1      

Streptomirus (Streptovancin): A miracle treatment for Necrotizing Fasciitis

By: Elsa Chen & Tosha Dave RGA 6201 3/19/2015

  2      

Table of Content Executive Summary ------------------------------------------------------------------------------------------3 Necrotizing Fasciitis Background

Unmet Medical Need and Rationale for Innovation of Streptomirus Summary of Streptovancin Development, Targeted Market

Introduction ----------------------------------------------------------------------------------------------------4 Company Overview ------------------------------------------------------------------------------------------5 Product Development Program -----------------------------------------------------------------------------6 Non-Clinical Studies -----------------------------------------------------------------------------------------6 Animal Pharmacology and Toxicology Pharmacokinetics Pharmacodynamics GLP Statement ------------------------------------------------------------------------------------------------8 Chemistry, Manufacturing, and Controls ------------------------------------------------------------------9 Drug Substance

Drug Substance Manufacturing Drug Product Drug Product Manufacturing Environmental Impact Analysis Report Packaging Establishment

IND Waiver and Requirement for Orphan Drug Designation ----------------------------------------12 Clinical Trials ------------------------------------------------------------------------------------------------13 Phase I Phase II

Phase III Clinical Pharmacology -------------------------------------------------------------------------------------16 Pharmacodynamics

Pharmacokinetics Label Information -------------------------------------------------------------------------------------------18 Label Design -------------------------------------------------------------------------------------------------19 Post Market Plan --------------------------------------------------------------------------------------------20

  3      

Executive Summary

Necrotizing Fasciitis Background:

Necrotizing fasciitis (NF) is a severe bacterial infection of skin. It is also known as Flesh- eating

infection or Flesh- eating Bacteria syndrome. NF, the name itself, defines the disease condition;

Necrotizing indicates the necrosis-premature death of cells and Fasciitis is indicator for Fascial

planes-bands of connective tissue (Davis, 2014). The infection initiates in the subcutaneous

tissue and spreads through fascial planes causing ample soft tissue destruction. NF can affect in

any part of body- more commonly the arms, legs, and abdominal wall (Davis, 2014) Patients of

NF may experience fever, chills, skin ulceration or necrotic scars on the skin. Although it can

affect people of any age group, any gender and any ethnicity, people with compromised immune

system (i.e. patients of diabetic, cancer, renal impairment or other chronic conditions) are more

prone to develop this infection. (Necrotizing Fasciitis: A Rare disease, especially for healthy,

2013). According to Center for Disease Control, almost 650-800 cases of NF are reported every

year in the United States (Necrotizing Fasciitis: A Rare disease, especially for healthy, 2013).

The mortality for the infection ranges from 20% to as high as 80% (Edlich, 2014). The total

incidents of NF recorded in the United States are less than 200,000; it falls under the category of

rare diseases under 21 CFR 316 (Orphan Drug Act , 2013).

Unmet Medical Need and Rationale for Innovation of Streptomirus

Few years back, surgical removal of the infectious part of body combined with supplemental

high doses of antibiotics was the only available treatment regimen for NF. In 2014, three other

treatments named Dalvance®, Sivextro® and Orbactiv™ got FDA approval for similar skin

infections. All of these treatments help terminating the disease progression but they do not help

curing the damage already caused to the body. These treatments require a prolonged intravenous

  4      

infusion (the longest one is 3 hours of infusion) and they take almost 48 to 72 hours to show any

therapeutic effects, after the administration of first dose. In that case patients will be suffering

from so much difficulties at least for two days even after receiving the treatment. In addition,

these treatments share similar profile of side effects including diarrhea, headache, nausea,

abscesses (limb and subcutaneous), vomiting, tachycardia, and infusion site reactions. In a

nutshell, it is necessary to develop a new, more effective and faster acting drug that is also able

to revert the tissue damage happened during the progression of the disease.

Summary of Streptovancin Development

Streptomirus (Streptovancin), a classical fermentation accidently found by two scientists of

Brigham and Women’s Hospital, was proven safer, faster and more effective treatment of NF in

non-clinical studies. Catalent Pharmaceutical Inc. legally took over all the rights over

Streptovancin and developed it further. In two adequate, well-controlled trials confirmed the

efficacy of Streptomirus and presented it a safer and more effective treatment compared to the

other three available treatments.

