DRUG INTERACTIONS- summary

Interaction with live vaccine indicated for prevention of Zaire ebolavirus infection: No vaccine interaction studies have been performed.

INMAZEB may reduce the efficacy of the live vaccine. The interval between live vaccination following initiation of INMAZEB therapy should be in accordance with current vaccination guidelines. 

DRUG INTERACTIONS- details

1. Vaccine Interactions-                                                                                                         No vaccine-therapeutic interaction studies have been performed in human subjects using INMAZEB.                                                                                                                             However, because of the potential for INMAZEB to inhibit replication of a live vaccine virus indicated for prevention of Zaire ebolavirus infection and possibly reduce the efficacy of the vaccine, avoid the concurrent administration of a live vaccine during treatment with INMAZEB.

The interval between live vaccination following initiation of INMAZEB therapy should be in accordance with current vaccination guidelines. The efficacy of INMAZEB among subjects who reported receipt of a recombinant live vaccine prior to their

U.S. FDA APPROVED  DRUGS DURING 2020

Sr.No-  41

ADVERSE REACTIONS

 The most common adverse events (incidence =20%) were pyrexia, chills, tachycardia, tachypnea, and vomiting. 

CONTRAINDICATIONS -                                                                                                       None

WARNINGS AND PRECAUTIONS-                                                                          

Hypersensitivity Reactions Including Infusion-Associated Events:           Hypersensitivity reactions including infusion-associated events have been reported during and post-infusion with INMAZEB. These may include acute, life-threatening reactions during and after the infusion.

Monitor patients and in the case of severe or life-threatening hypersensitivity reactions, discontinue the administration of INMAZEB immediately and administer appropriate emergency care.                                                                                  

 PATIENT COUNSELING INFORMATION

Hypersensitivity Reactions Including Infusion-Associated Events-                                    Inform patients that hypersensitivity reactions including infusion-associated events have been reported during and post-infusion with INMAZEB and to immediately report if they experience any symptoms of systemic hypersensitivity reactions 

Lactation-                                                                                                                          Instruct patients with Zaire ebolavirus infection not to breastfeed because of the risk of passing Zaire ebolavirus to the baby

Manufactured by: Regeneron Pharmaceuticals, Inc. 777 Old Saw Mill River Road Tarrytown, NY 10591-6707 U.S. License No. 1760

INMAZEB trademark is owned by Regeneron Pharmaceuticals, Inc. ©2020 Regeneron Pharmaceuticals, Inc. All rights reserved.

 CLINICAL PHARMACOLOGY

1. Mechanism of Action-                                                                                                     INMAZEB is an antiviral drug combination of three recombinant human IgG1? monoclonal antibodies (atoltivimab, maftivimab, and odesivimab) that inhibit Zaire ebolavirus.

2. Pharmacodynamics-                                                                                                       Atoltivimab, maftivimab, and odesivimab exposure-response relationships and the time course of pharmacodynamic response are unknown.

3. Pharmacokinetics-                                                                                                             No pharmacokinetic data are available in patients with Zaire ebolavirus infection. The pharmacokinetics of atoltivimab, maftivimab, and odesivimab in 18 healthy subjects 21 to 60 years of age are linear and dose-proportional over the range of 1 mg of atoltivimab, 1 mg of maftivimab, and 1 mg of odesivimab per kg to 50 mg of atoltivimab, 50 mg of maftivimab, and 50 mg of odesivimab per kg (0.02 to 1 times the approved recommended dosage) of INMAZEB following a single intravenous (IV) infusion.

Pharmacokinetic parameters for the individual antibodies of INMAZEB are provided.-  

 Pharmacokinetic Parameters of INMAZEB Administered IV in Healthy Subjects-         Atoltivimab 50 mg/kga Maftivimab 50 mg/kga Odesivimab 50 mg/kga

Systemic Exposure (n=6) Mean (SD) Cmax, mg/L 1,220 (101) 1,280 (68.0) 1,260 (81.2) Mean (SD) AUCinf, mg day/L 17,100 (4,480) 18,700 (4,100) 25,600 (5,040)

Distribution Mean (SD) Volume of Distribution at Steady State, mL/kg 58.2 (2.66) 57.6 (3.89) 56.0 (3.16)

Elimination Mean (SD) Elimination Half-Life (days) 21.2 (3.36) 22.3 (3.09) 25.3 (3.86) Mean (SD)

Clearance (mL/day/kg) 3.08 (0.719) 2.78 (0.558) 2.02 (0.374) a INMAZEB was administered at a total dose of 50 mg of atoltivimab, 50 mg of maftivimab, and 50 mg of odesivimab per kg in a 1:1:1 ratio.

Specific Populations -The effect of age (< 21 or > 60), renal impairment, or hepatic impairment on the pharmacokinetics of atoltivimab, maftivimab, and odesivimab is unknown. 

 USE IN SPECIFIC POPULATIONS-                                                                                       

8.1 Pregnancy Risk Summary -                                                                                                  Zaire ebolavirus infection is life-threatening for both the mother and fetus and treatment should not be withheld due to pregnancy 

Available data from the PALM trial and an expanded access program in which pregnant women with Zaire ebolavirus infection were treated with INMAZEB demonstrate the high rate of maternal and fetal/neonatal morbidity consistent with published literature regarding the risk associated with underlying maternal Zaire ebolavirus infection.

These data are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal/fetal outcome.

Animal reproduction studies with INMAZEB have not been conducted. Human monoclonal antibodies, such as INMAZEB, are transported across the placenta; therefore, INMAZEB has the potential to be transferred from the mother to the developing fetus.

The majority of such pregnancies result in maternal death with miscarriage, stillbirth, or neonatal death. Treatment should not be withheld due to pregnancy. 

2 .Lactation Risk Summary-                                                                                                 The Centers for Disease Control and Prevention recommend that patients with confirmed Zaire ebolavirus not breastfeed their infants to reduce the risk of postnatal transmission of Zaire ebolavirus infection.

 There are no data on the presence of atoltivimab, maftivimab, and odesivimab-ebgn in human or animal milk, the effects on the breastfed infant, or the effects on milk production.

Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to atoltivimab, maftivimab, or odesivimab-ebgn are unknown.

3.Pediatric Use -                                                                                                                     The safety and effectiveness of INMAZEB for the treatment of infection caused by Zaire ebolavirus have been established in pediatric patients from birth to less than 18 years of age.

Use of INMAZEB for this indication is supported by evidence from a multi-center, open label, randomized controlled trial of INMAZEB in adults and pediatric subjects that included 39 pediatric subjects birth to less than 18 years of age, including neonates born to a mother who is RT-PCR positive for Zaire ebolavirus infection.

4.Geriatric Use-                                                                                                                           Clinical studies of INMAZEB did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 154 subjects with Zaire ebolavirus infection who received INMAZEB in the randomized controlled trial, 5 (3.2%) were 65 years or older.

The limited clinical experience has not identified differences in responses between the elderly and younger subjects.