Merck (NYSE: MRK), known as MSD outside the United States and
Canada, today announced the U.S. Food and Drug Administration (FDA)
has approved a New Drug Application (NDA) for DIFICID®
(fidaxomicin) for oral suspension, and a supplemental New Drug
Application (sNDA) for DIFICID tablets for the treatment of
Clostridioides (formerly Clostridium) difficile-associated diarrhea
(CDAD) in children aged six months and older.1
DIFICID is a macrolide antibacterial medicine indicated in
adults and pediatric patients aged 6 months and older for treatment
of CDAD. To reduce the development of drug-resistant bacteria and
maintain the effectiveness of DIFICID and other antibacterial
drugs, DIFICID should be used only to treat infections that are
proven or strongly suspected to be caused by Clostridioides
difficile (C. difficile). DIFICID is contraindicated in patients
who have known hypersensitivity to fidaxomicin or any other
ingredient in DIFICID. DIFICID should only be used for the
treatment of CDAD. DIFICID is not expected to be effective for
treatment of other types of infections due to minimal systemic
absorption of fidaxomicin.
“C. difficile is an important cause of health care- and
community-associated diarrheal illness in children, and sustained
cure is difficult to achieve in some patients. The fidaxomicin
pediatric trial was the first randomized controlled trial of C.
difficile infection treatment in children,” said Dr. Larry K.
Kociolek, Associate Medical Director of Infection Prevention and
Control at Ann & Robert H. Lurie Children’s Hospital of
Chicago. “I am very excited to have a new C. difficile infection
treatment option for my pediatric patients.”
“Merck is committed to developing new treatments, as well as
expanding indications of existing ones, in order to provide more
solutions to treat infectious diseases, particularly among
children,” said Dr. Nicholas Kartsonis, senior vice president,
clinical research, infectious diseases and vaccines, Merck Research
Laboratories. “C. difficile infection is an urgent public health
challenge. We are grateful to the health care practitioners, the
patients and their families for their invaluable contributions in
helping to bring this new pediatric indication and the oral
suspension formulation for DIFICID to the U.S. market.”
Both applications received a priority review classification by
the FDA. The investigational pediatric indication for DIFICID was
granted Orphan Drug Designation in 2010.
Data Supporting the Approval of DIFICID in Pediatric
Patients
The FDA’s approval of the new formulation and new indication for
DIFICID was based on a Phase 3, multicenter, investigator-blind,
randomized, parallel group study (known as the SUNSHINE study,
NCT02218372), in which the safety and efficacy of fidaxomicin was
evaluated in pediatric patients from 6 months to less than 18 years
of age (one patient was less than six months of age). This study,
sponsored by Astellas Pharma Europe B.V. (with Merck & Co.,
Inc. as collaborator) included 148 randomized patients aged <18
years with confirmed CDI, of whom 142 received either fidaxomicin
(suspension or tablets, twice daily) or vancomycin (suspension or
tablets, four times daily) in a 2:1 ratio. Patients were randomized
by age group, as follows: 30 patients from 6 months to <2 years;
49 patients age 2 to <6 years, 40 patients age 6 to <12 years
and 29 patients age 12 to <18 years. Generally, the two
treatment groups were balanced regarding demographics and other
baseline characteristics. CDAD clinical response in the overall
pediatric population, assessed through two days following 10 days
of treatment, was similar between the fidaxomicin and vancomycin
groups (77.6% vs. 70.5% with a 95% CI for the treatment difference
of 7.5 [-7.4%, 23.9%]). Sustained clinical response, defined as the
proportion of treated patients with confirmed clinical response and
no CDAD recurrence through 30 days after the end of treatment, was
higher for fidaxomicin than for vancomycin (68.4% vs. 50.0% with a
95% CI for the treatment difference of 18.4 [1.5%, 35.3%]).
The safety of DIFICID in pediatric patients 6 months to less
than 18 years of age was evaluated in a Phase 2 single-arm trial in
38 patients and a Phase 3 randomized, active-controlled trial in 98
patients treated with DIFICID and 44 patients treated with
vancomycin. Treatment discontinuation due to adverse reactions
occurred in 7.9% (3/38) of patients in the Phase 2 trial, and in 1%
(1/98) and 2.3% (1/44) of DIFICID- and vancomycin-treated patients,
respectively, in the Phase 3 trial. The most common selected
adverse reactions occurring in ≥5% of pediatric patients treated
with DIFICID in the Phase 3 trial were pyrexia (13.3%), abdominal
pain (8.2%), vomiting (7.1%), diarrhea (7.1%), constipation (5.1%),
increased aminotransferases (5.1%) and rash (5.1%). One death
occurred in the Phase 2 single-arm trial and three deaths occurred
in the Phase 3 trial of DIFICID-treated patients. No deaths
occurred in vancomycin-treated patients during the study period (40
days). All deaths occurred in patients less than 2 years of age and
appeared to be related to underlying comorbidities.
