DRUG INTERACTIONS- summary

 • Strong CYP3A inhibitors:                                                                                              Avoid coadministration. 

• Combined P-gp and Strong CYP3A inhibitors:                                                                   Avoid coadministration. If coadministration cannot be avoided, reduce the dose of GAVRETO. 

• Strong CYP3A inducers:                                                                                                         Avoid coadministration. If coadministration cannot be avoided, increase the dose of GAVRETO.  

DRUG INTERACTIONS -details

1. Effects of Other Drugs on GAVRETO -                                                                          Strong CYP3A Inhibitors-

Avoid coadministration with strong CYP3A inhibitors. Coadministration of GAVRETO with a strong CYP3A inhibitor increases pralsetinib exposure, which may increase the incidence and severity of adverse reactions of GAVRETO.

Avoid coadministration of GAVRETO with combined P-gp and strong CYP3A inhibitors. If coadministration with a combined P-gp and strong CYP3A inhibitor cannot be avoided, reduce the GAVRETO dose.

Strong CYP3A Inducers-                                                                                            Coadministration of GAVRETO with a strong CYP3A inducer decreases pralsetinib exposure, which may decrease efficacy of GAVRETO.

Avoid coadministration of GAVRETO with strong CYP3A inducers. If coadministration cannot be avoided, increase the GAVRETO dose 

U.S. FDA APPROVED  DRUGS DURING 2020

Sr.No-  40

ADVERSE REACTIONS

 The most common adverse reactions (=25%) were fatigue, constipation, musculoskeletal pain, and hypertension. The most common Grade 3-4 laboratory abnormalities (=2 %) were decreased lymphocytes, decreased neutrophils, decreased phosphate, decreased hemoglobin, decreased sodium, decreased calcium (corrected), and increased alanine aminotransferase (ALT). 

CONTRAINDICATIONS-                                                                                                          None. 

WARNINGS AND PRECAUTIONS

• Interstitial Lung Disease (ILD)/Pneumonitis:                                                                 Withhold GAVRETO for Grade 1 or 2 reactions until resolution and then resume at a reduced dose. Permanently discontinue for recurrent ILD/pneumonitis.                          Permanently discontinue for Grade 3 or 4 reactions. 

• Hypertension:                                                                                                                        Do not initiate GAVRETO in patients with uncontrolled hypertension. Optimize blood pressure (BP) prior to initiating GAVRETO.                                                                                Monitor BP after 1 week, at least monthly thereafter and as clinically indicated. Withhold, reduce dose, or permanently discontinue GAVRETO based on severity. 

• Hepatotoxicity:                                                                                                               Monitor ALT and AST prior to initiating GAVRETO, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce dose, or permanently discontinue GAVRETO based on severity. 

• Hemorrhagic Events:                                                                                               Permanently discontinue GAVRETO in patients with severe or life-threatening hemorrhage. 

• Risk of Impaired Wound Healing:                                                                                   Withhold GAVRETO for at least 5 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing.                                   The safety of resumption of GAVRETO after resolution of wound healing complications has not been established. 

• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective non-hormonal contraception. 

 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

ILD/Pneumonitis-                                                                                                                     Advise patients to contact their healthcare provider if they experience new or worsening respiratory symptoms 

Hypertension-                                                                                                                             Advise patients that they will require regular blood pressure monitoring and to contact their healthcare provider if they experience symptoms of increased blood pressure or elevated readings 

Hepatotoxicity-                                                                                                                         Advise patients that hepatotoxicity can occur and to immediately contact their healthcare provider for signs or symptoms of hepatotoxicity 

Hemorrhagic Events-                                                                                                               Advise patients that GAVRETO may increase the risk for bleeding and to contact their healthcare provider if they experience any signs or symptoms of bleeding 

Risk of Impaired Wound Healing-                                                                                          Advise patients that GAVRETO may impair wound healing. Advise patients that temporary interruption of GAVRETO is recommended prior to any elective surgery 

Embryo-Fetal Toxicity-                                                                                                              Advise females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy 

Use in Specific Populations-                                                                                                Advise females of reproductive potential to use effective non-hormonal contraception during the treatment with GAVRETO and for 2 weeks after the final dose 

Advise males with female partners of reproductive potential to use effective contraception during treatment with GAVRETO and for 1 week after the final dose.

