DRUG INTERACTIONS- summary

 P-gp or BCRP inhibitors – Reduce ORLADEYO dosage when coadministered.

 P-gp inducers – Avoid use with ORLADEYO.

 CYP2D6, CYP3A4 or P-gp Substrates: Appropriately monitor or dose titrate narrow therapeutic index drugs that are predominantly metabolized by CYP2D6, CYP3A4 or are P-gp substrates when co-administered with ORLADEYO.

U.S. FDA APPROVED  DRUGS DURING 2020

Sr.No-  48

ADVERSE REACTIONS- 

 Most common adverse reactions (=10%) are abdominal pain, vomiting, diarrhea, back pain, and gastroesophageal reflux disease.

CONTRAINDICATIONS                                                                                                              - None 

WARNINGS AND PRECAUTIONS- 

An increase in QT prolongation can occur at dosages higher than the recommended 150 mg once daily dosage. Additional doses or doses of ORLADEYO higher than 150 mg once daily are not recommended. 

 PATIENT COUNSELING INFORMATION

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

Inform patients of the risks and benefits of ORLADEYO before prescribing or administering to the patient. 

DRUG INTERACTIONS-

Advise patients that ORLADEYO may interact with other drugs 

Advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products.

Not for Acute Treatment of HAE Attacks Advise patients to take their usual rescue medication to treat an acute attack of HAE.

Inform patients that the safety and effectiveness of ORLADEYO has not been established as an acute treatment for HAE attacks.

Advise patients that they should not take daily doses higher than 150 mg once daily or additional doses of ORLADEYO to treat an acute attack of HAE due to risk of QT prolongation..

For more information, visit www.ORLADEYO.com ORLADEYOTM is a trademark of BioCryst Pharmaceuticals, Inc. Manufactured for: BioCryst Pharmaceuticals, Inc. Durham, NC 27703 214094-BC-000

 CLINICAL PHARMACOLOGY

1. Mechanism of Action-

Berotralstat is a plasma kallikrein inhibitor that binds to plasma kallikrein and inhibits its proteolytic activity.

Plasma kallikrein is a protease that cleaves high-molecular-weight-kininogen (HMWK) to generate cleaved HMWK (cHMWK) and bradykinin, a potent vasodilator that increases vascular permeability resulting in swelling and pain associated with HAE.

2. Pharmacodynamics-                                                                                       Concentration-dependent inhibition of plasma kallikrein, measured as a reduction from baseline of specific enzyme activity, was demonstrated after oral administration of ORLADEYO once daily in patients with HAE.

Cardiac Electrophysiology-                                                                                                       At the recommended dose of 150 mg once daily, ORLADEYO does not prolong the QT interval to any clinically relevant extent. At 3-times the recommended dose, the mean (upper 90% confidence interval) increase in QTcF was 15.9 msec (23.5 msec). The observed increase in QTcF was concentration-dependent.

3. Pharmacokinetics-                                                                                                      Following oral administration of berotralstat 150 mg once daily, the steady state Cmax and area under the curve over the dosing interval (AUCtau) are 158 ng/mL (range: 110 to 234 ng/mL) and 2770 ng*hr/mL (range: 1880 to 3790 ng*hr/mL), respectively.

Following oral administration of berotralstat 110 mg once daily, the steady-state Cmax and AUCtau are 97.8 ng/mL (range: 63 to 235 ng/mL) and 1600 ng*hr/mL (range: 950 to 4170 ng*hr/mL), respectively.

Berotralstat exposure (Cmax and AUC) increases greater than proportionally with dose and steady state is reached by days 6 to 12. After once-daily administration, exposure of berotralstat at steady state is approximately 5 times that after a single dose.

The pharmacokinetics of berotralstat are similar between healthy adult subjects and in patients with HAE.

Absorption-                                                                                                                             The median time to maximum plasma concentration (Tmax) of berotralstat when administered with food is 5 hours (range: 1 to 8 hours).

Effect of Food-                                                                                                                         No differences in the Cmax and AUC of berotralstat were observed following administration with a high-fat meal, however the median Tmax was delayed by 3 hours, from 2 hours (fasted) to 5 hours (fed).

Distribution- Plasma protein binding is approximately 99%.

After a single dose of radiolabeled berotralstat 300 mg, the blood to plasma ratio was approximately 0.92.

Elimination- The median elimination half-life of berotralstat was approximately 93 hours (range: 39 to 152 hours).

Metabolism-                                                                                                                           Berotralstat is metabolized by CYP2D6 and by CYP3A4 with low turnover in vitro. After a single oral radiolabeled berotralstat 300 mg dose, berotralstat represented 34% of the total plasma radioactivity, with 8 metabolites, each accounting for between 1.8 and 7.8% of the total radioactivity.

Excretion-                                                                                                                              After a single oral radiolabeled berotralstat 300 mg dose, approximately 9% was excreted in urine (3.4% unchanged; range 1.8 to 4.7%) and 79% was excreted in feces.

Specific Populations-                                                                                                                  Body weight, age, gender, and race did not have a clinically meaningful influence on the systemic exposure of berotralstat.

