DRUG INTERACTIONS

 • CYP3A inducers: Avoid co-administration with strong CYP3A inducers                             • CYP3A Inhibitors: Monitor for COPIKTRA toxicities when coadministered with strong or moderate CYP3A inhibitors. Reduce COPIKTRA dose to 15 mg twice daily when co-administered with strong CYP3A4 inhibitors.                                                     • CYP3A substrates: Monitor for signs of toxicities when coadministering COPIKTRA with sensitive CYP3A substrates.

U.S. FDA APPROVED  DRUGS DURING 2018

Sr.No-  38

ADVERSE REACTIONS-

 The most common adverse reactions (> 20%) are diarrhea or colitis, neutropenia, rash, fatigue, pyrexia, cough, nausea, upper respiratory infection, pneumonia, musculoskeletal pain, and anemia.  

CONTRAINDICATIONS-                                                                                                        None

WARNING:                                                                                                                           FATAL AND SERIOUS TOXICITIES: INFECTIONS, DIARRHEA OR COLITIS, CUTANEOUS REACTIONS, and PNEUMONITIS.  

 See full prescribing information for complete boxed warning                                               • Fatal and/or serious infections occurred in 31% of COPIKTRA-treated patients. Monitor for signs and symptoms of infection. Withhold COPIKTRA if infection is suspected.   

 • Fatal and/or serious diarrhea or colitis occurred in 18% of COPIKTRA-treated patients. Monitor for the development of severe diarrhea or colitis. Withhold COPIKTRA.    

 • Fatal and/or serious cutaneous reactions occurred in 5% of COPIKTRA-treated patients. Withhold COPIKTRA.                                                                                                                                                                                                                                        • Fatal and/or serious pneumonitis occurred in 5% of COPIKTRA-treated patients. Monitor for pulmonary symptoms and interstitial infiltrates. Withhold COPIKTRA.

 PATIENT COUNSELING INFORMATION- 

 Advise the patient to read the FDA-approved patient labeling (Medication Guide).

 Physicians and healthcare professionals are advised to discuss the following with patients prior to treatment with COPIKTRA:  

• Infections-                                                                                                                         Advise patients that COPIKTRA can cause serious infections that may be fatal. Advise patients to immediately report symptoms of infection (e.g. fever, chills)

 • Diarrhea or Colitis-                                                                                                           Advise patients that COPIKTRA can cause serious diarrhea or colitis (inflammation of the gut) that may be fatal, and to notify their healthcare provider immediately about any new or worsening diarrhea, stool with mucus or blood, or abdominal pain.

• Cutaneous Reactions-                                                                                                       Advise patients that COPIKTRA can cause a serious skin rash that may be fatal, and to notify their healthcare provider immediately if they develop a new or worsening skin rash.

• Pneumonitis-                                                                                                                     Advise patients that COPIKTRA may cause pneumonitis (inflammation of the lungs) that may be fatal, and to report any new or worsening respiratory symptoms including cough or difficulty breathing.

 • Hepatotoxicity-                                                                                                                  Advise patients that COPIKTRA may cause significant elevations in liver enzymes, and that monitoring of liver tests is needed.  Advise patients to report symptoms of liver dysfunction including jaundice (yellow eyes or yellow skin), abdominal pain, bruising, or bleeding.

• Neutropenia-                                                                                                                     Advise patients of the need for periodic monitoring of blood counts.  Advise patients to notify their healthcare provider immediately if they develop a fever or any sign of infection.

 • Embryo-Fetal Toxicity-                                                                                                      - Advise females to inform their healthcare provider if they are pregnant or become pregnant.                                                                                                                              - Inform female patients of the risk to a fetus.                                                                    -Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after receiving the last dose of COPIKTRA.                                   - Advise males with female partners of reproductive potential to use effective contraception during treatment with COPIKTRA and for at least 1 month after the last dose.

• Lactation-                                                                                                                           Advise lactating women not to breastfeed during treatment with COPIKTRA and for at least 1 month after the last dose.

Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products, before and during treatment with COPIKTRA.

• Instructions for Taking COPIKTRA -                                                                               Advise patients to take COPIKTRA exactly as prescribed. COPIKTRA may be taken with or without food; the capsules should be swallowed whole.               

 Advise patients that if a dose is missed by fewer than 6 hours, to take the missed dose right away and take the next dose as usual.  If a dose is missed by more than 6 hours, advise patients to wait and take the next dose at the usual time.

Manufactured for:                                                                                                              Verastem, Inc. 117 Kendrick Street Suite 500 Needham, MA 02494

 CLINICAL PHARMACOLOGY-

 1.Mechanism of Action-                                                                                                  Duvelisib is an inhibitor of PI3K with inhibitory activity predominantly against PI3K-d and PI3K-? isoforms expressed in normal and malignant B-cells.  Duvelisib induced growth inhibition and reduced viability in cell lines derived from malignant B-cells and in primary CLL tumor cells.   

2.Pharmacodynamics-                                                                                                       At the recommended dose of 25 mg BID, reductions in levels of phosphorylated AKT (a downstream marker for PI3K inhibition) were observed in patients treated with COPIKTRA. 