Targeted Market

NF is affecting people in many different countries of the world. As Streptomirus was a drug for a

rare disease, it falls under the category of the Orphan drug (Orphan drug act 1984). As all the

patients of NF should be benefited from a significantly advanced treatment, Catalent decided to

launch Streptomirus globally. Catalent prepared for both FDA and EMEA Orphan Drug

Designations simultaneously. The priority was set for US market approval.

Introduction

Necrotizing Fasciitis can be caused by many different bacteria including group A Streptococcus

(group A strep), Klebsiella, Clostridium, E. coli, Staphylococcus aureus, and Aeromonas

  5      

hydrophila (Necrotizing Fasciitis: A Rare disease, especially for healthy, 2013). The most

common cause for NF is Group A Streptococcus bacteria (GAS). The GAS bacteria may enter

human body through an existing cut, lesion, insect bites or followed by a surgery (Necrotizing

Fasciitis (Flesh-Eating Bacteria), 2014). These entry points of bacteria shows signs such as

redness of skin and swelling; subsequent skin changes such as skin ulceration, thin-walled fluid-

filled blisters, black scars, gas formation in tissue and fluid accumulation and draining from the

infection site can occur with the infection progression. In addition, patients may also suffer from

fever and chills. The infection progresses very fast, therefore, early diagnosis and faster

treatment became very necessary. Streptomirus was proven to be safer, faster and more effective

treatment for NF from the analysis of clinical trials and now is approved by FDA for the

treatment of NF as of February 25, 2015.

Company overview

We, Catalent Pharmaceutical Inc. (located at 24 Peachtree Rd., Lexington, MA 02420) are in

high interest of developing treatments for rare diseases. Catalent has its own clinical trial sites,

manufacturing facility and packaging line- all in compliance with ICH guidelines (E6, GCPs)

and FDA regulations (21 CFR 50, 21 CFR 54, 21 CFR 56, 21 CFR 210, 21 CFR 211, 21 CFR

201). All the facilities are registered with FDA. The scientists from Brigham and Women’s

Hospital scheduled a meeting with us in August 2009 to discuss the study results from animal

studies of Streptovancin and request the further development of Streptovancin. After a detailed

review of the animal studies by scientist and microbiology experts, Catalent Pharmaceutical Inc.

agreed to take over the molecule Streptovancin for further development. Catalent took the

complete responsibility to bring Streptovancin to commercial market to benefit the patients of

NF. In order to perform all the necessary process without conflicts, Catalent legally bought all

  6      

the rights over Streptovancin and collected all the animal- testing data from the laboratory of

Brigham and Women’s Hospital.

Product Development Program

As Streptomirus was a treatment for rare disease, Catalent wanted to go global for the launch of

Streptomirus. As Streptomirus was developed as an Orphan drug, no Investigational New Drug

Application (IND) was required but the Orphan Drug Designation (DO A DESIGNATION: FDA

Orphan Drug Workshop, 2011). Catalent started clinical trials soon after the Streptovancin take

over. After observing therapeutic effects results in Phase 2, Catalent required Orphan Drug

Designation. Under the plan of going global, Catalent filed the request for Orphan Drug

Designation with both the OOPD of FDA - under 21 U.S.C. 360bb, FDCA section 506 and 21

CFR Part 316 and EMEA -under (EC) No 141/2000 and (EC) No 847/2000 (COMMON EMEA

/ FDA APPLICATION FOR ORPHAN MEDICINAL PRODUCT DESIGNATION, 2011).

Catalent got both the approval in July, 2013. In EOP2 meeting, Catalent discussed whether

Streptomirus is eligible for priority review. Catalent submitted a request for priority review in

March 2014 and got positive response from FDA. The Priority review NDA application for

Streptomirus was submitted on September 29, 2014 and just received approval letter on February

25, 2015. Catalent is currently deciding the launch date for Streptomirus in USA. It is also

preparing for marketing authorization application from EU simultaneously. Achieving marketing

approvals from Japan, Australia, China and India will be Catalent’s next step.

Non-clinical Studies (Cubist Pharmaceuticals, Inc., 2014) (Durata Therapeutics Inc., 2014)

All the non-clinical studies were done in Chen’s Laboratory at Brigham and Women’s Hospital

with the help of NIH grants. Animals were used in accordance with the National Institutes of

Health's Guide to the Care and Use of Laboratory Animals, and the study was approved by the

  7      

Bingham and Woman’s Hospital Animal Care Committee. Testing was performed on Swiss

Webster mice (in total 200: 3 sets of 50s and 1 set of 50 as control) and Beagles dogs (in total 24:

3 sets of 6 and 1 set of 6 as control).

