DRUG INTERACTIONS

1 Effect of GAMIFANT on Cytochrome P450 Substrates The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (such as IFN) during chronic inflammation.

By neutralizing IFN, use of GAMIFANT may normalize CYP450 activities which may reduce the efficacy of drugs that are CYP450 substrates due to increased metabolism. 

Upon initiation or discontinuation of concomitant GAMIFANT, monitor for reduced efficacy and adjust dosage of CYP450 substrate drugs as appropriate.  

BRIEF SUMMARY

EMAPALUMAB-izsg- (Nov 2018)

Indn-        To treat primary haemophaocytic lymphohistiocytosis (HLH) 

Comp-    Injection:                                                                                                                    • 10 mg/2 mL (5 mg/mL) solution in a single-dose vial    • 50 mg/10 mL (5 mg/mL) solution in a single-dose vial 

ADR-     The most common adverse reactions (= 20%) were: infections, hypertension, infusion-related reactions, and pyrexia. 

CI-    • None. 

 WARNINGS-

• Infections:                                                                                                              Monitor patients for signs and symptoms and treat promptly. Test for latent tuberculosis. Administer prophylactic treatment against Herpes Zoster, Pneumocystis jirovecii and fungal infections.

Pat Infm-

Infections                                                                                                                    Inform patients and their caregivers of the risk of developing infections during treatment  , and to report any symptoms of infection 

Vaccinations                                                                                                              Advise patients and their caregivers that the patient should not receive live or live attenuated vaccines during  treatment

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U.S. FDA APPROVED  DRUGS DURING 2018

Sr.No-  51

ADVERSE REACTIONS

The most common adverse reactions (= 20%) were: infections, hypertension, infusion-related reactions, and pyrexia. 

CONTRAINDICATIONS                                                                                               

• None. 

 WARNINGS AND PRECAUTIONS

• Infections:                                                                                                              Monitor patients for signs and symptoms and treat promptly. Test for latent tuberculosis. Administer prophylactic treatment against Herpes Zoster, Pneumocystis jirovecii and fungal infections.

• Live Vaccines:                                                                                                                Do not administer live or live attenuated vaccines to patients receiving GAMIFANT. 

• Infusion-Related Reactions:                                                                                      Monitor patients for infusion-related reactions. Interrupt infusion for severe infusion reactions and institute appropriate medical management.

 PATIENT COUNSELING INFORMATION

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

Infections                                                                                                                    Inform patients and their caregivers of the risk of developing infections during treatment with GAMIFANT, and to report any symptoms of infection 

Vaccinations                                                                                                              Advise patients and their caregivers that the patient should not receive live or live attenuated vaccines during GAMIFANT treatment 

Infusion-Related Reactions                                                                                        Advise patients and their caregivers of the potential for developing infusion-related reactions during treatment with GAMIFANT 

Manufactured by:                                                                                            Novimmune SA Geneva, Switzerland U.S. License Number 2082 Distributed by: Sobi Inc. 890 Winter Street Waltham, MA 02451

Manufactured at: Patheon Italia S.p.A 2° Trav. SX Via Morolense, 5 03013-Ferentino Italy Product of the United Kingdom

 CLINICAL PHARMACOLOGY

1. Mechanism of Action

Emapalumab-lzsg is a monoclonal antibody that binds to and neutralizes interferon gamma (IFN)

Nonclinical data suggest that IFN plays a pivotal role in the pathogenesis of HLH by being hypersecreted.

2. Pharmacodynamics

IFN Inhibition Emapalumab-lzsg reduces the plasma concentrations of CXCL9, a chemokine induced by IFN

Cardiac Electrophysiology At a dose of 3 mg/kg GAMIFANT does not prolong the QT interval to any clinically relevant extent.

 3.Pharmacokinetics-                                                                                                     The pharmacokinetics of emapalumab-lzsg were evaluated in healthy adult subjects and in patients with primary HLH.

Following a 1 mg/kg emapalumab-lzsg dose, median steady state peak concentration was 44 mcg/mL, which was 2.9 times higher than after the first dose. The median steady state trough concentration was 25 mcg/mL, which was 4.3 times higher than after the first dose.

Emapalumab-lzsg AUC increases slightly more than proportionally between 1 and 3 mg/kg doses, and less than proportionally at 3, 6, and 10 mg/kg doses.

Emapalumab-lzsg exhibits target-mediated clearance dependent on IFN production, which can vary between and within patients as a function of time and can affect the recommended dosage.

Emapalumab-lzsg steady state is achieved by the 7th infusion when the IFN? production is moderate. At high IFN? production, steady-state is reached earlier due to a shorter half-life.

Distribution                                                                                                                    The central and peripheral volumes of distribution in a subject with body weight of 70 kg are 4.2 and 5.6 L, respectively.

Elimination                                                                                                       Emapalumab-lzsg elimination half-life is approximately 22 days in healthy subjects, and ranged from 2.5 to 18.9 days in HLH patients.

Metabolism                                                                                                                     The metabolic pathway of emapalumab-lzsg has not been characterized. Like other protein therapeutics, GAMIFANT is expected to be degraded into small peptides and amino acids via catabolic pathways.

Specific Populations                                                                                                   Body weight (2 to 82 kg) was a significant covariate of emapalumab-lzsg pharmacokinetics, supporting body weight-based dosing.

No clinically significant differences in the pharmacokinetics of emapalumab-lzsg were observed based on age (0.02 to 56 year), sex (53% Females), race (71.4% Caucasian, 12.2% Asian and 8.2% Black), renal impairment including dialysis, or hepatic impairment (mild, moderate, and severe).

Drug Interaction Studies

No drug-drug interaction studies have been conducted with GAMIFANT.

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary

There are no available data on GAMIFANT use in pregnant women to inform a drug-associated risk of adverse developmental outcomes.

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

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

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 is no information regarding the presence of emapalumab-lzsg in human milk, the effects on the breastfed child, or the effects on milk production.

Published data suggest that only limited amounts of therapeutic antibodies are found in breast milk and they do not enter the neonatal and infant circulations in substantial amounts.

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

3. Pediatric Use       

Safety and effectiveness of GAMIFANT have been established in pediatric patients, newborn and older, with primary HLH that is reactivated or refractory to conventional therapies.

Use of GAMIFANT is supported by a single-arm trial in 27 pediatric patients with reactivated or refractory primary HLH. This study included pediatric patients in the following age groups: 5 patients newborn to 6 months, 10 patients 6 months to 2 years, and 12 patients from 2 years to 13 years 

4.Geriatric Use

Clinical studies of GAMIFANT did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.