Geriatric Patients -                                                                                                                   Based on the population pharmacokinetic analyses that included elderly patients (= 65 to 74 years, N=25), age does not have a clinically meaningful impact on the systemic exposure of berotralstat 

Pediatric Patients-                                                                                                               Based on population pharmacokinetic analyses that included pediatric patients 12 to <18 years of age, exposure at steady state following oral administration of berotralstat 150 mg once daily was approximately 20% higher compared to adults. The higher exposure in adolescents is not considered to be clinically meaningful.

Patients with Renal Impairment-                                                                                               The pharmacokinetics of a single 200 mg oral dose of berotralstat were studied in subjects with severe renal impairment (CLCR less than 30 mL/min). When compared to a concurrent cohort with normal renal function (CLCR greater than 90 mL/min), no clinically relevant differences were observed; Cmax was increased by 47%, while AUC0-last was increased by 14% 

The pharmacokinetics of berotralstat has not been studied in patients with End-Stage Renal Disease (CLCR less than 15 mL/min or eGFR less than 15 mL/min/1.73 m2 or patients requiring hemodialysis).

Patients with Hepatic Impairment-                                                                                            The pharmacokinetics of a single 150 mg oral dose of berotralstat were studied in subjects with mild, moderate and severe hepatic function (Child-Pugh Class A, B, and C, respectively).

The pharmacokinetics of berotralstat were unchanged in subjects with mild hepatic impairment compared to subjects with normal hepatic function. In subjects with moderate hepatic impairment; Cmax was increased by 77%, while AUC0-inf was increased by 78%. In subjects with severe hepatic impairment, Cmax was increased by 27%, while AUC0-last was decreased by 5%.

The median half-life of berotralstat was increased by 37% and 22% in patients with moderate and severe hepatic impairment, respectively, in comparison to healthy subjects.

The percent of unbound berotralstat increased 2-fold from a mean of 1.2% in healthy subjects to a mean of 2.4% in subjects with severe hepatic impairment.

Drug Interaction Studies-                                                                                                     Effect of Other Drugs on the Pharmacokinetics of ORLADEYO Berotralstat is a P-gp and BCRP substrate. Cyclosporine, a P-gp and BCRP inhibitor, increased berotralstat Cmax by 25%, AUC0-last by 55%, and AUC0-inf by 69% [see Drug Interactions (7.1)].

 Effect of ORLADEYO on the Pharmacokinetics of Other Drugs-                            Berotralstat 150 mg once daily is a moderate inhibitor of CYP2D6 and CYP3A4, and a weak inhibitor of CYP2C9 and CYP2C19.

Berotralstat at 300 mg dose is an inhibitor of P-gp and is not an inhibitor of BCRP (rosuvastatin exposure was decreased by approximately 20%).

 USE IN SPECIFIC POPULATIONS

1 Pregnancy Risk Summary

1 Pregnancy Risk Summary -                                                                                              There are insufficient data in pregnant women available to inform drug-related risks with ORLADEYO use in pregnancy.

Based on animal reproduction studies, no evidence of structural alterations was observed when berotralstat was administered orally to pregnant rats and rabbits during organogenesis at doses up to approximately 10 and 2 times, respectively, the maximum recommended human daily dose (MRHDD) in adults on an AUC basis 

The background risk of major birth defects and miscarriage for the indicated population is unknown.

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 berotralstat in human milk, its effects on the breastfed infant, or its effects on milk production. However, when a drug is present in animal milk, it is likely that the drug will be present in human milk. 

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ORLADEYO and any potential adverse effects on the breastfed infant from ORLADEYO or from the underlying maternal condition.

3.Pediatric Use-                                                                                                                      The safety and effectiveness of ORLADEYO for prophylaxis to prevent attacks of hereditary angioedema have been established in pediatric patients aged 12 and older.

Use of ORLADEYO in this population is supported by evidence from an adequate and well-controlled study (Trial 1) that included adults and a total of 6 adolescent patients aged 12 to <18 years of age.

The safety and effectiveness of ORLADEYO in pediatric patients < 12 years of age have not been established.

4.Geriatric Use-                                                                                                                      The safety and effectiveness of ORLADEYO were evaluated in a subgroup of patients (N=9) aged = 65 years . Results of the subgroup analysis by age were consistent with overall study results.

The safety profile from an additional 5 elderly patients aged = 65 years enrolled in the open-label, long-term safety study (Trial 2) was consistent with data from Trial 1 

5. Renal Impairment-                                                                                                               No dosage adjustment of ORLADEYO is recommended for patients with mild, moderate or severe renal impairment.

ORLADEYO has not been studied in patients with End-Stage Renal Disease (CLCR < 15 mL/min or eGFR < 15 mL/min/1.73 m2 or patients requiring hemodialysis), and, therefore is not recommended for use in these patient populations [see Clinical Pharmacology (12.3)].

6.Hepatic Impairment-                                                                                                            No dosage adjustment of ORLADEYO is recommended for patients with mild hepatic impairment . In patients with moderate or severe hepatic impairment (Child-Pugh B or C), the recommended dose of ORLADEYO is 110 mg once daily with food