Microbiology Testing

Mechanism of Action

The antibacterial activities of Streptovancin are caused by binding with the bacterial plasma

ribosome, inhibit protein synthesis process, eliminate the growth factor for GAS and decrease the

toxin production. Streptovancin alter the selective process of the bacterial cell membrane,

preventing toxins from leaving the cell to cause tissue damage. Streptovancin is bacteriostatic

against group A streptococci.

Mechanism of Resistance

The development of bacterial resistant to Streptovancin has not been observed, either in vitro or

in animal infection experiment.

Interaction with other Antimicrobials

Streptovancin showed synergistic interactions with nafcillin when tested in vitro. Streptovancin

did not show synergistic interactions with the following antibacterial agents: linezolid, rifampin

daptomycin, aztreonam, vancomycin, ketoconazole, and levofloxacin. The clinical significance

of these findings is currently unknown.

Acute and Sub chronic toxicity

Increased level of lever enzyme (ALT, AST) was shown in toxicology studies in mice and dogs

when Streptovancin was administered daily for 20-29 days. Splenic B cells level was

significantly decreased in a two-month immunotoxicology study in mice when Streptovancin

was administered at 45mg/kg/day for 15 consecutive days. Hepatocyte necrosis was observed in

  8      

dogs when Streptovancin was administered at 60mg/kg/day for 25 consecutive days. The

relationship between these findings in the animal toxicology studies after 16 and 25 consecutive

dosing days to the indicated clinical dose are unclear. Animal toxicology testing are in

compliances with ICH S4, and 21 CFR part 58.

Genotoxicity

Streptovancin was tested negative in all in vitro tests in mouse bone marrow micronucleus

assays. All Genotoxicity testing were conducted with compliance of ICH S2.

Reproductive toxicology

In a fertility study, Streptovancin had no adverse effects on the fertility at a dose of 24mg/kg/day

in mice. Reduction of fertility in male and female mice were observed at a dose of 48mg/kg/day,

signs of parental toxicity were also observed at this dose. All testing were conducted in

compliances with ICH S5, and 21 CFR part 58.

Drug Interaction

No potential drug interactions were identified. Nonclinical studies demonstrated that

Streptovancin is not a substrate, inhibitor, or inducer for hepatic CYP450 enzymes.

Streptovancin pharmacokinetics was not affected by co-administration with known CYP450

substrates, inducers, or inhibitors, or by individual medications.

Carcinogenicity

Long-term carcinogenesis studies have not been conducted with Streptovancin, in accordance

with ICH S1B.

GLP Statement

Catalent Pharmaceuticals Inc., 24 Peachtree Rd., Lexington, MA 02420, has been inspected by

the FDA and has been found to be in compliance to OECD Principles of Good Laboratory

  9      

Practice (GLP) valid from January 1, 2010 to December 31, 2015. The FDA recognizes and

confirms that the test facility is able to conduct studies in compliance with the OECD principles

of GLP.

Chemistry, Manufacturing, and Controls (Cubist Pharmaceuticals, Inc., 2014) (Durata

Therapeutics Inc., 2014)

The CMC section is to summarize our product and manufacturing method, to demonstrate that

Streptovancin is a safe and effective new drug to treat necrotizing fasciitis caused by GAS. This

section is development in accordance with current GMP guidance by the FDA, also complied

with ICH guideline Q6B, Q7, Q8, Q9, and Q10. Stability testing is done during the

manufacturing process according to 21 CFR 312.23, ICH guideline Q1A (R2), Q5C, and Q1E.

Final product release criteria testing are performed on each lot of product manufactured in

accordance with 21 CFR 211.165.

Drug Substance

The chemical name and Structure of Streptovancin are shown below:

Structure

  10      

Chemical name

4,34-dichloro-26-demethyl-42deoxy-72-O-glucopyranuronosy-6-[(methylundecanoy)propyl]-43-

N-carbamoy-3 oxxoxazolidin-8-methyl-tetrachlorophosphate-5-Benzodiaciglucan-37

hydrochloride

Chemical Formula and Molecular Weight

C162H206O26N17Cl11P, 3220 g/mol

Physical Description

Streptovancin is a crystal white powder; it has a sweet and fruity odor, odor threshold is

6,42PPM. The taste threshold in water is 70 mg/l. It has a density of 16.4g/cm3, boiling point at

32oC, and a melting point at 152oC.

