U.S. FDA APPROVED  DRUGS DURING 2017

 PATIENT COUNSELING INFORMATION

Hepatotoxicity, Including Hepatic Veno-occlusive Disease (VOD) (also known as Sinusoidal Obstruction Syndrome)

Inform patients that liver problems, including severe, life-threatening, or fatal VOD, and increases in liver tests may develop during BESPONSA treatment.

Inform patients that they should seek immediate medical advice if they experience symptoms of VOD, which may include elevated bilirubin, rapid weight gain, and abdominal swelling that may be painful.

Inform patients that they should carefully consider the benefit/risk of BESPONSA treatment if they have a prior history of VOD or serious ongoing liver disease 

Increased Risk of Post-HSCT Non-Relapse Mortality-                                               Inform patients that there is an increased risk of post-HSCT non-relapse mortality after receiving BESPONSA, that the most common causes of post-HSCT non-relapse mortality included infection and VOD.

Infection-                                                                                                                      Advise patients to report signs and symptoms of infection 

Myelosuppression                                                                                                       Inform patients that decreased blood counts, which may be life-threatening, may develop during BESPONSA treatment and that complications associated with decreased blood counts may include infections, which may be life-threatening or fatal, and bleeding/hemorrhage events. Inform patients that signs and symptoms of infection, bleeding/hemorrhage, or other effects of decreased blood counts should be reported during treatment with BESPONSA 

Infusion Related Reactions                                                                                          Advise patients to contact their health care provider if they experience symptoms such as fever, chills, rash, or breathing problems during the infusion of BESPONSA 

QT Interval Prolongation                                                                                          Inform patients of symptoms that may be indicative of significant QTc prolongation including dizziness, lightheadedness, and syncope. Advise patients to report these symptoms and the use of all medications to their healthcare provider.

Embryo-Fetal Toxicity                                                                                              Advise males and females of reproductive potential to use effective contraception during BESPONSA treatment and for at least 5 and 8 months after the last dose, respectively 

Advise females of reproductive potential to avoid becoming pregnant while receiving BESPONSA.                                                                                                                   

Advise women to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with BESPONSA.

Inform the patient of the potential risk to the fetus [see Warnings and Precautions (5.7),

Lactation                                                                                                                           Advise women against breastfeeding while receiving BESPONSA and for 2 months after the last dose 

This product’s label may have been updated. For current full prescribing information, please visit www.BESPONSA.com. US License No. 003 LAB-0763-0.12

Manufactured by Wyeth pharmaceuticals Inc

 CLINICAL PHARMACOLOGY

1. Mechanism of Action                                                                                        Inotuzumab ozogamicin is a CD22-directed antibody-drug conjugate (ADC). Inotuzumab recognizes human CD22. The small molecule, N-acetyl-gamma-calicheamicin, is a cytotoxic agent that is covalently attached to the antibody via a linker.

Nonclinical data suggest that the anticancer activity of inotuzumab ozogamicin is due to the binding of the ADC to CD22-expressing tumor cells, followed by internalization of the ADC-CD22 complex, and the intracellular release of N-acetyl-gamma-calicheamicin dimethylhydrazide via hydrolytic cleavage of the linker

Activation of N-acetyl-gamma-calicheamicin  dimethylhydrazide induces double-strand DNA breaks, subsequently inducing cell cycle arrest and apoptotic cell death.

2. Pharmacodynamics

During the treatment period, the pharmacodynamic response to BESPONSA was characterized by the depletion of CD22-positive leukemic blasts.

Cardiac Electrophysiology                                                                                               In a randomized clinical study in patients with relapsed or refractory ALL, increases in QTcF of = 60 msec from baseline were measured in 4/162 patients (3%) in the BESPONSA arm and 3/124 patients (2%) in the Investigator’s choice of chemotherapy arm.

Increases in QTcF of > 500 msec were observed in none of the patients in the BESPONSA arm and 1/124 patients (1%) in the Investigator’s choice of chemotherapy arm.

Central tendency analysis of the QTcF interval changes from baseline showed that the highest mean (upper bound of the 2-sided 90% CI) for QTcF was 15.3 (21.1) msec, which was observed at Cycle 4/Day 1/1 hour in the BESPONSA arm .

3. Pharmacokinetics                                                                                                     The mean Cmax of inotuzumab ozogamicin was 308 ng/mL. The mean simulated total AUC per cycle was 100,000 ng?h/mL. In patients with relapsed or refractory ALL, steady-state drug concentration was achieved by Cycle 4.

Following administration of multiple doses, a 5.3 times accumulation of inotuzumab ozogamicin was predicted by Cycle

4. Distribution-                                                                                                                  N-acetyl-gamma-calicheamicin dimethylhydrazide is approximately 97% bound to human plasma proteins in vitro. In humans, the total volume of distribution of inotuzumab ozogamicin was approximately 12 L.

Elimination                                                                                                                     The pharmacokinetics of inotuzumab ozogamicin was well characterized by a 2-compartment model with linear and time-dependent clearance components. In 234 patients with relapsed or refractory ALL, the clearance of inotuzumab ozogamicin at steady state was 0.0333 L/h and the terminal half-life (t½) was 12.3 days.

Following administration of multiple doses, a 5.3 times accumulation of inotuzumab ozogamicin was predicted by Cycle

 Metabolism-                                                                                                                     In vitro, N-acetyl-gamma-calicheamicin dimethylhydrazide was primarily metabolized via nonenzymatic reduction. In humans, N-acetyl-gamma-calicheamicin dimethylhydrazide serum levels were typically below the limit of quantitation.

Specific Populations                                                                                                     The effect of intrinsic factors on inotuzumab ozogamicin pharmacokinetics was assessed using a population pharmacokinetic analysis unless otherwise specified. Age (18 to 92 years of age), sex, and race  (Asian versus non-Asian [Caucasian, Black, and Unspecified]) had no clinically significant effect on the pharmacokinetics of inotuzumab ozogamicin.       

Body surface area was found to significantly affect inotuzumab ozogamicin disposition. BESPONSA is dosed based on body surface area .

Patients with Renal Impairment                                                                                   The clearance of inotuzumab ozogamicin in patients with mild renal impairment (creatinine clearance [CLcr; based on the Cockcroft-Gault formula] 60-89 mL/min; n=237), moderate renal impairment (CLcr 30-59 mL/min; n=122), or severe renal impairment (CLcr 15-29 mL/min; n=4) was similar to patients with normal renal function (CLcr =90 mL/min; n=402).

The safety and efficacy of inotuzumab ozogamicin in patients with end stage renal disease with or without hemodialysis is unknown.

Patients with Hepatic Impairment                                                                                The clearance of inotuzumab ozogamicin in patients with mild hepatic impairment (total bilirubin =ULN and AST > ULN, or total bilirubin >1.0-1.5 × ULN and AST any level; n=150) was similar to patients with normal hepatic function (total bilirubin/AST =ULN; n=611).

There is insufficient data in patients with moderate and severe hepatic impairment (total bilirubin >1.5 ULN).

Drug Interactions                                                                                                                  In vitro Effect of Metabolic Pathways and Transporter Systems on BESPONSA N-acetyl-gamma-calicheamicin dimethylhydrazide is a substrate of P-glycoprotein (P-gp).