EA IND Protocol TPOXX

6402_EA IND_TPOXX_Protocol.pdf

Centralized Institutional Review for the CDC Expanded Access Investigational New Device (EA-IND) for "Use of Tecovirimat (TPOXX®) for Treatment of Human Non-Variola Orthopoxvirus Infections.

EA IND Protocol TPOXX

OMB: 0920-1366

Document [pdf]
Download: pdf | pdf
**Obtain informed consent prior to tecovirimat initiation**

Expanded Access IND Protocol: Use of Tecovirimat (TPOXX®) for Treatment of Human
Non-Variola Orthopoxvirus Infections in Adults and Children
IND No. 116,039
CDC IRB No. 6402
Version 6.0
July 20, 2022
Principal Investigator:
Brett Petersen, M.D., M.P.H.

Sponsored by:
Centers for Disease Control and Prevention
In Collaboration with:
Biomedical Advanced Research and Development Authority
Office of the Assistant Secretary for Preparedness and Response
Department of Health and Human Services

This expanded access IND protocol for tecovirimat is held by the Centers for Disease Control
and Prevention. Unauthorized reproduction or misuse beyond the intended purpose of the
protocol is prohibited.

PROGRAM CONTACT INFORMATION
Coordinating Program:
Poxvirus and Rabies Branch
Division of High-Consequence Pathogens and Pathology (DHCPP)
National Center for Emerging and Zoonotic Infectious Diseases (NCEZID)
1600 Clifton Road, MS H24-12, Atlanta, GA 30329
Phone: (404) 639-4129
Email: [email protected]
Clinical:
Sponsor Principal Investigator
Brett Petersen, M.D., M.P.H.
Epidemiology Team Lead, Poxvirus and Rabies Branch
DHCPP, NCEZID, CDC
1600 Clifton Road NE, MS H24-12, Atlanta, GA 30333
Email: [email protected]
Regulatory:
Yon Yu, Pharm.D.
Lead, Regulatory Affairs and Clinical Guidelines Team
Emergency Preparedness and Response Branch,
Division of Preparedness and Emerging Infections, NCEZID, CDC
1600 Clifton Road NE, MS H24-11, Atlanta, GA 30333
Email: [email protected]
CDC Emergency Operation Center: (770) 488-7100

IND 116,039 Tecovirimat (CDC IRB #6402)

Page i

Version 6.0
July 20, 2022

TABLE OF CONTENTS
1.0

INTRODUCTION
1
INTRODUCTIONAND
ANDBACKGROUND
BACKGROUND..............................................................................................
..............................................................................................1
1.1 Unmet Medical Need and Rationale for Use of Tecovirimat under Expanded Access IND ..........
1
..........1
2.0 PROGRAM OBJECTIVE .........................................................................................................................
2
.........................................................................................................................2
2.1 Tecovirimat Eligibility
.................................................................................................................... 2
Eligibility....................................................................................................................2
2.2 Tecovirimat Ineligibility .................................................................................................................
3
.................................................................................................................3
3.0 PRODUCT
3
PRODUCTDESCRIPTION
DESCRIPTION.....................................................................................................................
.....................................................................................................................3
3.1 Tecovirimat
............................................................................................................... 3
TecovirimatFormulations
Formulations...............................................................................................................3
4.0 DOSAGE
4
DOSAGEAND
ANDADMINISTRATION
ADMINISTRATIONOF
OFTECOVIRIMAT
TECOVIRIMAT...................................................................
...................................................................4
4.1 Oral
4
OralTherapy
Therapyfor
forAdults
Adultsand
andChildren
Children............................................................................................
............................................................................................4
4.2 IV
5
IVTherapy
Therapyfor
forAdults
Adultsand
andChildren
Children...............................................................................................
...............................................................................................5
4.4 Discontinuation
6
Discontinuationof
ofTecovirimat
Tecovirimat......................................................................................................
......................................................................................................6
4.5 Drug-Drug
6
Drug-DrugInteractions
Interactions...................................................................................................................
...................................................................................................................6
5.0 POSSIBLE
......................................................................... 7
POSSIBLERISKS
RISKSOF
OFTECOVIRIMAT
TECOVIRIMATTREATMENT
TREATMENT.........................................................................7
6.0 SPECIAL
....................................................................................................................... 7
SPECIALPOPULATIONS
POPULATIONS.......................................................................................................................7
6.1 Pregnancy
........................................................................................................................................ 7
Pregnancy........................................................................................................................................7
6.2 Lactation..........................................................................................................................................
7
Lactation..........................................................................................................................................7
6.3 Pediatric
7
PediatricPopulation
Population........................................................................................................................
........................................................................................................................7
6.4 Patients
8
Patientswith
withRenal
RenalImpairment
Impairment......................................................................................................
......................................................................................................8
7.0 CLINICAL
........................................................ 8
CLINICALASSESSMENT
ASSESSMENTAND
ANDMONITORING
MONITORINGOF
OFPATIENTS
PATIENTS........................................................8
Optional Laboratory Testing .....................................................................................................................
9
.....................................................................................................................9
8.0 RECORDING
10
RECORDINGAND
ANDREPORTING
REPORTINGADVERSE
ADVERSEEVENTS
EVENTS.....................................................................
.....................................................................10
8.1 Definitions (21 CFR 312.32).........................................................................................................
10
312.32).........................................................................................................10
8.2 Treating Clinician Reporting Requirements to CDC ....................................................................
11
....................................................................11
8.3 CDC Reporting Requirements to FDA and CDC Institutional Review Board (IRB)
................... 11
(IRB)...................11
9.0 REGULATORY AND ADMINISTRATIVE REQUIREMENTS .........................................................
12
.........................................................12
10.0 SUMMARY OF AVAILABLE SAFETY AND EFFICACY DATA OF TECOVIRIMAT ..................
13
..................13
10.1 Human Safety Data of Tecovirimat ..............................................................................................
13
..............................................................................................13
10.2 Clinical
14
ClinicalUse
Useof
ofTecovirimat
Tecovirimatin
inNV-OPXV-infected
NV-OPXV-infectedPatients
Patients(2007−2021)
(2007−2021).................................
.................................14
10.3 Tecovirimat
.................................................................................................. 17
TecovirimatEfficacy
Efficacyin
inAnimals
Animals..................................................................................................17
10.4 Pharmacokinetics
.................................................................................................................. 17
PharmacokineticsData
Data..................................................................................................................17
11.0 REFERENCES
17
REFERENCES........................................................................................................................................
........................................................................................................................................17

ATTACHMENTS
Attachment 1:

Informed
InformedConsent/Parental
Consent/ParentalPermission
PermissionForm
Form

Attachment 2:

Case
CaseReport
ReportForms:
Forms:
Form A: Patient Intake Form
Form B: Clinical Outcome Form
Form C: Patient Diary

Attachment 3:

Instructions
Instructionsfor
forOpening
Openingand
andMixing
MixingTecovirimat
TecovirimatCapsules
Capsuleswith
withFood
Foodfor
forThose
ThoseWho
WhoCannot
Cannot
Swallow Pills, Especially Infants and Children

Attachment 4:

Optional
OptionalLesion
LesionSamples
Samplesfor
forResistance
ResistanceTesting
TestingatatCDC
CDC

Attachment 5:

Optional
OptionalPharmacokinetic
PharmacokineticSampling
Samplingfor
forTesting
TestingatatAlturas
AlturasAnalytics
Analytics

Attachment 6:

Fillable-pdf
Fillable-pdfMedWatch
MedWatchForm
Form(complete
(completeand
andreturn
returnto
toCDC
CDCfor
forSerious
SeriousAdverse
AdverseEvents)
Events)

Attachments are posted on Information for Healthcare Providers on Obtaining and Using TPOXX (Tecovirimat)
for Treatment of Monkeypox | Monkeypox | Poxvirus | CDC
IND 116,039 Tecovirimat (CDC IRB #6402)

