DRUG INTERACTIONS

 Strong or Moderate CYP3A4 Inhibitors:                                                                          Reduce TIBSOVO dose with strong CYP3A4 inhibitors. Monitor patients for increased risk of QTc interval prolongation   

Strong CYP3A4 Inducers:                                                                                                   Avoid concomitant use with TIBSOVO (7.1, 12.3). ? Sensitive CYP3A4 substrates: Avoid concomitant use with TIBSOVO                                                                               

 QTc Prolonging Drugs:                                                                                                    Avoid concomitant use with TIBSOVO. If coadministration is unavoidable, monitor patients for increased risk of QTc interval prolongation

BRIEF SUMMARY

IVOSIDENIB- (July (2018)

Indn-      To treat patients with relapsed or refractory acute myeloid leukemia

Comp-   Tablets: 250 mg-  is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test 

ADR-  The most common adverse reactions (=20%) were fatigue, leukocytosis, arthralgia, diarrhea, dyspnea, edema, nausea, mucositis, electrocardiogram QT prolonged, rash, pyrexia, cough, and constipation

CI-      None

WARNINGS -                                                                                                                    QTc Interval Prolongation: Monitor electrocardiograms and electrolytes. If QTc interval prolongation occurs, dose reduce or withhold, then resume dose or permanently discontinue  the drug

Pat Inform-

Differentiation Syndrome-                                                                                                  Advise patients of the risks of developing differentiation syndrome as early as 1 day after start of therapy and during the first 3 months on treatment.                                  

 Ask patients to immediately report any symptoms suggestive of differentiation syndrome, such as fever, cough or difficulty breathing, rash, decreased urinary output, low blood pressure, rapid weight gain, or swelling of their arms or legs, to their healthcare provider for further evaluation

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U.S. FDA APPROVED  DRUGS DURING 2018

Sr.No-  22

ADVERSE REACTIONS-

The most common adverse reactions (=20%) were fatigue, leukocytosis, arthralgia, diarrhea, dyspnea, edema, nausea, mucositis, electrocardiogram QT prolonged, rash, pyrexia, cough, and constipation

CONTRAINDICATIONS-                                                                                                        None

WARNINGS AND PRECAUTIONS-

 QTc Interval Prolongation: Monitor electrocardiograms and electrolytes. If QTc interval prolongation occurs, dose reduce or withhold, then resume dose or permanently discontinue TIBSOVO                                                                                               

 Guillain-Barré Syndrome:                                                                                                 Monitor patients for signs and symptoms of new motor and/or sensory findings. Permanently discontinue TIBSOVO in patients who are diagnosed with Guillain-Barré syndrome

INDICATIONS AND USAGE-

TIBSOVO is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test 

DOSAGE AND ADMINISTRATION-                                                                                     500 mg orally once daily with or without food until disease progression or unacceptable toxicity Avoid a high-fat meal.

DOSAGE FORMS AND STRENGTHS-                                                                              Tablets: 250 mg

 PATIENT COUNSELING INFORMATION

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

Differentiation Syndrome-                                                                                                  Advise patients of the risks of developing differentiation syndrome as early as 1 day after start of therapy and during the first 3 months on treatment.                                       

 Ask patients to immediately report any symptoms suggestive of differentiation syndrome, such as fever, cough or difficulty breathing, rash, decreased urinary output, low blood pressure, rapid weight gain, or swelling of their arms or legs, to their healthcare provider for further evaluation.

QTc Interval Prolongation-                                                                                                Inform patients of symptoms that may be indicative of significant QTc interval prolongation including dizziness, lightheadedness, and fainting.                                       

 Advise patients to report these symptoms and the use of all medications to their healthcare provider

Drug Interactions-                                                                                                                                              Advise patients to inform their healthcare providers of all concomitant medications, including over-the-counter medications, vitamins, and herbal products.

Guillain-Barré Syndrome-                                                                                                Inform patients of symptoms that may be indicative of Guillain-Barré syndrome, including new signs or symptoms of motor and/or sensory neuropathy, such as weakness or tingling sensation in the legs, arms, or upper body, numbness and pain on one side or both sides of the body, changes to any sensory function, or burning or prickling sensation, or difficulty breathing.                                                                           

    Advise patients to report these symptoms to their healthcare provider.