Lactation-                                                                                                                                      Advise women not to breastfeed during treatment with GAVRETO and for 1 week after the final dose 

Infertility -                                                                                                                                    Advise males and females of reproductive potential that GAVRETO may impair fertility 

Drug Interactions-                                                                                                                     Advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products 

Administration-                                                                                                                          Advise patients to take GAVRETO on an empty stomach, at least 1 hour before and at least 2 hours after a meal 

Manufactured for: Blueprint Medicines Corporation, 45 Sidney Street, Cambridge, MA 02139, USA

 CLINICAL PHARMACOLOGY-   

1. Mechanism of Action-                                                                                                    Pralsetinib is a kinase inhibitor of wild-type RET and oncogenic RET fusions (CCDC6-RET) and mutations (RET V804L, RET V804M and RET M918T) with half maximal inhibitory concentrations (IC50s) less than 0.5 nM.

2. Pharmacodynamics-                                                                                                       Pralsetinib exposure-response relationships and the time course of pharmacodynamics response have not been fully characterized.

Cardiac Electrophysiology-                                                                                                        The QT interval prolongation potential of GAVRETO was assessed in 34 patients with RET fusion-positive solid tumors administered at the recommended dosage. No large mean increase in QTc (> 20 ms) was detected in the study.

3. Pharmacokinetics -                                                                                                                 At 400 mg once daily under fasting conditions, the steady state geometric mean [% coefficient of variation (CV%)] of maximum observed plasma concentration (Cmax) and area under the concentration-time curve (AUC0-24h) of pralsetinib was 2830 (52.5%) ng/mL and 43900 (60.2%) h•ng/mL, respectively.

Pralsetinib Cmax and AUC increased inconsistently over the dose range of 60 mg to 600 mg once daily (0.15 to 1.5 times the recommended dose).                                                    Pralsetinib plasma concentrations reached steady state by 3 to 5 days. The mean accumulation ratio was < 2­ fold after once-daily repeated oral administration.

Absorption-                                                                                                                             The median time to peak concentration (Tmax) ranged from 2 to 4 hours following single doses of pralsetinib 60 mg to 600 mg. 

Food Effect-                                                                                                                          Following administration of a single dose of 400 mg GAVRETO with a high-fat meal, (approximately 800 to 1000 calories with 50 to 60% of calories from fat), the mean (90% CI) Cmax of pralsetinib was increased by 104% (65%, 153%), the mean (90% CI) AUC0-INF was increased by 122% (96%,152%), and the median Tmax was delayed from 4 to 8.5 hours, compared to the fasted state.

Distribution -                                                                                                                          The mean (CV%) apparent volume of distribution (Vd/F) of pralsetinib is 228 L (75%). Protein binding of pralsetinib is 97.1% and is independent of concentration. The blood-to-plasma ratio is 0.6 to 0.7.

Elimination-                                                                                                                                 The mean (±standard deviation) plasma elimination half-life (T½) of pralsetinib 14.7 hours (6.5) following single doses and 22.2 hours (13.5) following multiple doses of pralsetinib. The mean (CV%) apparent oral clearance (CL/F) of pralsetinib is 9.1 L/h (60%) at steady state.

Metabolism-                                                                                                                             Pralsetinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP2D6 and CYP1A2, in vitro. Following a single oral dose of approximately 310 mg of radiolabeled pralsetinib to healthy subjects, pralsetinib metabolites from oxidation (M531, M453, M549b) and glucuronidation (M709) were detected as 5% or less.

Excretion-                                                                                                                             Approximately 73% (66% as unchanged) of the total administered radioactive dose [14C] pralsetinib was recovered in feces and 6% (4.8% as unchanged) was recovered in urine.

Specific Populations-                                                                                                                No clinically significant differences in the PK of pralsetinib were observed based on age (18 to 87 years), sex, race (256 White, 2 Black, or 147 Asian), and body weight (29.5 to 149 kg).

Mild and moderate renal impairment-   (CLcr 30 - 89 mL/min) had no effect on the exposure of pralsetinib. Pralsetinib has not been studied in patients with severe renal impairment (CLcr < 15 mL/min).