Page ii

Version 6.0
July 20, 2022

1.0
INTRODUCTION AND BACKGROUND
Orthopoxviruses (OPXVs) belonging to the Poxviridae family that infect humans are variola virus
(smallpox), vaccinia virus (the virus in smallpox vaccine ACAM2000 and smallpox/monkeypox vaccine
Jynneos), monkeypox virus, cowpox virus, Akhmeta virus and Alaskapox virus. Variola virus, the etiologic
cause of smallpox, is the only one that affects humans exclusively, while the others are zoonotic
infections that can also be transmitted person-to-person. Poxvirus infections may be localized to the skin
or disseminated. The initial site of infection may be the skin, a mucosal surface, or the respiratory tract.
Orthopoxviruses, such as monkeypox, can also cause serious clinical illness including, but not limited to
encephalitis, severe inflammatory response syndrome, respiratory failure, painful head and neck lymph
node swelling with or without associated airway and/or swallowing compromise, extensive dermal
disruption during rash phase, and/or other septic syndromes.
Since the worldwide eradication of smallpox, the other orthopoxviruses or non-variola orthopoxvirus
(NV-OPXV) infections are emerging as a growing public health concern given the potential for spread
through international travel, especially among populations that have not been previously vaccinated, and
delayed recognition of NV-OPXV infections by healthcare professional who may be less familiar with
these infections. Recent cases of human monkeypox (MPX) in countries outside of west and central
Africa underscore the risk of spread of MPX from beyond its normal endemic region and the potential for
sustained local transmission.
In 2003, a MPX outbreak occurred in the United States (U.S.) through direct or indirect contact with
MPXV-infected prairie dogs, where 47 confirmed or probable cases of human monkeypox were
identified: 37% of cases were hospitalized, although illness severity was usually mild. Two patients were
hospitalized with severe disease; there were no deaths reported. To prevent transmission of MPX, a
replication-competent smallpox vaccine (Dryvax®, which is no longer available) was administered to 30
individuals (pre-exposure to 7 and post-exposure to 23) with no reported serious adverse events following
smallpox vaccination [1, 2].
During September 2018–May 2021, seven unrelated persons traveling from Nigeria received diagnoses of
monkeypox in non-African countries: five in the United Kingdom and one each in Israel and Singapore
[3-5]. Response to the cases in United Kingdom included offering vaccination with Imvanex (marketed as
Jynneos® in the U.S.) as post-exposure prophylaxis (PEP) and antiviral treatment in 3 MPX-infected
individuals (1 received tecovirimat; 2 received brincidofovir). In July and November 2021, two
independent cases of MPX in travelers from Nigeria were diagnosed in Texas and Maryland and one
patient was treated with tecovirimat[6, 7]. Emerging cases of MPX reported in European countries and the
U.S. in May 2022 with ongoing transmissions highlight the need for prevention and treatment measures.
Refer to https://www.cdc.gov/poxvirus/monkeypox/outbreak/us-outbreaks.html for summary of U.S.
monkeypox cases.
Vaccination is the key modality for prevention of orthopoxvirus infections. There are two FDA-approved
vaccines, ACAM2000 (replication-competent, live vaccinia vaccine approved for smallpox for adults and
children) and Jynneos (replication-deficient, Modified Vaccinia Ankara-Bavarian Nordic [MVA-BN]
approved for smallpox and monkeypox in adults 18 years and older). However, vaccination must occur
soon after exposure to be effective in preventing or reducing the seriousness of the disease caused by
orthopoxvirus infections. During an outbreak, effective therapeutic options also are necessary.
Additionally, with widespread vaccination, vaccinia vaccine-related complications may occur that
necessitate treatment options.
1.1
Unmet Medical Need and Rationale for Use of Tecovirimat under Expanded Access IND
Currently, there is no treatment approved by the Food and Drug Administration (FDA) for non-variola
orthopoxvirus, including MPX. Although tecovirimat is FDA-approved for treatment of smallpox in
adults and children, the approved indication is limited to smallpox. Therefore, this intermediate-size
EA-IND 116,039 Tecovirimat (CDC IRB #6402)

Page 1

Version 6.0
July 20, 2022

patient population expanded access Investigational New Drug (IND), sponsored by the Centers for
Disease Control and Prevention (CDC) and authorized by FDA, is to allow access to and use of stockpiled
tecovirimat for treatment of non-variola orthopoxvirus (NV-OPXV) infection in adults and children.
While the effectiveness of tecovirimat in treating human non-variola orthopoxvirus infections, including
monkeypox, has not been evaluated, it may be reasonable to anticipate potential treatment benefit based
on animal efficacy data that supported FDA-approval for smallpox treatment and limited clinical uses of
tecovirimat in the treatment of NV-OPXV infected individuals to date.
Tecovirimat has been shown to be effective against various orthopoxviruses in multiple animal challenge
models [8-10]. Tecovirimat was approved for smallpox under the FDA’s Animal Rule, which allows
efficacy findings from adequate and well-controlled animal studies to support an FDA approval when it is
not feasible or ethical to conduct efficacy trials in humans.
2.0
PROGRAM OBJECTIVE
The purpose of this expanded access IND (compassionate use) program is to provide stockpiled
tecovirimat for treatment or prevention of non-variola orthopoxvirus infections (e.g., vaccinia,
monkeypox, cowpox or other human virus infection identified as an orthopoxvirus) and secondary
treatment of complications from replication-competent vaccinia vaccine in adults and children.
To monitor clinical use of tecovirimat, including any occurrence of serious adverse events, patient
monitoring and outcomes information are also intended to be collected under this expanded access IND
program to the extent feasible (e.g., baseline clinical conditions, progression/improvement during
treatment, recovered or not recovered from orthopoxvirus infection). Please refer to Section 7.0 Clinical
Assessment and Monitoring of Patients.
2.1
Tecovirimat Eligibility
All patient populations, who meet eligibility criteria, can receive tecovirimat treatment under this IND
program (e.g., children and all adults including pregnant and nursing individuals, and prisoners). Other
concomitant treatments and vaccination (e.g., ACAM2000, Jynneos) are allowed under this IND program
for tecovirimat.
2.1.1 Primary or early empiric treatment
Tecovirimat treatment may be initiated for patients with laboratory confirmed non-variola orthopoxvirus
infection or suspected infection based on known exposure(s) and/or clinical manifestations of disease.
Patients with an initial negative OPXV test, but for whom both epidemiologic and clinical evidence
suggests OPXV disease (particularly if clinical progression is worsening), should be re-tested but be
treated with tecovirimat while results are pending. If results from re-testing confirm orthopoxvirus,
patients should continue tecovirimat treatment. If results from re-testing are in agreement with the initial
negative orthopoxvirus results, tecovirimat should be suspended in those patients.
2.1.2 Secondary treatment
Patients with complications of replication-competent vaccinia infection (e.g., serious inadvertent
inoculation with vaccinia, eczema vaccinatum, severe generalized vaccinia, or progressive vaccinia)
resulting from vaccination, secondary transmission, or other exposure are eligible for treatment with
tecovirimat. Tecovirimat may be used if a patient is ineligible for Vaccinia Immune Globulin Intravenous
(VIGIV) treatment, or after VIGIV treatment has been exhausted, or in conjunction with VIGIV and/or
other therapies based on the treating clinician’s clinical judgment. For more information, see
https://www.cdc.gov/smallpox/clinicians/vaccine-adverse-events5.html
2.1.3 Post-exposure prophylaxis (PEP)
Tecovirimat may be considered for post-exposure prophylaxis on an individual case-by-case basis in
consultation with CDC (Emergency Operations Center [EOC] (770) 488-7100; [email protected])
EA-IND 116,039 Tecovirimat (CDC IRB #6402)

Page 2

Version 6.0
July 20, 2022

depending on the known high-risk exposure to a confirmed or probable case of NV-OPXV infection (as
defined on https://www.cdc.gov/poxvirus) and clinical conditions that necessitate an alternative or
complementary option to PEP vaccination based on clinical judgment, including taking into account
exposure risk level and clinical status of the exposed individual (e.g., allergic to vaccine components,
immunocompromising conditions).
2.1.4 Considerations for IV tecovirimat:
Adults and children who are unable to take oral therapy or for whom there is a concern that oral drug
absorption may be altered should be considered for treatment with IV tecovirimat. These include critically
ill patients hospitalized and unable to feed sufficiently by mouth, as oral tecovirimat absorption is
expected to be lower in these patients since bioavailability of oral tecovirimat is dependent on adequate
intake of a full, fatty meal. Patients with gastric bypass or evidence of gastrointestinal disfunction that
may negatively impact drug absorption may also be considered for treatment with IV tecovirimat. In the
absence of an oral tecovirimat suspension formulation, IV tecovirimat may be considered for children
weighing less than 13 kg based on clinical assessment of risk/benefit and if determined appropriate by the
treating clinician in consultation with CDC.
Patients who receive IV tecovirimat should be switched to the oral formulation as soon as they are able to
take oral medications and/or gastrointestinal disfunction impacting absorption has resolved. The timing of
transition to oral therapy is based on the clinical judgement of the treating clinician depending on the
clinical progress of the patient.
2.2

Tecovirimat Ineligibility
• Patient
Patientor
orlegally
legallyauthorized
authorizedrepresentative
representativeunwilling
unwillingto
tosign
signan
aninformed
informedconsent
consentand
andrefuse
refuse
tecovirimat treatment
• Known
Knownallergy
allergyto
totecovirimat
tecovirimatand/or
and/orinactive
inactiveingredients
ingredientsin
intecovirimat
tecovirimat
• For
ForIV
IVtecovirimat
tecovirimatonly:
only:patients
patientswith
withsevere
severerenal
renalimpairment
impairment(creatinine
(creatinineclearance
clearance<30
<30
mL/min). Oral tecovirimat is an option for patients with severe renal impairment.

