop (any grade) was three months. This ranges from 1 day to 32 years, with the majority occurring in 6 months.
  • Before starting the therapy, treat any prior infections.
  • Any new or worsening symptoms/signs of infection should be reported to the doctor immediately.
  • Grade 3 and higher infections: Withhold treatment until the infection is under control. Then, resume treatment with the same dose or a reduced dosage.
  • Patients who took the drug have been diagnosed with serious, even fatal, Pneumocystis Jirovecii pneumonia (PCP).
  • Duvelisib patients should be given PCP prophylaxis. Continue PCP prophylaxis up to the time that the absolute CD4+ cell count is >200 cells/microliter after treatment discontinuation.
  • If PCP (any grade) suspicion is raised, discontinue treatment immediately.
  • Treatment has been shown to reduce the risk of CMV reactivation/infection.
  • To prevent CMV infection and relapse, consider prophylactic antivirals.
  • If you have CMV infection or viremia in a clinical setting, stop taking the drug until the infection or viremia has resolved.
  • Do not resume therapy if the dose is reduced or the same. CMV reactivation by PCR or antigen testing should be monitored at least once every 30 days.

• Pulmonary toxicities: [US Boxed Warning]

  • In 5% of patients who received duvelisib, fatal and/or severe pneumonitis were reported.
  • Monitor for symptoms such as pulmonary infiltrates and pulmonary symptoms.If pulmonary toxicities develop, keep duvelisib in your hand.
  • The median time it took for pneumonitis to develop (any grade) was four months. This ranged from 9 days to 27 years, with the majority of cases occurring in 9 months.
  • Pneumonitis lasted on average for 1 month. However, most cases resolve within 2 months.
  • Patients who present with new or progressing pulmonary symptoms or signs (eg, cough or dyspnea), should be given withhold treatment and evaluated for the etiology.
  • If pneumonitis has become infectious, you may resume treatment at the previous dose once symptoms and signs have resolved.
  • Moderate non-infectious pneumonia (grade 2) can be managed with systemic corticosteroids. Once the symptoms resolve, you may resume treatment (at a reduced dosage).
  • If non-infectious pneumonia recurs or doesn't respond to corticosteroid steroids therapy, discontinue treatment and treat with systemic corticosteroids if severe or life-threatening noninfectious pneumonia.

Duvelisib: 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:

• Monitor CBC with differential count. Patients with neutropenia grade 3 or 4 should be monitored at least once every 2 weeks during the initial 2 months.
• Hepatic function (ALT/AST during treatment).
• Test for pregnancy in females with reproductive potential (to confirm pregnancy status before treatment).
• Monitor for signs/symptoms such as CMV infection (by PCR/antigen test and PCP). Monitor for CMV infection after duvelisib treatment.
• Be on the lookout for signs/symptoms such as dermatologic toxicity or gastrointestinal toxicities (colitis, diarrhea).
• Monitor for symptoms such as pulmonary infiltrates and pulmonary symptoms. Monitor the patient to ensure compliance.

How to administer Duvelisib (Copiktra)?

Oral:

• Administer with or without food.
• It is not affected by food. Swallow the capsules whole. Do not open, break, or chew capsules.

Provide PCP prophylaxis during treatment and continue until the absolute CD4+ T cell count is >200 cells/microliter. 6eConsider prophylactic antivirals during treatment to prevent CMV infection and reactivation. 

Mechanism of action of Duvelisib (Copiktra):

• It is an oral PI3K inhibiter with dual inhibitory activities, primarily against PI3K–d and PI3K–g, which are both expressed in hematologic malignancies.
• The inhibition of PI3Kd decreased tumor cell proliferation and allowed normal cells to survive. 
• The inhibition of PI3Kg decreases the migration and differentiation of tumor microenvironment support cell cells.
• Duvelisib reduced the viability of cell line derived from malignant CLL and B-cells cells. 
• Duvelisib also inhibits B-cell receptor signaling pathways, CXCR12-mediated chemotaxis by malignant B cells, as well as CXCL12 induced T cell migration and MCF and IL-4-driven M2 macrophage polarization.

Protein binding:

• >98%

Metabolism:

• It is metabolized in the liver primarily via CYP3A4

Bioavailability: 42% Half-life elimination:

• 4.7 hours

Time to peak:

• 1 to 2 hours

Excretion:

• Feces: 79% (11% as unchanged drug);
• urine: 14% (<1% as unchanged drug)

International Brand Names of Duvelisib:

• Copiktra

Duvelisib Brand Names in Pakistan:

No Brands Available in Pakistan.