Patients with Hepatic Impairment -Mild hepatic impairment (total bilirubin =1.0 × ULN and AST > ULN, or total bilirubin >1.0 to 1.5 × ULN and any AST) had no effect on the PK of pralsetinib.

Pralsetinib has not been studied in patients with moderate (total bilirubin >1.5 to 3.0 × ULN and any AST) or severe (total bilirubin > 3.0 ULN and any AST) hepatic impairment.

Drug Interaction Studies-                                                                                                  Clinical Studies and Model-Informed Approaches- Combined P-gp and Strong CYP3A Inhibitors:                                                                                                           Coadministration of itraconazole 200 mg once daily with a single GAVRETO 200 mg dose increased pralsetinib Cmax by 84% and AUC0-INF by 251%.

Strong CYP3A Inducers: Coadministration of rifampin 600 mg once daily with a single GAVRETO 400 mg dose decreased pralsetinib Cmax by 30% and AUC0-INF by 68%.

Mild CYP3A Inducers: No clinically significant differences in the PK of pralsetinib were identified when GAVRETO was coadministered with mild CYP3A inducers.

Acid-Reducing Agents: No clinically significant differences in the PK of pralsetinib were observed when coadministered with gastric acid reducing agents.

In Vitro Studies Cytochrome P450 (CYP) Enzymes:                                                           Pralsetinib is a time-dependent inhibitor of CYP3A4/5 and; an inhibitor of CYP2C8, CYP2C9, and CYP3A4/5, but not an inhibitor of CYP1A2, CYP2B6, CYP2C19 or CYP2D6 at clinically relevant concentrations. Pralsetinib is an inducer of CYP2C8, CYP2C9, and CYP3A4/5 but not an inducer of CYP1A2, CYP2B6, or CYP2C19 at clinically relevant concentrations.

Transporter Systems:                                                                                                             Pralsetinib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but not a substrate of bile salt efflux pump (BSEP), organic cation transporter [OCT]1, OCT2, organic anion transporting polypeptide [OATP]1B1, OATP1B3, multidrug and toxin extrusion [MATE]1, MATE2-K, organic anion transporter [OAT]1, or OAT3.

Pralsetinib is an inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, MATE1, MATE2-K, and BSEP, but not an inhibitor of OCT1, OCT2, and OAT1A3 at clinically relevant concentrations

 USE IN SPECIFIC POPULATIONS

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

There are no available data on GAVRETO use in pregnant women to inform drug-associated risk. Advise pregnant women of the potential risk to a fetus. 

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 pralsetinib or its metabolites in human milk or their effects on either the breastfed child or on milk production.

Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with GAVRETO and for 1 week after the final dose. 

3. Females and Males of Reproductive Potential-                                                        Based on animal data, GAVRETO can cause embryolethality and malformations at doses resulting in exposures below the human exposure at the clinical dose of 400 mg daily 

Pregnancy Testing- Verify pregnancy status of females of reproductive potential prior to initiating GAVRETO 

Contraception- GAVRETO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Females - Advise females of reproductive potential to use effective non-hormonal contraception during treatment with GAVRETO and for 2 weeks after the final dose. GAVRETO may render hormonal contraceptives ineffective.

Males- Advise males with female partners of reproductive potential to use effective contraception during treatment with GAVRETO and for 1 week after the final dose.

Infertility- Based on histopathological findings in the reproductive tissues of male and female rats and a dedicated fertility study in which animals of both sexes were treated and mated to each other, GAVRETO may impair fertility 

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

5. Geriatric Use-                                                                                                                         Of the 438 patients in ARROW who received the recommended dose of GAVRETO at 400 mg once daily, 30% were 65 years or older. No overall differences in pharmacokinetics (PK), safety or efficacy were observed in comparison with younger patients.

6 Hepatic Impairment- GAVRETO has not been studied in patients with moderate hepatic impairment (total bilirubin >1.5 to 3.0 × upper limit of normal [ULN] and any aspartate aminotransferase [AST]) or severe hepatic impairment (total bilirubin >3.0 × ULN and any AST).

No dose adjustment is required for patients with mild hepatic impairment (total bilirubin = ULN and AST > ULN or total bilirubin > 1 to 1.5 times ULN and any AST] .