3.0
PRODUCT DESCRIPTION
Tecovirimat (tecovirimat monohydrate) is an inhibitor of the orthopoxvirus VP37 envelope wrapping
protein, which prevents the formation of egress-competent enveloped virions necessary for cell-to-cell
and long-range dissemination of virus [10]. Depending upon the poxvirus species, its inhibitory activity is
from 600- to several thousand-fold greater than that of cidofovir and other drugs used for treatment of
orthopoxviruses. In cell culture assays, the effective concentrations of tecovirimat resulting in a 50%
reduction in virus-induced cytopathic effect (EC50), were 0.016–0.067μM, 0.014–0.039 μM, 0.015 μM,
and 0.009 μM for variola, monkeypox, rabbitpox, and vaccinia viruses, respectively. There is no structural
resemblance of tecovirimat to any other compound currently used in human therapeutics; therefore, no
comparison or correlation can be made to human experience for any other known drug. Refer to
tecovirimat Package Insert for additional details.
3.1
Tecovirimat Formulations
Tecovirimat is available as oral capsules and injection vials. Each capsule contains 200 mg of tecovirimat
active ingredient and comes in unit of use bottle containing 42 capsules. All inactive
ingredients/excipients are generally recognized as safe and are United States Pharmacopeia /National
Formulary grade. The capsules include the following ingredients: colloidal silicon dioxide, croscarmellose
sodium, hydroxypropyl methyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline
cellulose, and sodium lauryl sulfate.
Tecovirimat injection (200 mg/20 mL) single-dose vial contains tecovirimat monohydrate (unmicronized)
equivalent to 200 mg tecovirimat and the excipient hydroxypropyl betadex (8000 mg) (hydroxypropyl-β­
EA-IND 116,039 Tecovirimat (CDC IRB #6402)

Page 3

Version 6.0
July 20, 2022

cyclodextrin). The vial stopper is not made with natural rubber latex. Tecovirimat injection must be
diluted with 2 parts 0.9% normal saline or 5% dextrose solution prior to infusion.
Tecovirimat capsules should be stored at room temperature at 20−25°C (68−77°F). Excursions are
permitted to 15−30°C (59−86°F).
Tecovirimat injection vials should be stored at 2–8°C (36–46°F). Do not freeze. Short-term storage of
maximum 24 hours at ambient temperature is acceptable. The immediate container/packaging of
tecovirimat does not have a printed expiry date. To determine the expiration date, find the lot number on
the product label and refer to the table on the following website to locate the corresponding expiration
date: https://aspr.hhs.gov/SNS/Pages/Monkeypox.aspx.
DOSAGEAND
ANDADMINISTRATION
ADMINISTRATIONOF
OFTECOVIRIMAT
TECOVIRIMAT
4.0
DOSAGE
Tecovirimat dosing for adults and children are as shown in Table 1 (oral) and Table 2 (IV) for 14 days of
therapy. In certain clinical situations, modifications to the dose, frequency, and duration may be
appropriate or necessary depending on the individual patient’s clinical condition, disease progression,
therapeutic response, and/or clinical judgement. For clinical decisions regarding dosing adjustments,
contact the CDC (EOC (770) 488-7100; [email protected]) for clinical consultation among the treating
clinician(s), CDC, and FDA, if necessary.
4.1

OralTherapy
Therapyfor
forAdults
Adultsand
andChildren
Children
Oral
Table 1. Recommended Oral Dosage Instructions for 14 Days*
Weight (kg)**
Weight (lbs)
Recommended Dose (mg)*
<6
<13
50 mg (¼ capsule) every 12 hours
6 to < 13
13 to < 28
100 mg (½ capsule) every 12 hours
13 to < 25
28 to < 55
200 mg (1 capsule) every 12 hours
25 to < 40
55 to < 88
400 mg (2 capsules) every 12 hours
40 to < 120
88 to < 264
600 mg (3 capsules) every 12 hours
120 and above
≥ 264
600 mg (3 capsules) every 8 hours

* Tecovirimat capsules should be taken within 30 minutes after a full meal containing moderate or high fat.
Treatment duration is 14 days but may be longer (not to exceed 90 days) or shorter depending on the progression
of the disease and clinical condition of the patient. Data on duration other than 14 days are limited.
** Please refer to Attachment 3 for instructions on opening capsules and mixing with food for infants and
children who require less than a 200 mg dose or who are unable to swallow capsules. Opening tecovirimat
capsules and mixing with food for children weighing < 13 kg, which differs from the FDA-approved tecovirimat
package insert, is allowed under this IND protocol.

The adult dosing does not preclude pregnant or nursing individuals if careful clinical assessment of
risk/benefit deems tecovirimat treatment appropriate per the treating clinician’s clinical judgement (see
Section 6.0 for Special Populations).
PK information is not available for pediatrics. The pediatric doses are solely based on predicted exposures
from population PK simulation predicted to provide pediatric patients with exposures comparable to the
observed exposure in healthy adult volunteers receiving oral 600 mg doses twice daily. Oral doses less
than 200 mg require careful preparation by a caregiver (e.g., opening a capsule and mixing portion of
capsule contents with a food/liquid vehicle) and has the potential for inaccurate dosing. Suboptimal
dosing increases the potential for development of resistance. Tecovirimat absorption may likely be
decreased and result in potential suboptimal exposure in ill children, particularly young children, who are
unable or unwilling to take a full meal prior to tecovirimat administration. The potential for inaccurate
dosing when opening capsules for doses below 200 mg may be higher in the outpatient setting.
For inpatients (adults and children) unable to feed by mouth and have no evidence of gastrointestinal
disfunction, tecovirimat may be administered via a nasogastric tube per hospital protocol based on clinical
EA-IND 116,039 Tecovirimat (CDC IRB #6402)

Page 4

Version 6.0
July 20, 2022

judgment on an individual basis if IV tecovirimat is unavailable or IV infusion is not feasible (e.g., lack of
syringe pumps).
4.1.1 Administration of Oral Therapy
Oral tecovirimat should be taken by mouth with a full glass of water within 30 minutes after eating a full
meal of moderate or high fat (ideally about 600 calories and 25 grams of fat) in order to improve
bioavailability.
4.1.2 Duration of Oral Therapy
Total duration of tecovirimat treatment for patients of all ages is 14 days but may be longer (not to exceed
90 days) or shorter depending on the progression of the disease and clinical condition of the patient. Dose
adjustments may be required per individual clinical considerations during the course of tecovirimat
treatment.
4.1.3 Outpatients who are Unable to Swallow Capsules
For outpatients (adults and children) who require less than a 200 mg dose or who are unable to swallow
capsules, treating clinicians should provide instructions on how to open capsules and mix with food
(Attachment 3). The dosing instructions for using less than 1 capsule (200 mg) have not been formally
evaluated but are included to provide dosing options for younger age children, especially if IV tecovirimat
is not available or feasible for administration.
4.2 IV Therapy for Adults and Children
IV tecovirimat is contraindicated in patients with severe renal impairment (creatinine clearance <30 mL/min).
Table 2. Recommended Pediatric and Adult Tecovirimat Injection for IV Infusiona
Weight
(kg)

Weight (lbs)

<35 kgd

< 77 lbs

Recommended Dose
6 mg/kg every 12 hours
by IV infusion over 6
hours
200 mg every 12 hours by
IV infusion over 6 hours

Volume of IV
Tecovirimatb
0.6 mL/kg

Volume of
Diluentc

Total Volume for
Infusion

1.2 mL/kg

Varies by weight

35 kg to
77 to < 264 lbs
20 mL
40 mL
60 mL
<120 kg
120 kg
300 mg every 12 hours by
30 mL
60 mL
90 mL
and
≥ 264 lbs
IV infusion over 6 hours
abovef
a Patients should be switched to tecovirimat oral capsules to complete the 14-day treatment course as soon as oral
therapy can be tolerated. Treatment duration may be longer (not to exceed 90 days) or shorter depending on the
progression of the disease and clinical condition of the patient.
b 10 mg/mL stock solution containing 40% hydroxypropyl betadex (8 g per vial) with water for injection.
c Diluent is either 0.9% (w/v) sodium chloride injection or 5% (w/v) dextrose injection solution.
d IV tecovirimat dose of 6 mg/kg for children <3 kg is allowed under this IND protocol, which differs from the
FDA-approved tecovirimat package insert. Individualized dosing may need to be considered depending on the
neonate or infant weight and any underlying conditions. Pediatric doses are solely based on predicted exposures
from population PK simulation based on observed exposure in healthy adult subjects receiving 600 mg oral
doses twice daily.
e For children under 2 years of age: monitor renal function during the treatment course given the potential for drug
accumulation due to renal immaturity of pediatric patients less than 2 years.
f Depending on size of syringe available with syringe pump system, two separate syringes may be needed for each
6-hour administration

Based on currently available information, the infusion should be administered over 6 hours via syringe
pump. The 6-hour duration of infusion is based on how the IV formulation was evaluated, observed
transient ataxia in nonhuman primates dosed over 4 hours at 30 mg/kg, and to target optimal antiviral
effect. The administration via syringe pump is based on available compatibility data for the formulation.
Cyclodextrin in tecovirimat formulation has an elevated risk for potential leaching of impurities from
EA-IND 116,039 Tecovirimat (CDC IRB #6402)