Tumor Lysis Syndrome-                                                                                                     Advise patients on the risks of developing tumor lysis syndrome.                                       

Advise patients on the importance of maintaining high fluid intake, and the need for frequent monitoring of blood chemistry values.

Gastrointestinal Adverse Reactions-                                                                              Advise patients on the risks of experiencing gastrointestinal reactions such as diarrhea, nausea, mucositis, constipation, vomiting, decreased appetite and abdominal pain.           

Ask patients to report these events to their healthcare provider, and advise patients how to manage them.

Lactation -                                                                                                                          Advise women not to breastfeed during treatment with TIBSOVO and for at least 1 month after the final dose

Dosing and Storage Instructions-                                                                                Advise patients to swallow tablets whole and not to split, crush, or chew TIBSOVO tablets.                     

Advise patients to avoid taking TIBSOVO with a high-fat meal.                                          Instruct patients that if a dose of TIBSOVO is vomited, not to take an additional dose, and wait until the next scheduled dose is  due.                                                                   

 If a dose of TIBSOVO is missed or not taken at the usual time, instruct patients to take the dose as soon as possible unless the next dose is due within 12 hours. Patients can return to the normal schedule the following day.                                                                

Store- TIBSOVO at room temperature from 20°C to 25°C (68°F to 77°F).

Manufactured for and marketed by:                                                                               Agios Pharmaceuticals, Inc. Cambridge, MA 02139 TIBSOVO® is a registered trademark of Agios Pharmaceuticals, Inc. © 2018 Agios Pharmaceuticals, Inc.

CLINICAL PHARMACOLOGY

1. Mechanism of Action-                                                                                                     Ivosidenib is a small molecule inhibitor that targets the mutant isocitrate dehydrogenase 1 (IDH1) enzyme. Susceptible IDH1 mutations are defined as those leading to increased levels of 2-hydroxyglutarate (2-HG) in the leukemia cells and where efficacy is predicted by-                                                                                                                                     1) clinically meaningful remissions with the recommended dose of ivosidenib and/or     

2) inhibition of mutant IDH1 enzymatic activity at concentrations of ivosidenib sustainable at the recommended dosage according to validated methods. The most common of such mutations are R132H and R132C substitutions.

2. Pharmacodynamics-                                                                                                       Multiple doses of ivosidenib 500 mg daily were observed to decrease plasma 2-HG concentrations in patients with hematological malignancies to levels similar to those observed at baseline in healthy subjects. In bone marrow, 2-HG concentrations were reduced by >90%.

Cardiac Electrophysiology-                                                                                               A concentration-dependent QTc interval prolongation of approximately 16.1 msec (90% CI: 13.3, 18.9) was observed at the steady-state Cmax following a 500 mg daily dose based on an analysis of 171 patients with an IDH1 mutation, including 136 patients with relapsed or refractory AML, who received TIBSOVO 500 mg daily.   

  Co-administration with moderate or strong CYP3A inhibitors is expected to further increase QTc interval prolongation from baseline.

3 Pharmacokinetics-                                                                                                            The following ivosidenib pharmacokinetic parameters were observed following administration of ivosidenib 500 mg as a single dose or daily dose (for steady-state), unless otherwise specified.

The mean peak plasma concentration (Cmax) is 4,503 ng/mL [% coefficient of variation (%CV: 38)] after a single dose, and 6,551 ng/mL (%CV: 44) at steady-state. The steady-state area under the concentration time curve (AUC) is 117,348 ng·hr/mL (%CV: 50).

The AUC and Cmax of ivosidenib increase in a less than dose-proportional manner from 200 mg to 1,200 mg daily (0.4 to 2.4 times the approved recommended dosage). Accumulation ratios were approximately 1.9 for AUC and 1.5 for Cmax over one month. Steady-state plasma levels are reached within 14 days.

Absorption-                                                                                                                        The median time to Cmax is approximately 3 hours.

Effect of Food-                                                                                                                   Following administration of a single dose in healthy subjects, a high-fat meal (approximately 900 to 1,000 calories, 500 to 600 fat calories, 250 carbohydrate calories and 150 protein calories) increased ivosidenib Cmax by 98% (90% CI: 79%, 119%) and AUCinf by approximately 25%.

Distribution-                                                                                                                   The mean apparent volume of distribution of ivosidenib at steady-state is 234 L (%CV: 47). Protein binding of ivosidenib ranges from 92 to 96% in vitro.