Cardiac Electrophysiology-                                                                                         The effect of multiple doses of COPIKTRA 25 and 75 mg BID on the QTc interval was evaluated in patients with previously treated hematologic malignancies.  Increases of > 20 ms in the QTc interval were not observed.

3. Pharmacokinetics-                                                                                                        Duvelisib exposure increased in a dose-proportional manner over a dose range of 8 mg to 75 mg twice daily (0.3 to 3 times the recommended dosage). At steady state following 25 mg BID administration of duvelisib in patients, the geometric mean (CV%) maximum concentration (Cmax) was 1.5 (64%) µg/mL and AUC was 7.9 (77%) µg•h/mL.

Absorption-                                                                                                                        The absolute bioavailability of 25 mg duvelisib after a single oral dose in healthy volunteers was 42%.  The median time to peak concentration (Tmax) was observed at 1 to 2 hours in patients.

 Effect of Food-                                                                                                                   COPIKTRA may be administered without regard to food.                                             The administration of a single dose of COPIKTRA with a high-fat meal (fat accounted for approximately 50% of the total caloric content of the meal) decreased Cmax by approximately 37% and decreased the AUC by approximately 6%, relative to fasting conditions.

 Distribution-                                                                                                                     Protein binding of duvelisib is greater than 98% with no concentration dependence.  The mean blood-to-plasma ratio was 0.5.  The geometric mean (CV%) apparent volume of distribution at steady state (Vss/F) is 28.5 L (62%). Duvelisib is a substrate of P-glycoprotein (P-gp) and BCRP in vitro.   

Elimination-                                                                                                                        The geometric mean (CV%) apparent systemic clearance at steady-state is 4.2 L/hr (56%) in patients with lymphoma or leukemia.  The geometric mean (CV%) terminal elimination half-life of duvelisib is 4.7 hours (57%).

 Metabolism-                                                                                                                       Duvelisib is primarily metabolized by cytochrome P450 CYP3A4.

Excretion-                                                                                                                           Following a single 25 mg oral dose of radiolabeled duvelisib, 79% of the radioactivity was excreted in feces (11% unchanged) and 14% was excreted in the urine (< 1% unchanged).

 Specific Populations-                                                                                                         Age (18 to 90 years), sex, race, renal impairment (creatinine clearance 23 to 80 mL/ min), hepatic impairment (Child Pugh Class A, B, and C) and body weight (40 to 154 kg) had no clinically significant effect on the exposure of duvelisib.

 Drug Interaction Studies-                                                                                               

 Strong and Moderate CYP3A Inhibitors-                                                                      Co-administration of strong CYP3A inhibitor ketoconazole (at 200 mg BID for 5 days), a strong inhibitor of CYP3A4, with a single oral 10 mg dose of COPIKTRA in healthy adults (n= 16) increased duvelisib Cmax by 1.7-fold and AUC by 4-fold.

 Strong and Moderate CYP3A4 Inducers-                                                                         Co-administration of 600 mg once daily rifampin, a strong CYP3A inducer, for 7 days with a single oral 25 mg COPIKTRA dose in healthy adults (N = 13) decreased duvelisib Cmax by 66% and AUC by 82%.

The effect of moderate CYP3A4 induction has not been studied.

CYP3A4 Substrates-                                                                                                          Co-administration of multiple doses of COPIKTRA 25 mg BID for 5 days with single oral 2 mg midazolam, a sensitive CYP3A4 substrate, in healthy adults (N = 14), increased in the midazolam AUC by 4.3-fold and Cmax by 2.2-fold.

 USE IN SPECIFIC POPULATIONS-

1.Pregnancy  Risk Summary -                                                                                           Based on findings from animal studies and the mechanism of action, COPIKTRA can cause fetal harm when administered to a pregnant woman.      

There are no available data in pregnant women to inform the drug-associated risk.

 The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.  All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

2.  Lactation Risk Summary-                                                                                            There are no data on the presence of duvelisib and/or its metabolites in human milk, the effects on the breastfed child, or on milk production.

 Because of the potential for serious adverse reactions from duvelisib in a breastfed child, advise lactating women not to breastfeed while taking COPIKTRA and for at least 1 month after the last dose. 

3. Females and Males of Reproductive Potential  Pregnancy Testing-                         COPIKTRA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].  Conduct pregnancy testing before initiation of COPIKTRA treatment. 

Contraception  Females-                                                                                         Based on animal studies, COPIKTRA can cause fetal harm when administered to a pregnant woman.  Advise females of reproductive potential to use effective contraception during treatment with COPIKTRA and for at least 1 month after the last dose. 

Males-                                                                                                                                 Advise male patients with female partners of reproductive potential to use effective contraception during treatment with COPIKTRA and for at least 1 month after the last dose. Infertility  Based on testicular findings in animals, male fertility may be impaired by treatment with COPIKTRA.

 There are no data on the effect of COPIKTRA on human fertility.

3. Pediatric Use-                                                                                                                Safety and effectiveness of COPIKTRA have not been established in pediatric patients.  Pediatric studies have not been conducted.

5.  Geriatric Use-                                                                                                                 Clinical trials of COPIKTRA included 270 patients (61%) that were 65 years of age and older and 104 (24%) that were 75 years of age and older.  No major differences in efficacy or safety were observed between patients less than 65 years of age and patients 65 years of age and older.