Page 5

Version 6.0
July 20, 2022

administration equipment into the solution during dosing. This has been mitigated through appropriate
studies for syringe pumps. However, the risk has not been evaluated for IV bags.
4.2.1 Administration of IV Therapy
See the Package Insert for preparation and administration instructions. The volume of IV tecovirimat for
the needed dose (Table 2) must be diluted with 2 equal parts 0.9% normal saline or 5% dextrose solution
in prior to dosing in a syringe and should be administered via a syringe pump over a 6-hour period.
Tecovirimat injection should be stored at 2-8◦C (35-46◦F) and used as soon as possible after dilution (not
to exceed 24 hours post-dilution).
4.2.2 Duration of IV Therapy
The duration of IV tecovirimat for patients of all ages is 14 days if the patient’s condition necessitates IV
administration (e.g., inability to tolerate the oral form, severity of symptoms [e.g., systemic illness],
comorbidities, underlying disease, and/or other factors that may alter oral drug absorption). IV tecovirimat
should only be administered while patients are unable to take oral therapy or there is a concern that oral
drug absorption may be altered. Patients should be switched to the oral formulation as soon as they
are able to take oral medications and/or gastrointestinal disfunction impacting absorption has
resolved. Treating clinicians should consult with CDC regarding the timing of transition to oral therapy
and additional monitoring that may be needed to ensure adequate oral drug absorption.
4.4
Discontinuation of Tecovirimat
At any time during treatment, a patient may voluntarily discontinue or refuse tecovirimat treatment for
any reason, treatment may be terminated due to serious adverse events (SAEs) or clinically significant
abnormalities in laboratory values, or according to the clinical judgment of the treating clinician and/or
appropriate health authority.
4.5
Drug-Drug Interactions
Co-administration of tecovirimat with repaglinide may cause hypoglycemia. Monitor blood glucose and
monitor for hypoglycemic symptoms during co-administration. Tecovirimat is a weak inducer of
cytochrome P450 (CYP)3A and a weak inhibitor of CYP2C8 and CYP2C19. However, the effects are not
expected to be clinically relevant for most substrates of those enzymes based on the magnitude of
interactions and the duration of treatment of tecovirimat. See Table 3 for clinical recommendations for
select sensitive substrates. Based on a drug interaction study, no clinically significant drug interactions
have been observed when tecovirimat is co-administered with bupropion, flurbiprofen, or omeprazole.
Table 3 provides a listing of established or significant drug interactions.
Table 3. Significant Drug Interactions
Concomitant Drug Class:
Drug Name
Blood Glucose-Lowering Agent:
Repaglinideb

Effect on
Concentrationa
↑ repaglinide

Central Nervous System Depressant:
↓ midazolam
Midazolamb
a
↓ = decrease, ↑ = increase
b
These interactions have been studied in healthy adults.

Clinical Effect/Recommendation
Monitor blood glucose and monitor for hypoglycemic
symptoms in patients when tecovirimat is coadministered with repaglinide
Monitor for effectiveness of midazolam

A complete list of concomitant medications and medication history should be documented, and patients
should be monitored for any AEs (Section 8.0 for required AE reporting). Document all AEs in the
Adverse Event Form (Attachment 2, Form B).
No vaccine-drug interaction studies have been performed in human subjects. Some animal studies,
including non-human primate studies, have indicated that co-administration of tecovirimat at the same
EA-IND 116,039 Tecovirimat (CDC IRB #6402)

Page 6

Version 6.0
July 20, 2022

time as live smallpox vaccine (vaccinia virus) may reduce the immune response to the vaccine [11]. The
clinical impact of this interaction on vaccine efficacy is unknown.
5.0
POSSIBLE RISKS OF TECOVIRIMAT TREATMENT
Co-administration with repaglinide may cause hypoglycemia. Monitor blood glucose and monitor for
hypoglycemic symptoms during co-administration. Other risks associated with administration of
tecovirimat to patients with orthopoxvirus infections are unknown. See Section 10.1 for more information
on human safety, including adverse events to oral and IV tecovirimat.
Contraindications, Warnings, and Precautions
Given the theoretical safety concern of renal toxicity related to hydroxypropyl betadex exposure, under
this protocol, IV tecovirimat is contraindicated in patients with severe renal impairment (creatinine
clearance <30 mL/min). In patients with mild (defined as creatinine clearance 50-80 mL/min) and
moderate (defined as creatinine clearance 30-49 mL/min) renal impairment, IV tecovirimat should be used
with caution (i.e., case-by-case determination to treat with IV tecovirimat based on clinical judgment
regarding the risk/benefit for the patient). Serum creatinine levels should be closely monitored and, if
renal toxicity is suspected, consideration should be given to modifying the regimen to the oral
formulation, if feasible. Because of the potential risk of hydroxypropyl betadex accumulation, renal
function and laboratory values should be monitored during the course of therapy for all patients who
receive IV tecovirimat. See Section 6.4 for additional information.
6.0
SPECIAL POPULATIONS
Tecovirimat treatment may be considered for patients in the following special populations based on
careful clinical assessment of individual patient’s clinical condition and weighing the serious risk of
orthopoxvirus infection and potential benefit of tecovirimat with the potential risks of this product.
6.1
Pregnancy
Tecovirimat has not been studied in pregnant individuals; however, reproductive development studies
have been performed in mice and rabbits and no embryo-fetal abnormalities were recorded. Pregnant mice
were administered tecovirimat orally at doses up to 1,000 mg/kg/day from gestation Days 6-15
(approximately 23 times higher than human exposure at the recommended human dose). Considering the
serious, and potentially deadly, risks associated with orthopoxvirus infections (e.g., vaccinia [including
complications from smallpox vaccine or secondary exposure to a smallpox-vaccinee], monkeypox, and
cowpox), the potential benefits of treatment with oral or intravenous tecovirimat may outweigh the
unknown pregnancy risks associated with tecovirimat.
6.2
Lactation
No studies of tecovirimat use in nursing individuals have been conducted. Considering the serious, and
potentially deadly, risks associated with orthopoxvirus infections (e.g., variola, vaccinia [including
complications from smallpox vaccine or secondary exposure to a replication-competent smallpox­
vaccinee], monkeypox, and cowpox), the potential benefits of treatment with oral or intravenous
tecovirimat may outweigh the unknown risks associated with tecovirimat use during lactation. Because of
the potential for virus transmission through direct contact with the breastfed infant, breastfeeding is not
recommended while the nursing individual has active lesions. A lactating individual may consider
interrupting breastfeeding and may consider pumping and discarding breast milk during treatment.
In lactating mice given oral tecovirimat doses up to 1,000 mg/kg/day, mean tecovirimat milk to plasma
ratios up to approximately 0.8 were observed at 6 and 24 hours post-dose when administered orally on
lactation Day 10 or 11.
6.3
Pediatric Population
As in adults, the effectiveness of tecovirimat in pediatric patients is based solely on efficacy studies in
animal models of orthopoxvirus disease. As exposure of healthy pediatric subjects to tecovirimat with no
EA-IND 116,039 Tecovirimat (CDC IRB #6402)

Page 7

Version 6.0
July 20, 2022

potential for direct clinical benefit is not ethical, PK simulation was used to derive dosing regimens that
are predicted to provide pediatric patients with exposures comparable to the observed exposure in adults
receiving 600 mg twice daily. The dosage for pediatric patients is based on weight. In March 2007, SIGA
provided tecovirimat to support an emergency investigational new drug application (E-IND) (No. 74,773)
sponsored by the CDC for the treatment of a 28-month-old child with eczema vaccinatum. See Section
10.2 for more information. Considering the serious, and potentially deadly, risks associated with
orthopoxvirus infections (e.g., vaccinia [including complications from smallpox vaccine or secondary
exposure to a smallpox-vaccinee], monkeypox, and cowpox), the potential benefits of treatment with oral
or intravenous tecovirimat may outweigh the unknown pediatric risks associated with tecovirimat.
IV tecovirimat
There are limited data regarding the use of hydroxypropyl-β-cyclodextrin, an ingredient in IV tecovirimat,
in pediatric patients < 2 years of age. Given the potential for drug accumulation due to renal immaturity in
pediatric patients less than 2 years, monitoring of renal function during the treatment course is
recommended.
6.4
Patients with Renal Impairment
Tecovirimat capsules:
No dosage adjustment is required for patients with mild, moderate or severe renal impairment or patients
with end stage renal disease (ESRD) requiring hemodialysis [see Clinical Pharmacology (12.3)].
IV tecovirimat:
IV tecovirimat is contraindicated in patients with severe renal impairment (creatinine clearance below 30
mL/min). Because of the potential risk of hydroxypropyl betadex accumulation, renal function and
laboratory values should be monitored during the course of therapy for all patients receiving IV
tecovirimat.
7.0
CLINICAL ASSESSMENT AND MONITORING OF PATIENTS
Upon presentation, the patient should be thoroughly assessed per clinician’s judgement to evaluate the
potential need for tecovirimat. This may include a medical history, review of concomitant medications,
and a physical examination with vital signs (e.g., weight, blood pressure, pulse, respiratory rate,
temperature, and height). Clinical assessment and monitoring can be conducted in person or by
telemedicine, whichever is feasible.
Treating clinicians or their designees will be responsible for patient follow-up, monitoring, and reporting
collected information to CDC. The following report forms are required to be completed, retained, and/or
returned to CDC:
•