Drug Substance Manufacturing

Catalent Pharmaceuticals, Inc. is the manufacturer of Streptovancin. Catalent Pharmaceuticals is

functioning in compliance with current GMP guidance published by the FDA, and ICH Q7.

Streptovancin is a product from fermentation of the N. vaccinii species of the Streptococcus

bacteria. N. vaccinii is a plant pathogen; they were collected from blueberry plants in the wild,

screened, identified, and sterile by the scientist, then cultivated in the manufacturing facility.

Once the bacteria are collected, a fermentation process is done by mixing the bacteria with

alcohol and 78% concentration of CO2, then store in a fermentation box with a constant

temperature of 140oF (60oC) for 5 days. After the fermentation period, we have a sterilization

process, and then we have our product, Streptovancin. The harvesting stage takes approximately

10 days, including the collection of the bacteria and the fermentation process.

Drug Product

  11      

The finished dosage form of Streptovancin is a sterile white powder, Edetate disodium (EDTA)

and sodium hydroxide is added with Streptovancin in the package to pH adjustment.

Drug Product Manufacturing

After collecting the Streptovancin, Edetate disodium (EDTA) and sodium hydroxide is added to

the mixture, then sterilized with Ethylene oxide before individual packaging. For every 40 mg of

Streptovancin, 1.5 mg of EDTA and 0.4 mg of sodium hydroxide is added for pH adjustment.

Every vial of Streptomirus contains a total of 41.9 mg of Streptovancin mixture.

Environmental Impact Analysis Report

In accordance with Guidance for Industry: Environmental Assessment of Human Drugs and

Biologics Applications, Catalent Pharmaceuticals Inc. has filed an NDA pursuant to section

505(b) of the Federal Food, Drug, and Cosmetic Act for Streptomirus (Streptovancin), 40 mg,

packaged in single-use vials. An EA has been submitted in pursuant to 21 CFR part 25.

Streptomirus is treatment drug for necrotizing fasciitis; it is intended to be used in hospitals and

clinics by healthcare professionals, disposal methods for Streptomirus are determined by the end

users’ policy for drug product.

Packaging Establishment

Packaging – Content, Quality, and Net Weight

Each box of Streptomirus contains 12 vials of Streptovancin; each vial includes 41.9 mg of

Streptovancin mixture (equivalent to 40 mg of Streptovancin). The net weight of the one

Streptomirus box is 760g.

Shelf Life

The shelf life for Streptomirus is two years in original package.

Container Closure System

  12      

Streptovancin are stored and sealed in single dose glass fliptop vials after production to prevent

contamination. The fliptop vials have three layer of protection: rubber seal with the glass

container, an aluminum foil layer on top, then the plastic fliptop lid. To open the vial, first

remove the plastic lid, it will peel off the center of the aluminum foil, thus exposing the rubber

seal for needle puncture.

Storage Condition

Unreconstituted Streptomirus (Streptovancin) should be stored at 25oC (77oF); excursions

permitted to 15 to 30oC (59 to 86oF). Package should avoid prolong exposure to direct sunlight.

Streptomirus should not be stored in areas that are higher than 60% in humidity.

IND Waiver and Requirement for Orphan Drug Designation

Catalent was not required to submit an IND application as Streptovancin was to be developed as

Orphan drug and all the clinical trials were conducted within borders of Massachusetts. Even

though IND submission was not required, it did not change other standard protocols and

regulations for clinical research and NDA submission. Catalent was required to request for

Orphan Drug Designation under 21 CFR 316 before the marketing approval. According to 21

CFR 316.20 and 21 CFR 316.21, Orphan Drug Designation request includes some clinical safety

and efficacy data; Catalent waited to get some data from Phase 2 trials.

Under the plan of going global, Catalent filed the request for Orphan Drug Designation with both

the OOPD of FDA - under 21 U.S.C. 360bb, FDCA section 506 and 21 CFR Part 316 and

EMEA -under (EC) No 141/2000 and (EC) No 847/2000 (COMMON EMEA / FDA

APPLICATION FOR ORPHAN MEDICINAL PRODUCT DESIGNATION, 2011). Catalent

got both the approval in July, 2013.