Elimination-                                                                                                                       Ivosidenib has a terminal half-life of 93 hours (%CV: 67) and an apparent clearance (CL/F) of 4.3 L/hour (%CV: 50).

Metabolism-                                                                                                                        Ivosidenib is the predominant component (>92%) of total radioactivity in plasma. Ivosidenib is primarily metabolized by CYP3A4 with minor contributions by N-dealkylation and hydrolytic pathways.

Excretion-                                                                                                                             After a single oral administration of radiolabeled ivosidenib to healthy subjects, 77% of ivosidenib was eliminated in the feces (67% as unchanged) and 17% in the urine (10% as unchanged).

Specific Populations-                                                                                                       No clinically meaningful effects on the pharmacokinetics of ivosidenib were observed based on age (18 years to 89 years), sex, race (White, Asian, Black or African American), body weight (38 to 150 kg), ECOG performance status, mild or moderate renal impairment (eGFR =30 mL/min/1.73m2, MDRD), or mild hepatic impairment (total bilirubin = upper limit of normal [ULN] and aspartate aminotransferase [AST] > ULN or total bilirubin 1.0 to 1.5 times ULN and any AST).

The pharmacokinetics of ivosidenib in patients with severe renal impairment (eGFR <30 mL/min/1.73m2, MDRD), renal impairment requiring dialysis, moderate hepatic impairment (total bilirubin 1.5 to 3.0 times the ULN and any value for AST), or severe hepatic impairment (total bilirubin greater than 3.0 times the ULN and any value for AST) is unknown. 

Drug Interaction Studies

Clinical Studies and Model-Based Approaches

Effect of Strong or Moderate CYP3A4 Inhibitors on Ivosidenib Itraconazole was used as a strong CYP3A4 index inhibitor to evaluate the effect of CYP3A4 inhibition on the pharmacokinetics of ivosidenib single-dose in a drug-drug interaction study in healthy subjects.                                                                                                                         

Co-administration of 250 mg ivosidenib with itraconazole (200 mg itraconazole once daily for 18 days) increased ivosidenib single-dose AUC to 269% of control (90% CI: 245%, 295%) with no change in Cmax.

Effect of Strong CYP3A4 Inducers on Ivosidenib-                                                        Co-administration of ivosidenib with a strong CYP3A4 inducer (600 mg rifampin once daily for 15 days) is predicted to decrease ivosidenib steady-state AUC by 33%.

Effect of Ivosidenib on CYP3A4 Substrates-                                                                  Ivosidenib induces CYP3A4, including its own metabolism. Co-administration of ivosidenib with CYP3A4 substrates such as itraconazole is expected to decrease itraconazole steady-state AUC to a clinically relevant extent.

Effect of Gastric Acid Reducing Agents on Ivosidenib-                                                 Gastric acid reducing agents (e.g., proton pump inhibitors, H2-receptor antagonists, antacids) do not affect ivosidenib concentrations. 

In vitro Studies

Metabolic Pathways Ivosidenib may induce CYP2B6, CYP2C8, and CYP2C9 and therefore may affect the pharmacokinetics of sensitive substrates of these enzymes [see Drug Interactions (7.2)].

Drug Transporter Systems Ivosidenib is a substrate for P-glycoprotein (P-gp). Ivosidenib is not a substrate for BCRP or hepatic transporters OATP1B1 and OATP1B3.

Ivosidenib does not inhibit BCRP, OATP1B1, OATP1B3, OAT1, and OCT2 at clinically relevant concentrations. Ivosidenib is an inhibitor of OAT3 and P-gp.

 USE IN SPECIFIC POPULATIONS-    

1.Pregnancy Risk Summary-                                                                                             Based on animal embryo-fetal toxicity studies, TIBSOVO may cause fetal harm when administered to a pregnant woman. There are no available data on TIBSOVO use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications.                                                                                                                                                                                                                                  In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.    

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

  Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with TIBSOVO and for at least 1 month after the last dose.

3. Pediatric Use-                                                                                                                 The safety and effectiveness of TIBSOVO in pediatric patients have not been established.

4. Geriatric Use-                                                                                                                   One hundred and twelve (63%) of the 179 patients with relapsed or refractory AML in the clinical study were 65 years of age or older and 40 patients (22%) were 75 years or older. No overall differences in effectiveness or safety were observed between patients 65 years and older and younger patients.