•
•

•

ObtainInformed
InformedConsent
Consent––prior
priorto
toinitiating
initiatingtecovirimat
tecovirimattreatment;
treatment;provide
provideaacopy
copyto
tothe
thepatient
patientand
and
Obtain
retain a copy at the treating facility/institution. A copy does NOT need to be returned to CDC. Only if
the signed informed consent forms cannot be maintained at the treating facility/institution, then they
can be sent to CDC within 3 working days of tecovirimat initiation.
CompleteForm
FormFDA
FDA1572
1572and
andreturn
returnto
toCDC
CDCwithin
within33working
workingdays
daysof
oftecovirimat
tecovirimatinitiation.
initiation.
Complete
PatientIntake
IntakeForm
Form(Attachment
(Attachment22––Form
FormA).
A).Please
Pleasereturn
returnto
toCDC
CDCwithin
within33working
workingdays
daysof
of
Patient
tecovirimat initiation. The form includes fields for:
o Medical
Medicalhistory,
history,baseline
baselinesigns/symptoms,
signs/symptoms,vital
vitalsigns,
signs,concomitant
concomitantmedications
medications
o Clinical
Clinicallaboratory
laboratoryparameters,
parameters,ififperformed
performedper
pertreating
treatingclinician’s
clinician’sclinical
clinicaljudgment
judgment
depending on patient’s underlying condition, then attach a copy of clinical laboratory results
(e.g., hematology, chemistry, urinalysis).
ClinicalOutcome
OutcomeForm
Form(Attachment
(Attachment22––Form
FormB).
B).Please
Pleasereturn
returnto
toCDC
CDCwithin
within33working
workingdays
daysof
of
Clinical
last patient follow-up. The form includes fields for:

EA-IND 116,039 Tecovirimat (CDC IRB #6402)

Page 8

Version 6.0
July 20, 2022

o Progress
Progressof
oftecovirimat
tecovirimattherapy
therapyand
andclinical
clinicaloutcomes,
outcomes,clinical
clinicallabs
labs(if
(ifperformed
performedbased
basedon
on
clinical judgment depending on patient’s underlying condition), and lesion/scab and serum
samples (if collected).
o Occurrence
Occurrenceof
ofSAEs
SAEs––ififyes,
yes,reported
reportedby
bycompleting
completingaafillable-PDF
fillable-PDFMedWatch
MedWatchForm
Form
(Attachment 6) and returning to CDC via email ([email protected]) within 72 hours of
awareness or sooner if possible. A fillable-PDF MedWatch Form can also be downloaded
from MedWatch Forms for FDA Safety Reporting | FDA.
Optional lesion photos: If feasible, take lesion photos at baseline prior to tecovirimat treatment, and
post-treatment to follow lesion progression and healing during treatment. When submitting photos,
please indicate date the photo was taken, the corresponding tecovirimat treatment day, patient name or
MRN, and treating facility.
Methods of returning the above information are:
• Secure Share File for lesion photos and large file sizes (please zip multiple files and use filenames
with patient identifier, hospital name, and date): https://centersfordiseasecontrol.sharefile.com/r
https://centersfordiseasecontrol.sharefile.com/r-­
r3941801ebcbd4002b4dfe98e314ec697

•

Encrypted email: [email protected] (personally identifiable information should not be emailed
without encryption)

•

Fax: 404-902-5921

For outpatients: If feasible, treating clinicians may provide a diary form (Attachment 2 – Form C) for
patients to complete at home daily and voluntarily return it directly to CDC.
Optional Laboratory Testing
Under this IND program, the following laboratory testing are not required and optional per treating
clinician’s decision:
• Perform
Performclinical
clinicallaboratory
laboratorytesting
testing(e.g.,
(e.g.,hematology,
hematology,chemistry,
chemistry,urinalysis)
urinalysis)per
pertreating
treating
clinician’s clinical judgment depending on the underlying clinical conditions to monitor the safety
of tecovirimat treatment (e.g., baseline, during, or post treatment) as appropriate.
•

Ideally,obtain
obtainaasample
samplefrom
fromatatleast
least11lesion
lesionprior
priorto
totecovirimat
tecovirimattreatment
treatmentbut
butonly
onlyififbaseline
baseline
Ideally,
diagnostic testing wasn’t already performed. Ideally, obtain samples from any new lesions that
develop during tecovirimat treatment or after completion of tecovirimat treatment for
development of antiviral resistance mutations. Submit samples to CDC with CDC Form 50.34,
50.34
and indicate Poxvirus Molecular Detection (CDC-10515) as the test order (code).
See Attachment 4 (Optional Lesion Samples to CDC for Resistance Testing) for collection and
shipping instructions on information. The resistance testing at CDC is available if there is clinical
suspicion of lower effectiveness (not resolving lesion, new lesions). Results will not be made
available to guide individual patient management, but will be used for public health purpose of
monitoring potential emergence of antiviral resistance.
Serology testing at CDC is available if requested by the treating clinicians. Testing may be
considered if there are concerns that the patient may not develop a normal immune response.
Samples collected at baseline may be important for later interpretation.

•

feasibleto
toparticipate
participatein
inplasma
plasmapharmacokinetic
pharmacokineticsample(s)
sample(s)collection
collectionfor
fortesting
testingatataadesignated
designated
IfIffeasible
laboratory (Alturas Analytics) to help inform drug exposure, see Attachment 5 for instructions.
Clinicians may consider prioritizing collection of PK samples from certain patients (e.g., pediatric
or critically ill patients) whose drug exposure levels may need to be monitored. Results may not be

EA-IND 116,039 Tecovirimat (CDC IRB #6402)

Page 9

Version 6.0
July 20, 2022

available in time for directly informing individual patient management, but would inform drug
exposure levels of patients with orthopoxvirus infections.
Table 4. Summary of Clinical Assessment and Monitoring Parameters
Pre-Tecovirimat
Treatment a

Days
Parameters

Sign Informed Consent
Inclusion/Exclusion Criteria
Baseline clinical
assessmentb; Give patient
the Diary formc
Clinical progress
Serious Adverse Eventsd
Lesion Photosb

Hematology, chemistry,
urinalysis
Lesion samples

During Tecovirimat
Treatment a

Patient Intake Form
(Attachment 2 -A)

Clinical Outcome Form (Attachment 2 -B)

Prior to first dose of
Tecovirimat
(≤ 24 hours)

Day 1-14

b

c
d

Outpatients: 7-10 Days after treatment
completion
Inpatients: Upon Discharge

x
x
x
N/A

x

x

N/A

x

x

Optional

Optional (between days
7-14)

Optional

Optional

Optional

Optional

Optional
(for any new lesions)

Optional
(for any new lesions post-treatment)

PK samples
a

Post Completion of Tecovirimat
Treatment a

Optional

For outpatients, assessment may be conducted via telemedicine.
Optional digital photos of lesions at baseline and during therapy (between days 7−14), if feasible.

Give Patient Diary form (Attachment 2C) to the patient for completing and returning directly to CDC by the
patient.

SAEs must be reported by emailing a completed fillable-PDF MedWatch Form (Attachment 6) to CDC ([email protected])
within 72 hours of awareness or sooner if possible.

8.0

RECORDING AND REPORTING ADVERSE EVENTS

8.1
Definitions (21 CFR 312.32)
An ADVERSE EVENT (AE) is any untoward medical occurrence associated with the use of tecovirimat
in humans, whether or not considered related to tecovirimat. It can be any unfavorable and unintended
sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated with the use of
tecovirimat, without any judgment about causality.
A SUSPECTED ADVERSE REACTION is any AE for which there is a reasonable possibility that
tecovirimat caused the AE. It is a subset of all AEs for which there is a reasonable possibility that
EA-IND 116,039 Tecovirimat (CDC IRB #6402)

Page 10

Version 6.0
July 20, 2022

tecovirimat caused the event. “Reasonable possibility” means there is evidence to suggest a causal
relationship between tecovirimat and the AE. “Suspected adverse reaction” implies a lesser degree of
certainty about causality than “adverse reaction.”
An ADVERSE REACTION is any AE caused by tecovirimat. Adverse reactions are a subset of all
suspected adverse reactions for which there is a reason to conclude that tecovirimat caused the event.
UNEXPECTED: An AE is considered “unexpected” if it is not listed in this protocol or Package Insert,
or is not listed at the specificity or severity observed.
SERIOUS: An AE or suspected adverse reaction is considered “serious” if in the view of either the
treating clinician or CDC, it results in any of the following outcomes:
death
• death
life-threateningAE
AE
• aalife-threatening
inpatienthospitalization
hospitalizationor
orprolongation
prolongationof
ofexisting
existinghospitalization
hospitalization
• inpatient
persistentor
orsignificant
significantincapacity
incapacityor
orsubstantial
substantialdisruption
disruptionof
ofthe
theability
abilityto
toconduct
conductnormal
normallife
life
• aapersistent
functions
congenitalanomaly/birth
anomaly/birthdefect
defect
• aacongenital
NOTE: Important medical events that may not result in death, be life-threatening, or require
hospitalization may be considered serious when, based upon appropriate medical judgment, they may
jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes
previously listed.
LIFE-THREATENING: An AE or suspected adverse reaction is considered “life-threatening” if, in the
view of either the treating clinician or CDC, its occurrence places the patient at immediate risk of death. It
does not include an AE or suspected adverse reaction that, had it occurred in a more severe form, might
have caused a death.
8.2
Treating Clinician Reporting Requirements to CDC
All SAEs must be reported. These include all SAEs that the patient reports spontaneously, those the
clinician observes, and those the clinician elicits in response to open-ended questions. All SAEs, whether
or not the treating clinician considers the event to be drug-related, must be reported by emailing a
completed fillable-PDF MedWatch Form (Attachment 6) to CDC ([email protected]) within 72 hours
of awareness or sooner if possible.
8.3
CDC Reporting Requirements to FDA and CDC Institutional Review Board (IRB)
CDC will review all AEs and report serious, unexpected suspected adverse reactions to FDA within 15
calendar days of initial receipt or after determining that the information qualifies for reporting under 21
CFR 312.32I(1).
In cases of unexpected suspected adverse reactions that are fatal or life-threatening (serious), CDC will
report to FDA as soon as possible, but no later than 7 calendar days after initial receipt of the information
(21 CFR 312.32(c)(2)).
All three (3) of the definitions contained in the requirement must be met for expedited reporting to FDA:
Serious,
1. Serious,
Unexpected,and
and
2. Unexpected,
SuspectedAdverse
AdverseReaction.
Reaction.
3. Suspected
AEs that do not meet the requirements for expedited reporting will be reported to FDA in the IND Annual
Report.
EA-IND 116,039 Tecovirimat (CDC IRB #6402)