  13      

Clinical Trials

All the clinical trials were performed at Catalent’s clinical sites, it was Catalent’s primary

responsibility to protect the rights, safety and welfare of the subjects participating in clinical trial

under 21 CFR 312.50. Catalent submitted the clinical study protocol, Informed Consent Forms

and Investigator’s Brochure to the IRB (following all the regulations under 21 CFR 56) for

review. Catalent did not start the subject enrollment until the study protocol got IRB approval

(21 CFR 312.50). Informed Consent Forms were explained in detail to the participants of the

clinical trials; participants were given sufficient time to discuss with family member before

signing the ICFs. Signed ICFs were collected before any clinical study and submitted to

following the 21 CFR 50 Subpart B. Catalent also examined whether all the investigators

involved in clinical study were adequately qualified and certified (21 CFR 312.50). All the

investigators had to sign Form FDA 1572 for the financial disclosures before the end of clinical

trials, the Forms were submitted to FDA (21 CFR 54.4). All clinical trial information and the

SAEs were recorded in accordance with 21 CFR 312.60. Everything was performed in

compliance with ICH guideline M3 (R2) and E6.

Phase I

Phase 1 clinical trials were performed under ICH guidelines M3 (R2) and E6, 21 CFR 50, 21

CFR 54, 21 CFR 56.

Total of 56 [45 Adults (Age 21 to 45) and 11 geriatric patients (age 65 and over)] Healthy

volunteers were tested for acute and repeated dose toxicity for 10 consecutive days with a

maximum daily dose of 300mg. The reasons behind choosing geriatric patients were: (1) they

represent a larger part of US population and most of them have compromised immune system,

ultimately they are more susceptible for NF. (2) Most of the geriatric patients are already on

  14      

other medication for chronic diseases such as diabetes, hypertension, and rheumatoid arthritis; by

enrolling them in clinical studies, drug-drug interactions could be studied passively, if any.

Results: The No Observed Adverse Effect Level (NOAEL) observed at 240mg per day. Minor

metabolites of Streptovancin found in Urine of all volunteers. Nausea, vomiting and minor

dizziness were observed in 90% of patients but no other significant adverse reactions were

recorded. Streptovancin showed sufficient results to prove the safety of the drug in healthy

Volunteers.

Patient enrollment details for Phase II and Phase III trials are shown in Table 1.

Table 1. Patient enrollment details for Phase II and Phase III trials Phase of clinical trial Phase II Phase III Study Design Randomized Adequate, well-controlled Total Enrollment 220 1614 Eligibility criteria Inclusion criteria:

Diagnosis of Necrotizing Fasciitis Age ranged from 21 to 75 Exclusion criteria: Pregnancy Severe systemic disease

Inclusion criteria: Diagnosis of Necrotizing Fasciitis Age ranged from 21 to 75 Exclusion criteria: Pregnancy Severe systemic disease

Gender Both (125 men, 95 women) Both (887 men, 727 women) Age 21 to 75 21 to 75 Ethnicity: Caucasian African American Asian Hispanic/ Latino

198 7 15 0

1253 87 239 35

Phase II

Phase II Clinical trials were performed in compliance with ICH Guideline E4, E6 and E8.

In two randomized trials, 110 patients were tested for single-dose (IV injection) toxicity studies

and 110 patients were tested for multi-dose regimen (IV injection) with total dose ranging from

  15      

200mg to no greater than 300mg per day at different time intervals. The efficacy endpoint was to

study no increase in the skin lesion in the patients of Necrotizing Fasciitis.

Results: The patients who were administered with multi-dose regimen of Streptovancin showed

better results; no increase in skin lesion was observed after 25-29 hours. The patients with single-

dose administration showed a little increase in skin lesion after 15 hours of administration.

Higher percentage of adverse events of nausea, dizziness, diarrhea and vomiting were observed

as side effects of Streptovancin. Blurred vision was observed in some patients.

Phase III

This clinical trial was performed under ICH Guidelines E4, E6, E8, E9, and E10. Dose selection

was done in compliance with ICH guideline S1C (R2).

