DRUG INTERACTIONS-

No dedicated drug interaction studies have been conducted.

U.S. FDA APPROVED  DRUGS DURING 2018

Sr.No-  33

ADVERSE REACTIONS-

The most common adverse reactions are injection site reactions, upper respiratory infections, headache, rash, myalgia, dizziness, and diarrhea.

 CONTRAINDICATIONS-                                                                                                          None.

WARNINGS AND PRECAUTIONS-

Hypersensitivity reactions have been observed. In case of a severe hypersensitivity reaction, discontinue TAKHZYRO administration and institute appropriate treatment.

INDICATIONS AND USAGE-

TAKHZYRO is a plasma kallikrein inhibitor (monoclonal antibody) indicated for prophylaxis to prevent attacks of hereditary angioedema (HAE) in patients 12 years and older.

DOSAGE AND ADMINISTRATION-

For subcutaneous use only                                                                                                  • Administer 300 mg every 2 weeks. Dosing every 4 weeks may be considered in some patients                                                                                                                                • Patients may self-administer.

DOSAGE FORMS AND STRENGTHS-                                                                              Injection: 300 mg/2 mL (150 mg/mL) solution in a single-dose vial.

PATIENT COUNSELING INFORMATION-

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

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

Hypersensitivity-                                                                                                                Advise patients to seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions

 Self-administration:                                                                                                          • Ensure that the patient/caregiver receives clear instructions and training on subcutaneous administration and has demonstrated the ability to perform a subcutaneous injection                                                                                                      . • Instruct patients or caregivers in the technique of proper syringe and needle disposal, and advise them not to reuse these items. Instruct patients to dispose needles and syringes in a puncture-resistant container. For more information, visit www.TAKHZYRO.com

Manufactured by:                                                                                                               Dyax Corp. 300 Shire Way Lexington, MA 02421

TAKHZYROTM is a trademark or registered trademark of Dyax Corp., a wholly-owned, indirect subsidiary of Shire plc. SHIRE and the Shire Logo are trademarks or registered trademarks of Shire Pharmaceutical Holdings Ireland Limited or its affiliates.

 ©2018 Shire. All rights reserved

CLINICAL PHARMACOLOGY-       

 1.Mechanism of Action-                                                                              Lanadelumab-flyo is a fully human monoclonal antibody (IgG1/?-light chain) that binds plasma kallikrein and inhibits its proteolytic activity.                                                           

2. Pharmacodynamics-                                                                                                       Concentration-dependent inhibition of plasma kallikrein, measured as reduction of cHMWK levels, was demonstrated after subcutaneous administration of TAKHZYRO 150 mg q4wks, 300 mg q4wks or 300 mg q2wks in patients with HAE. TAKHZYRO did not prolong the QT/QTc interval.

3. Pharmacokinetics-                                                                                                       Following subcutaneous administration, the pharmacokinetics of lanadelumab-flyo was approximately dose-proportional in the therapeutic dose range in patients with HAE 

The pharmacokinetic properties and exposure (steady state) of lanadelumab-flyo in HAE patients, following subcutaneous administration of 150 mg q4wks, 300 mg q4wks and 300 mg q2wks.

Following subcutaneous administration of TAKHZYRO, peak plasma concentrations are reached within 5 days, and terminal elimination half-life is ~2 weeks. The anticipated time to reach steady state concentration was approximately 70 days.

 At steady-state, the mean accumulation ratio is approximately 1.44, 1.42, and 2.43 for dosing regimen of 150 mg q4wks, 300 mg q4wks and 300 mg q2wks, respectively.

Specific Populations Population-                                                                                     Pharmacokinetic analyses showed that age, gender and race did not meaningfully influence the pharmacokinetics of lanadelumab-flyo after correcting for body weight.

Body weight was identified as an important covariate describing the variability of clearance and volume of distribution, resulting in higher exposure (AUC and Cmax) in lighter patients. However, this difference is not considered to be clinically relevant and no dose adjustments are recommended for any of these demographics.

 Pediatric Population-                                                                                                         Based on population pharmacokinetics (PK) analyses, the mean lanadelumab-flyo (±SD) AUCss was 629 (204) µg*day/mL following SC administration of TAKHZYRO 300 mg every 2 weeks in pediatric patients 12 to less than 18 years of age. This is approximately 37% higher than the mean AUCss in adult patients (460 µg*day/mL) under the same dosing regimen, due to lower body weight in pediatric patients.

 Renal Impairment-                                                                                                          No dedicated studies have been conducted to evaluate the PK of lanadelumab-flyo in renal impairment patients. Based on population pharmacokinetic analysis, renal impairment (estimated GFR: 60 to 89 mL/min/1.73m2, [mild, N=98] and 30 to 59 mL/min/1.73m2, [moderate, N=9]) had no effect on the clearance or volume of distribution of lanadelumab-flyo. Concomitant medications

The use of analgesic, antibacterial, antihistamine, anti-inflammatory and anti-rheumatic medications had no effect on clearance and volume of distribution of lanadelumab-flyo.

 For breakthrough HAE attacks, use of rescue medications such as plasma-derived and recombinant C1-INH, icatibant or ecallantide had no effects on clearance and volume of distribution of lanadelumab-flyo.

USE IN SPECIFIC POPULATIONS-                                             

1.Pregnancy-                                                                                                                       Risk Summary There are no available data on TAKHZYRO use in pregnant women to inform any drug associated risks. Monoclonal antibodies such as lanadelumab-flyo are transported across the placenta during the third trimester of pregnancy; therefore, potential effects on a fetus are likely to be greater during the third trimester of pregnancy.

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 to 4% and 15 to 20%, respectively.

2. Lactation-                                                                                                                         Risk Summary There are no data on the presence of lanadelumab-flyo in human milk, its effects on the breastfed infant, or its effects on milk production.

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

3.Pediatric Use-                                                                                                                    The safety and efficacy of TAKHZYRO were evaluated in a subgroup of patients (N=10) aged 12 to <18 years in Trial 1. Results of the subgroup analysis by age were consistent with overall study results.

An additional 13 adolescent patients aged 12 to <18 years were enrolled in the open-label extension study. The safety and efficacy of TAKHZYRO in pediatric patients < 12 years of age have not been established.

4. Geriatric Use-                                                                                                                   The safety and efficacy of TAKHZYRO were evaluated in a subgroup of patients (N=5) aged =65 years in Trial 1. Results of the subgroup analysis by age were consistent with overall study results.

OVERDOSAGE                                                                                                              There is no clinical experience with overdosage of TAKHZYRO.