Page 11

Version 6.0
July 20, 2022

CDC will report all serious and unexpected suspected adverse reactions and incidents to CDC IRB
according to CDC IRB’s policy and procedures.
9.0
REGULATORY AND ADMINISTRATIVE REQUIREMENTS
CDC, the sponsor of the IND, and all licensed healthcare providers who request and receive
tecovirimat under this IND protocol will abide by the Code of Federal Regulations (in particular,
21 CFR Parts 50, 56, and 312). The IND protocol is subject to FDA’s review and authorization as
well as review and approval by an Institutional Review Board (IRB). CDC IRB serves as the
central IRB for review and approval and of tecovirimat IND protocol, and has determined it nonresearch (i.e., does not constitute human subjects research per 45 CFR 46.102(l)). Therefore,
participating sites may use CDC IRB’s approval of this protocol that meets FDA’s requirements
regarding IRB review per 21 CFR Parts 50 and 56.
Any change or modification to the IND protocol that affects purpose, procedures, or significant data or
administrative aspects of the program will require a formal amendment. Such amendments will be
submitted to FDA for review and approved by the CDC IRB prior to implementation. Revised IND
protocol and/or procedural modifications will be communicated by CDC to the clinicians and medical
facilities participating in the tecovirimat treatment.
Data Management and Handling
IND case report forms (Attachment 2), laboratory results, visit summaries, hospital discharge
summaries, medical records, etc., may be used as source documents. The information obtained through
the case report forms of this IND protocol and additional supplemental information provided by treating
clinicians to CDC will be maintained by the CDC. Any analysis of data contents will be conducted
without individual identifiers. The information gathered under this expanded access IND program and
any analysis generated will be reported to the FDA as part of the annual report for this IND. Data from
case report forms and other related information collected under this IND may also be provided to SIGA
Technologies, Inc. and the Department of Health and Human Services/Biomedical Advanced Research
and Development Authority (HHS/BARDA). Information about specific treating clinicians (i.e., names,
CVs, or Form FDA 1572) and/or hospitals/sites may be shared with FDA, and local public health
jurisdictions, and the manufacturer. Any information pertaining to treating clinicians and/or participating
sites that are provided to the manufacturer is limited to use in the manufacturer’s discussions with health
authorities concerning this CDC-sponsored IND program.
Informed Consent
Informed consent in compliance with 21 CFR 50 must be obtained via the enclosed informed
consent/permission form (Attachment 1) from the patient before tecovirimat is administered. If the
patient is unable to give consent, consent can be obtained from the next-of-kin or legal
guardian/representative.
A single consent form (Attachment 1) will be used to obtain informed consent/parental permission.
Waiver of assent for children (7–11 years of age) under 21 CFR 50.55(c)(1) and for children (12–17 years
of age) under 21 CFR 50.55(c)(2) was approved by the CDC IRB for all patients under this IND program.
Parental permission will be sought in accordance with 21 CFR 50.55 for children aged 12–17 years
(permission of only one parent is required). The ultimate responsibility for decision-making regarding
treatment with tecovirimat in minors should lie with the parent or guardian.
If a patient is unable to respond and make wishes known about tecovirimat treatment, and no next-of-kin
or legal representative is available, and the patient’s illness is life-threatening, per 21 CFR 50.23
“Exception from General Requirements”, informed consent may be deemed not feasible and the treating
clinician can make the determination to administer tecovirimat. The patient’s treating clinician and a
clinicians who is not otherwise participating in this expanded access IND program, will document on the
EA-IND 116,039 Tecovirimat (CDC IRB #6402)

Page 12

Version 6.0
July 20, 2022

last page of the informed consent form (Attachment 1). Notify CDC via email ([email protected])
within 3 working days of tecovirimat initiation when the treatment determination was made based on the
mentioned certification by the treating and an independent clinician.
10.0

SUMMARY OF AVAILABLE SAFETY AND EFFICACY DATA OF TECOVIRIMAT

10.1 Human Safety Data of Tecovirimat
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in
the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and
may not reflect the rates observed in practice. The safety of tecovirimat has not been studied in patients
with smallpox or non-variola orthopoxvirus disease.
Oral tecovirimat
The largest safety study of oral tecovirimat was in 359 healthy adult subjects ages 18–79 years in a Phase
3 clinical trial.
Most Frequently Reported Adverse Reactions to Oral Tecovirimat
The most frequently reported adverse reactions were headache and nausea. Adverse reactions that
occurred in at least 2% of subjects in the tecovirimat treatment group are shown in Table 5.
Table 5. Adverse Reactions Reported in ≥ 2% of Healthy Adult Subjects Receiving at Least One
Dose of Oral Tecovirimat 600 mg

a

Headache
Nausea
Abdominal Paina
Vomiting

TPOXX 600 mg N =359 (%)
12
5
2
2

Placebo N = 90 (%)
8
4
1
0

Includes abdominal pain, abdominal pain upper, abdominal distension, abdominal discomfort, abdominal pain lower, and
epigastric pain.

Adverse Reactions Leading to Discontinuation of Oral Tecovirimat
Six subjects (2%) had tecovirimat discontinued due to adverse reactions. Each of these subject’s adverse
reactions (with severity) is listed below:
• Electroencephalogram
Electroencephalogramchange,
change,abnormal
abnormal
• Mild
Mildupset
upsetstomach,
stomach,dry
drymouth,
mouth,decreased
decreasedconcentration
concentrationand
anddysphoria
dysphoria
• Mild
Mildnausea
nauseaand
andfever,
fever,moderate
moderatediarrhea,
diarrhea,severe
severeheadache
headache
• Mild
Mildpalpable
palpablepurpura
purpura
• Mild
Mildnausea,
nausea,fever
feverand
andchills
chills
• Mild
Mildfacial
facialredness,
redness,facial
facialswelling
swellingand
andpruritus
pruritus
Less Common Adverse Reactions to Oral Tecovirimat
Clinically significant adverse reactions that were reported in < 2% of subjects exposed to
tecovirimat and at rates higher than subjects who received placebo are listed below:
•
•
•
•
•
•
•

Gastrointestinal:
Gastrointestinal:dry
drymouth,
mouth,chapped
chappedlips,
lips,dyspepsia,
dyspepsia,eructation,
eructation,oral
oralparesthesia
paresthesia
General
Generaland
andadministration
administrationsite:
site:pyrexia,
pyrexia,pain,
pain,chills,
chills,malaise,
malaise,thirst
thirst
Investigations:
abnormal
electroencephalogram,
hematocrit
decreased,
Investigations: abnormal electroencephalogram, hematocrit decreased,hemoglobin
hemoglobindecreased,
decreased,heart
heart
rate increased
Musculoskeletal
Musculoskeletaland
andconnective
connectivetissue:
tissue:arthralgia,
arthralgia,osteoarthritis
osteoarthritis
Nervous
Nervoussystem:
system:migraine,
migraine,disturbance
disturbancein
inattention,
attention,dysgeusia,
dysgeusia,paresthesia
paresthesia
Psychiatric:
Psychiatric:depression,
depression,dysphoria,
dysphoria,irritability,
irritability,panic
panicattack
attack
Respiratory,
Respiratory,Thoracic
Thoracicand
andMediastinal
MediastinalDisorders:
Disorders:oropharyngeal
oropharyngealpain
pain

EA-IND 116,039 Tecovirimat (CDC IRB #6402)

Page 13

Version 6.0
July 20, 2022

•

Skin and
and subcutaneous
subcutaneous tissue:
tissue: palpable
palpable purpura,
purpura, rash,
rash, pruritic
pruritic rash,
rash, facial
facial redness,
redness, facial
facial swelling
swelling
Skin
and pruritis

Adverse Events to IV Tecovirimat
The most frequently reported AEs in a multiple-dose study of IV tecovirimat included infusion site pain,
infusion site swelling, infusion site erythema, infusion site extravasation, and headache. Three subjects
(12%) had their treatment with IV tecovirimat discontinued due to an AE for the following reasons:
infusion site extravasation (moderate); infusion site extravasation (mild); infusion site swelling and pain
(mild). Adverse reactions that occurred in at least 4% of subjects in the tecovirimat treatment group are in
Table 6. Adverse reactions that were reported in in < 4% of subjects exposed to tecovirimat and at rates
higher than subjects who received placebo were: infusion site discomfort, infusion site edema, myalgia,
arthritis, back pain, muscle tightness, diarrhea, photophobia, and pruritus generalized.
Table 6. Adverse Reactions Reported in ≥ 4% of Healthy Adult Subjects receiving IV Tecovirimat
At Least One Dose of IV Tecovirimat 240 mg
IV Tecovirimat 600 mg N =26 (%) Placebo N = 6 (%)
Infusion Site Pain
73
67
Infusion Site Swelling
39
67
Infusion Site Erythema
23
67
Infusion Site Extravasation
19
50
Headache
15
0