Two adequate, well-controlled trials were performed; 941 patients were treated with

Streptovancin and 673 patients were treated with comparison treatment of Sivextro, Dalvance

and Orbactiv. The primary endpoint of the study was to see no increase in the skin lesion after

the first day and the secondary endpoint was to observe 30% decrease in skin lesions.

Results: Best dosing regimen analyzed was IV injection of 40mg of Streptovancin, every 4 hours

for a day followed by 40mg of Streptovancin IV injection twice a day for 3 days. No increase in

skin lesion after first day and 35%-40% decrease in skin lesions after 48-55 hours depending on

the severity were observed.

During the entire clinical study, 2 patients withdrawal from adverse events (extreme vomiting

and diarrhea) from Streptovancin were recorded and 7 patients dropped from the side effects of

comparative treatments. Follow-up with those patients was performed according to ICH E6.

  16      

Clinical Pharmacology (Cubist Pharmaceuticals, Inc., 2014) (Durata Therapeutics Inc., 2014)

Pharmacokinetics

Streptovancin pharmacokinetic parameters have been characterized in healthy subjects and

patients. All testing were conducted in compliance with ICH S7A. Pharmacokinetic parameters

following administration of Streptovancin following intravenous administration of 40mg every 4

hours for the first 24 hours are shown in Table 2.

Table 2. Mean (Standard Deviation) Streptovancin Pharmacokinetic Parameters Following Multiple Intravenous Administration of 40mg Every 4 hours For the First 24 Hours Pharmacokinetic Parameters of Streptovancinv

Intravenous Injection Steady State

Cmax (mcg/mL) 3.5 (0.8) Tmax (hr)✚ 2.5 (1.0-8.5) AUC (mc�hr/mL)¤ 30.2 (7.4) CL or CL/F (L/hr) 7.3 (3.5) v Cmax, maximum concentration; Tmax, time to reach Cmax; AUC, area under the concentration-time curve; CL, systemic clearance; CL/F, apparent oral clearance ✚ Median (range) ¤ AUC is AUC0-∞ (AUC from time 0 to infinity) for first day doses administration and AUC0-24 (AUC from time 0 to 24 hours) for multiple-dose administration Absorption

Peak concentration reached at the end of the first intravenous injection of Streptovancin.

Concentration-time profile suggested one does of 40mg every 4 hours for the first 24 hours,

followed by 40mg twice a day for 3 days. Streptovancin is formulated for intravenous injection;

the bioavailability for this administration is 100%.

Distribution

Streptovancin is reversibly bound to human plasma proteins, approximately 93-97%. The mean

steady state volume of distribution of Streptovancin in healthy adults following six doses 40mg

injection ranged from 75 to 87 L (approximately twice total body water). The mean

  17      

concentrations of Streptovancin achieved in skin blister fluid remain above 25mg/L up to 4 days

post dose.

Metabolism

A minor metabolite of Streptovancin (benzozolin) was observed in the urine of healthy subjects.

There was no degradation of Streptovancin observed in human liver microsomes; Streptovancin

is not a substrate, inhibitor, or inducer for hepatic CYP450 enzymes. No other significant

circulating metabolites were found in humans.

Excretion

Following administration of 40mg of Streptovancin every 4 hours for the first 24 hours in

healthy subjects, 60% of the doses were eliminated via the liver, 25% of the doses were excreted

in urine. Most of the elimination process occurs within 104 hours after injection.

Pharmacodynamics

The antibacterial activity of Streptovancin appears to best correlate with the ratio of area under

the concentration-time curve to minimal inhibitory concentration (AUC/MIC) for Group A

Streptococcus based on animal models of infection. An exposure-response analysis of a single

study in patients with complicated skin and skin structure infections supports the 40mg per dose,

12 continuous doses regimen. All testing were conducted with compliance of ICH S7A and ICH

M3.

Cardiac  Electrophysiology  

In   a   randomized,   positive-­‐   and   placebo-­‐controlled   crossover   thorough  QT/QTc   study,   56  

enrolled   healthy   subjects   received   a   therapeutic   dose   of   Streptovancin   240mg,  

supratherapeutic   dose   of   Streptovancin   300mg,   and   placebo.   No   significant   effects   of  

  18      

Streptovancin  on  heart  rate  or  electrocardiogram  morphology  were  shown.  Streptovancin  

does  not  have  any  clinical  relevant  adverse  effect  on  cardiac  repolarization.  