10.2 Clinical Use of Tecovirimat in NV-OPXV-infected Patients (2007−2021)
No human efficacy data are currently available. However, prior to the 2022 monkeypox outbreak, oral
tecovirimat was used under expanded access IND (EA-IND) to treat 7 cases in the United States
(including one pediatric patient) and in at least 5 cases outside the United States. Three of the U.S.
patients were treated under this protocol. The outcomes of the clinician uses described below suggest
tecovirimat may provide clinical benefit in the treatment of orthopoxvirus infections.
E-IND No. 74,773: In March 2007, at the request of CDC, SIGA provided tecovirimat for the treatment of
a 28-month old male child with eczema vaccinatum due to direct contact with a vaccinia vaccinee [12].
The patient’s history included eczema and failure to thrive. The patient presented to the emergency room
with high fever and severe eczema. Initially, the child was treated with Vaccinia Immune Globulin
Intravenous (Human) (VIGIV) but his condition continued to worsen and on hospital Day 6 he exhibited
progressive metabolic then respiratory acidosis, hypoalbuminemia, hypothermia, and hypotension through
March 10, 2007. Tecovirimat was orally administered via a nasogastric tube for 14 days, beginning on
March 11, 2007 (hospital Day 9). The dosing regimen of tecovirimat was:
50 mg (5 mg/kg) March 11−12
75 mg (7.5 mg/kg) March 13−14
100 mg (10 mg/kg) daily from March 19−24
Tecovirimat doses were adjusted to achieve a target peak level of 1,000 ng/ml, based on the efficacy NHP
studies available at the time. Prior to initiation of tecovirimat, the child also received cidofovir (5 mg/kg)
and repeated doses of VIGIV, with the last dose of VIGIV administered on March 27, 2007. Clinical
signs of the child’s improvement were observed within 1 week of the anti-viral intervention (tecovirimat
and cidofovir) and VIGIV. The child was extubated on April 2, 2007, moved out of intensive care on
April 8, 2007, and discharged to home on April 19, 2007 (hospital Day 48). There were no AEs that could
be attributed to tecovirimat. (Vora et. al., 2008)
E-IND No. 104,793: On March 2, 2009, CDC received information of a possible progressive vaccinia
(PV) case involving a 20-year-old male military smallpox vaccinee [13]. The patient’s history included
EA-IND 116,039 Tecovirimat (CDC IRB #6402)

Page 14

Version 6.0
July 20, 2022

post-vaccination neutropenic fever which was diagnosed on January 28, 2009 as acute myelogenous
leukemia M0 (AML M0). Approximately two weeks after a second round of induction chemotherapy, the
patient’s vaccination site deteriorated to a deep bulla, 4 cm in diameter, with a raised edge and central
bleeding crust. Viral culture of a lesion swab and PCR viral analysis confirmed the presence of
orthopoxvirus. Serum showed equivocal to absent anti-orthopoxvirus IgG or IgM by an ELISA test.
Based on the patient’s history and test results, a diagnosis of PV was made. After receiving an initial dose
of VIGIV, oral and topical tecovirimat was administered per the following dosing regimen:
400 mg once daily (oral) March 5−19, except March 8 (no dose administered)
800 mg once daily (oral) March 20–24
1200 mg once daily (oral) March 25–May 18
Topical 1%, 0.5 mL once daily March 6, April 21–May 12
1%, 0.5 mL twice daily March 7–April 20
Doses were adjusted to achieve a peak level of tecovirimat of 1500 ng/mL. The patient also received
repeated doses of VIGIV, topical Imiquimod, and six oral doses of CMX001 (lipidated cidofovir). Early
in treatment, the patient developed Pseudomonas aeruginosa sepsis, multiorgan failure, required stress
dose steroids because of his prior induction regimens, required excessive vasopressor support ultimately
later resulting in bilateral trans-tibial amputation. Also later during treatment, methicillin-resistant
Staphylococcus aureus infection was detected in vaccination satellite lesions. Despite the patient’s
protracted clinical course with sepsis and superinfections, probably due to cellular immunodeficiencies,
after more than 2 months of antiviral therapy, the patient was ultimately discharged in September 2009
after testing negative for vaccinia virus.
E-IND No. 106,338: On August 15, 2009, CDC notified SIGA to provide tecovirimat for the treatment of
a 35-year-old female patient who developed vesiculopustular skin lesions on her arm and hand due to
accidental exposure to recombinant-vaccinia-based rabies vaccine in a bait found by the patient’s dog
[14]. The patient had a history of Crohn’s disease and was undergoing treatment with daily azathioprine
and infliximab every 6 weeks. On August 22, 2009, after vaccinia-positive PCR results, the patient was
given VIGIV and started on a daily oral dose of tecovirimat (400 mg) for 14 days. The lesions healed and
the patient was discharged on August 29, 2009.
E-IND No. 112,324: In May 2011, tecovirimat was used to treat a 25-year-old healthy, immunocompetent
female patient with a history of acne who was believed to have contracted a live vaccinia virus infection
on her chin while changing a bandage covering the smallpox vaccination site of her boyfriend, a military
contractor. The patient was treated with VIGIV and placed under house quarantine. A daily oral dose of
tecovirimat (400 mg) was administered for 14 days. The patient responded well to treatment, with no
apparent AEs. As of August 2011, the patient was doing well and her lesions had completely healed with
minimal scarring.
IND 116,039, CDC IRB #6402: In January 2016, a previously healthy 19-year-old male in the U.S.
military sought treatment for complications that developed 1 day after receiving ACAM2000® (live
vaccinia vaccination) inoculation [15]. Symptoms included malaise requiring bed rest, odynophagia, and
retrosternal chest pain. Later the patient developed worsening erythema and deep pain in the area
surrounding the inoculation site, a lesion on his right scalp, and a lesion on his left flank. PCR results of
the lesion swabs confirmed the presence of orthopoxvirus. The patient was diagnosed with acute myeloid
leukemia. Due to the need for the patient to receive chemotherapy and concern for immunosuppression
that might lead to progression of vaccinia infection, the patient received oral tecovirimat 600 mg twice
daily (BID) for a total duration of 62 days. No dose adjustments were made during his tecovirimat
treatment course. The patient tolerated the course of tecovirimat well; there were no reports of adverse
events. Throughout the patient’s course, he received three doses of VIGIV and treatment for acute
myeloid leukemia including chemotherapy.
EA-IND 116,039 Tecovirimat (CDC IRB #6402)

Page 15

Version 6.0
July 20, 2022

IND 116,039, CDC IRB #6402: In January 2019, an unvaccinated healthy 26-year-old female laboratorian
working with vaccinia virus developed a single vesicular lesion and swelling on her left index finger 10
days after a needle-stick injury [16]. Two days later, she developed fever, left axillary lymphadenopathy,
malaise, pain, and worsening edema of her finger. The patient received 600 mg orally BID for a total of
14 days. During the patient’s course, she received a single dose of VIGIV and antibiotics (clindamycin
and cephalexin) because of concern about possible secondary bacterial infection. Within 48 hours of
treatment initiation, fever and lymphadenopathy resolved, and the local pain and edema decreased. During
treatment with tecovirimat and antibiotics, the patient experienced mild adverse events (i.e., nausea, loss
of appetite, fatigue, myalgia, and pruritus), and pain in her left finger and arm. Areas of necrotic tissue did
not fully resolve until day 94.
IND 116,039, CDC IRB #6402: In July 2021, an early middle-aged male developed fever, cough, and
fatigue, followed by onset of a diffuse rash within 1 week of traveling in Nigeria. The patient had
extensive pustular rash on his face. His symptoms progressed to diarrhea, vomiting, cough, subjective
fever, fatigue, and purulent rash. The patient was confirmed to have monkeypox virus infection and was
treated with a 14-day course of tecovirimat, receiving 600 mg oral BID for the first 19 doses and 200 mg
IV BID for the remaining 9 doses. The patient was reported not to have experienced any tecovirimat­
related AEs and experienced resolution of monkeypox symptoms.
Tecovirimat use outside the US:
InDecember
December2009,
2009,the
theDivision
Divisionof
ofInfectious
InfectiousDiseases
DiseasesatatHelsinki
HelsinkiUniversity
UniversityCentral
CentralHospital
Hospital
• In
requested from SIGA tecovirimat for compassionate use in a 32-year-old female patient who was
suffering from severe keratoconjunctivitis. The patient had been on various treatments since
September 2009 and the chief physician reported the possibility of orthopoxvirus infection, as she
tested PCR-positive for ocular cowpox virus. Plasma, serum and tear tecovirimat concentrations
were monitored during treatment, and appeared adequate. There were no serious drug-related AEs
reported. As of April 2010, the patient’s corneal inflammation had improved. Orthopoxviral
culture remained negative, but the PCR assay still tested positive.
• In August 2019, SIGA provided TPOXX capsules for treatment of a 32-year-old male patient with
cowpox infection. The patient had a kidney transplant in 2006 and had taken immunosuppressive
drugs (tacrolimus and mycophenolate mofetil). A total of 18 doses of TPOXX were administered. The
patient was hospitalized for 15 days and was in intensive care for 5 days for the orthopoxvirus
infection; however the patient did not recover from the infection. The patient’s liver and kidney
functions worsened over time. Additionally, he experienced severe worsening of oral mucosa [sic],
obstruction of airways with acute respiratory failure and cardiopulmonary resuscitation (CPR), and
septic shock. In September 2019, the patient died from multi-organ failure due to cowpox. The patient
was reported to have tolerated the shorter than recommended course of TPOXX well. Information on
adverse events with an onset after the initiation of TPOXX was not provided.
• In August 2019, SIGA provided TPOXX capsules for treatment of a 57-year-old white female with
cowpox who had had a history of lung transplantation and renal impairment. The patient was treated
with an extended course of TPOXX for one month, discontinued TPOXX, and then restarted TPOXX
treatment again at the end of November until the patient succumbed to renal failure in March 2020. No
adverse events attributed to TPOXX were reported.
• In November 2019, SIGA provided TPOXX capsules for treatment of a 35-year-old white female with
a pre-existing condition of neurodermitis (atopic dermatitis) with no smallpox vaccination record and
unknown exposure date. Her baseline physical assessment on November 2019 recorded 5 lesions
assumed to be cowpox over <10% of her body (right hand). She received TPOXX capsules twice daily
for a total of 7 days (14 doses). Note this is shorter than the 14-day courses recommended for
treatment. The patient reported no adverse events during the treatment. The patient recovered from the
infection.
• In 2021, a patient who was part of a cluster of cases with monkeypox in the UK associated with travel
from Nigeria was treated with a 2-week course of oral tecovirimat (600 mg twice daily) after
EA-IND 116,039 Tecovirimat (CDC IRB #6402)

Page 16

Version 6.0
July 20, 2022

developing malaise, headache, pharyngitis, and vesicles on her thorax that were PCR positive for
monkeypox [4]. The patient’s blood and upper respiratory tract samples became PCR negative 48
hours after initiation of tecovirimat and remained negative at 72 hours. The patient did not develop
new lesions 24 hours of tecovirimat therapy and reported no adverse effects after 2 weeks of
tecovirimat treatment.

10.3 Tecovirimat Efficacy in Animals
The effectiveness of tecovirimat for treatment of smallpox disease has not been determined in humans
because adequate and well-controlled field trials have not been feasible and inducing smallpox disease in
humans to study the drug’s efficacy is not ethical. Therefore, the effectiveness of tecovirimat for
treatment of smallpox disease was established based on results of adequate and well-controlled animal
efficacy studies of non-human primates and rabbits infected with non-variola orthopoxviruses. Survival
rates observed in the animal studies may not be predictive of survival rates in clinical practice.
Efficacy studies were conducted in cynomolgus macaques infected with monkeypox virus and New
Zealand white (NZW) rabbits infected with rabbitpox virus. The primary efficacy endpoint for these
studies was survival. Treatment with oral tecovirimat given at Day 4 and 5 post-challenge for 14 days
resulted in statistically significant improvement in survival relative to placebo, except when given to
cynomolgus macaques starting at Day 6 post-challenge. See the Package Insert for more information.
10.4 Pharmacokinetics Data
Because the effectiveness of tecovirimat cannot be tested in humans, a comparison of tecovirimat
exposures achieved in healthy human subjects to those observed in animal models of orthopoxvirus
infection (nonhuman primates and rabbits infected with monkeypox virus and rabbitpox virus,
respectively) in therapeutic efficacy studies was necessary to support the dosage regimen of 600 mg twice
daily for treatment of smallpox disease in humans. Overall, the PK profiles of tecovirimat and its
metabolites following a single oral dose and single, 6-hour IV infusion were similar in animal and human
studies [10, 17]. For both oral and IV routes of administrations, accumulation is observed after repeated
administration, and steady-state is achieved within 6 days. Refer to the Package Insert for PK parameters
of tecovirimat.
11.0 REFERENCES
1. Reynolds,
Reynolds,M.G.,
M.G.,etetal.,
al.,Clinical
ClinicalManifestations
Manifestationsof
ofHuman
HumanMonkeypox
MonkeypoxInfluenced
Influencedby
byRoute
Routeof
of
Infection. The Journal of Infectious Diseases, 2006. 194(6): p. 773-780.
2. Centers
Centersfor
forDisease
DiseaseControl
Controland
andPrevention,
Prevention,Update:
Update:Multistate
MultistateOutbreak
Outbreakof
ofMonkeypox—Illinois,
Monkeypox—Illinois,
Indiana, Kansas, Missouri, Ohio, and Wisconsin, 2003. JAMA, 2003. 290(3): p. 325-327.
3. Hobson,
Hobson,G.,
G.,etetal.,
al.,Family
Familycluster
clusterof
ofthree
threecases
casesof
ofmonkeypox
monkeypoximported
importedfrom
fromNigeria
Nigeriato
tothe
the
United Kingdom, May 2021. Euro Surveill, 2021. 26(32).
4. Adler,
Adler,H.,
H.,etetal.,
al.,Clinical
Clinicalfeatures
featuresand
andmanagement
managementof
ofhuman
humanmonkeypox:
monkeypox:aaretrospective
retrospective
observational study in the UK. Lancet Infect Dis, 2022.
5. Vaughan,
Vaughan,A.,
A.,etetal.,
al.,Two
Twocases
casesof
ofmonkeypox
monkeypoximported
importedto
tothe
theUnited
UnitedKingdom,
Kingdom,September
September2018.
2018.
Euro Surveill, 2018. 23(38).
6. Rao,
Rao,A.K.,
A.K.,etetal.,
al.,Monkeypox
Monkeypoxin
inaaTraveler
TravelerReturning
Returningfrom
fromNigeria
Nigeria--Dallas,
Dallas,Texas,
Texas,July
July2021.
2021.
MMWR Morb Mortal Wkly Rep, 2022. 71(14): p. 509-516.
7. Costello,
Costello,V.,
V.,etetal.,
al.,Imported
ImportedMonkeypox
Monkeypoxfrom
fromInternational
InternationalTraveler,
Traveler,Maryland,
Maryland,USA,
USA,2021.
2021.
Emerg Infect Dis, 2022. 28(5): p. 1002-1005.
8. Smith,
Smith,S.K.,
S.K.,etetal.,
al.,Effective
Effectiveantiviral
antiviraltreatment
treatmentof
ofsystemic
systemicorthopoxvirus
orthopoxvirusdisease:
disease:ST-246
ST-246
treatment of prairie dogs infected with monkeypox virus. J Virol, 2011. 85(17): p. 9176-87.
9. Sbrana,
Sbrana,E.,
E.,etetal.,
al.,Efficacy
Efficacyof
ofthe
theantipoxvirus
antipoxviruscompound
compoundST-246
ST-246for
fortreatment
treatmentof
ofsevere
severe
orthopoxvirus infection. Am J Trop Med Hyg, 2007. 76(4): p. 768-73.
10. SIGA Technologies, Inc. TPOXX Prescribing Information. Accessed
Accessed19
19July
July2022];
2022];Available
Available
from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/208627s007lbl.pdf
https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/208627s007lbl.pdf.
EA-IND 116,039 Tecovirimat (CDC IRB #6402)

Page 17

Version 6.0
July 20, 2022

11. Russo, A.T., et al., Co-administration of tecovirimat and ACAM2000 in non-human primates:
Effect of tecovirimat treatment on ACAM2000 immunogenicity and efficacy versus lethal
monkeypox virus challenge. Vaccine, 2020. 38(3): p. 644-654.
12. Vora, S., et al., Severe eczema vaccinatum in a household contact of a smallpox vaccinee. Clin
Infect Dis, 2008. 46(10): p. 1555-61.
13. Lederman, E.R., et al., Progressive Vaccinia: Case Description and Laboratory-Guided Therapy
With Vaccinia Immune Globulin, ST-246, and CMX001. J Infect Dis, 2012. 206(9): p. 1372-85.
14. Centers for Disease, C. and Prevention, Human vaccinia infection after contact with a raccoon
rabies vaccine bait - Pennsylvania, 2009. MMWR Morb Mortal Wkly Rep, 2009. 58(43): p. 1204­
7.
15. Lindholm, D.A., et al., Preemptive Tecovirimat Use in an Active Duty Service Member Who
Presented With Acute Myeloid Leukemia After Smallpox Vaccination. Clin Infect Dis, 2019.
69(12): p. 2205-2207.
16. Whitehouse, E.R., et al., Novel Treatment of a Vaccinia Virus Infection from an Occupational
Needlestick - San Diego, California, 2019. MMWR Morb Mortal Wkly Rep, 2019. 68(42): p. 943­
946.
17. Chen, Y., et al., Comparison of the safety and pharmacokinetics of ST-246(R) after i.v. infusion or
oral administration in mice, rabbits and monkeys. PLoS One, 2011. 6(8): p. e23237.

EA-IND 116,039 Tecovirimat (CDC IRB #6402)

Page 18

Version 6.0
July 20, 2022


File Typeapplication/pdf
File TitleExpanded Access IND Protocol: Use of Tecovirimat (TPOXX®) for Treatment of Human Non-Variola Orthopoxvirus Infections in Adults
AuthorCDC
File Modified2022-07-28
File Created2022-07-28

© 2022 OMB.report | Privacy Policy