Label information (Cubist Pharmaceuticals, Inc., 2014) (Durata Therapeutics Inc., 2014)

 

  19      

Label Design Principal Display Panel NDC 01869-040-01 Streptomirus (Streptovancin) for injection 40 mg per vial For Intravenous Injection Only Sterile Single Dose Vial 12 Vials    

  20      

Post Market Plans

No pediatric study was performed because Streptomirus, being an Orphan Drug, is exempt from

the pediatric study according to the regulation of PREA.

All the data collection extent will be decided with the help of FDA Draft Guidance: Guidance for

Industry: Determining the Extent of Safety Data Collection Needed in Late Stage Premarket and

Postapproval Clinical Investigations, published in February 2010.

Adverse events will be reported to MedWatch by physicians and the general public under 21

CFR 314.80 and 21 CFR 314.81.

We are about to submit marketing approval application for EU; we are also planning to get

marketing approval from Japan, China, India, and Australia.

  21      

References  COMMON  EMEA  /  FDA  APPLICATION  FOR  ORPHAN  MEDICINAL  PRODUCT  DESIGNATION.  (2011,  11).  Retrieved  from  FDA:  http://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=2&cad=rja&uact=8&ved=0CCUQFjAB&url=http%3A%2F%2Fwww.fda.gov%2Fdownloads%2FAboutFDA%2FReportsManualsForms%2FForms%2FUCM048361.pdf&ei=yfAJVcori9GCBIf3gbAC&usg=AFQjCNECHsLs7hGXz_ASXLxn-­‐Un4upqb4Q&si  

Cubist  Pharmaceuticals,  Inc.  (2014,  August).  HIGHLIGHTS  OF  PRESCRIBING  INFORMATION.  Retrieved  February  23,  2015,  from  U.S.  Food  and  Drug  Administration:  http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205435s000lbl.pdf  

Davis,  C.  P.  (2014,  12  22).  Necrotizing  Fasciitis  (Flesh-­‐  Eating  Disease)  .  Retrieved  from  MedicineNet.com:  http://www.medicinenet.com/necrotizing_fasciitis/article.htm  

DO  A  DESIGNATION:  FDA  Orphan  Drug  Workshop.  (2011,  11  2).  Retrieved  from  FDA:  http://www.fda.gov/downloads/ForIndustry/DevelopingProductsforRareDiseasesConditions/UCM215487.pdf  

Durata  Therapeutics  Inc.  (2014,  June).  HIGHLIGHTS  OF  PRESCRIBING  INFORMATION.  Retrieved  February  23,  2015,  from  U.S.  Food  and  Drug  Administration:  http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021883s000lbl.pdf  

Edlich,  R.  F.  (2014,  12  19).  Necrotizing  Fasciitis.  Retrieved  from  Medscape.com:  http://www.emedicinehealth.com/necrotizing_fasciitis/article_em.htm  

Necrotizing  Fasciitis  (Flesh-­‐Eating  Bacteria).  (2014,  July  10).  Retrieved  from  WebMD:  http://www.webmd.com/skin-­‐problems-­‐and-­‐treatments/necrotizing-­‐fasciitis-­‐flesh-­‐eating-­‐bacteria  

Necrotizing  Fasciitis:  A  Rare  disease,  especially  for  healthy.  (2013,  June  28).  Retrieved  from  Center  for  Disease  Control  and  Prevention:  http://www.cdc.gov/features/necrotizingfasciitis/  

Orphan  Drug  Act  .  (2013,  07  18).  Retrieved  from  FDA:  http://www.fda.gov/regulatoryinformation/legislation/federalfooddrugandcosmeticactfdcact/significantamendmentstothefdcact/orphandrugact/default.htm  

Reese,  J.  H.  (2014,  March  10).  FDA  Orphan  Drug  Designation  101.  Retrieved  March  18,  2015,  from  U.S.  Food  and  Drug  Administration:  http://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=9&ved=0CFMQFjAI&url=http%3A%2F%2Fwww.ema.europa.eu%2Fdocs%2Fen_GB%2Fdocument_library%2FPresentation%2F2014%2F03%2FWC500164160.pdf&ei=awkKVYvDCImfNo7Gg4gD&usg=AFQjCNFKfHw_jQ1CO3HL7j1J-­‐YNXMQ9Jlw&sig2=YeX8YRBPFK2VpAoiyjIj3A&bvm=bv.88528373,d.eXY