About Clostridioides difficile
Clostridioides (formerly Clostridium) difficile, also known as
C. difficile or C. diff, is one of the most common causes of health
care-associated infections in U.S. hospitals.2 Recent estimates
suggest C. difficile causes almost 500,000 infections annually in
the United States and is associated with approximately 29,000
deaths within 30 days of initial diagnosis.3 According to the CDC’s
Antibiotic Resistance Threats in the United States, 2019 (2019 AR
Threats Report), C. difficile is categorized as an urgent threat
and is stated as a public health threat that requires urgent and
aggressive action.4
Important Safety Information about DIFICID
(fidaxomicin)
DIFICID is contraindicated in patients who have known
hypersensitivity to fidaxomicin or any other ingredient in
DIFICID.
Acute hypersensitivity reactions, including dyspnea, rash,
pruritus, and angeioedema of the mouth, throat and face have been
reported with DIFICID. If a severe hypersensitivity reaction
occurs, DIFICID should be discontinued and appropriate therapy
should be instituted.
DIFICID is not expected to be effective for the treatment of
other types of infections due to minimal systematic absorption of
fidaxomicin. DIFICID has not been studied for the treatment of
infections other than CDAD. DIFICID should only be used for the
treatment of CDAD.
Only use DIFICID for infection proven or strongly suspected to
be caused by C. difficile. Prescribing DIFICID in the absence of a
proven or strongly suspected C. difficile infection is unlikely to
provide benefit to the patient and increases the risk of
development of drug-resistant bacteria.
The most common adverse reactions reported in adults are nausea
(11%), vomiting (7%), abdominal pain (6%), gastrointestinal
hemorrhage (4%), anemia (2%) and neutropenia (2%).
The most common adverse reactions in pediatric patients are
pyrexia (13.3%), abdominal pain (8.2%), vomiting (7.1%), diarrhea
(7.1%), constipation (5.1%), increased aminotransferases (5.1%) and
rash (5.1%).
Among patients receiving DIFICID (fidaxomicin), 33 (5.9%)
withdrew from trials as a result of adverse reactions. Vomiting was
the primary adverse reaction leading to discontinuation of dosing
(incidence of 0.5% for both DIFICID and vancomycin patients).
The safety and effectiveness of DIFICID have not been
established in pediatric patients younger than 6 months of age.
The recommended dose for adults is one 200 mg DIFICID tablet
orally twice daily for 10 days, with or without food.
The recommended dose for pediatric patients weighing at least
12.5 kg and able to swallow tablets is one 200 mg DIFICID tablet
administered orally twice daily for 10 days. If unable to swallow
tablets, pediatric patients may be dosed with DIFICID oral
suspension based on weight. DIFICID oral suspension should be
administered orally twice daily for 10 days.
No dose adjustment is recommended for patients 65 years of age
or older.
No dose adjustment is recommended for patients with renal
impairment.
No dosage adjustments are recommended when co-administering
DIFICID with substrates of P-gp or CYP enzymes.
The impact of hepatic impairment on the pharmacokinetics of
DIFICID has not been evaluated; however, because DIFICID and its
active metabolite (OP-1118) do not appear to undergo significant
hepatic metabolism, elimination of DIFICID and OP-1118 is not
expected to be significantly affected by hepatic impairment.
About Merck
For more than a century, Merck, a leading global
biopharmaceutical company known as MSD outside of the United States
and Canada, has been inventing for life, bringing forward medicines
and vaccines for many of the world’s most challenging diseases.
Through our prescription medicines, vaccines, biologic therapies
and animal health products, we work with customers and operate in
more than 140 countries to deliver innovative health solutions. We
also demonstrate our commitment to increasing access to health care
through far-reaching policies, programs and partnerships. Today,
Merck continues to be at the forefront of research to advance the
prevention and treatment of diseases that threaten people and
communities around the world - including cancer, cardio-metabolic
diseases, emerging animal diseases, Alzheimer’s disease and
infectious diseases including HIV and Ebola. For more information,
visit www.merck.com and connect with us on Twitter, Facebook,
Instagram, YouTube and LinkedIn.
Forward-Looking Statement of Merck & Co., Inc.,
Kenilworth, N.J., USA
This news release of Merck & Co., Inc., Kenilworth, N.J.,
USA (the “company”) includes “forward-looking statements” within
the meaning of the safe harbor provisions of the U.S. Private
Securities Litigation Reform Act of 1995. These statements are
based upon the current beliefs and expectations of the company’s
management and are subject to significant risks and uncertainties.
There can be no guarantees with respect to pipeline products that
the products will receive the necessary regulatory approvals or
that they will prove to be commercially successful. If underlying
assumptions prove inaccurate or risks or uncertainties materialize,
actual results may differ materially from those set forth in the
forward-looking statements.
Risks and uncertainties include but are not limited to, general
industry conditions and competition; general economic factors,
including interest rate and currency exchange rate fluctuations;
the impact of pharmaceutical industry regulation and health care
legislation in the United States and internationally; global trends
toward health care cost containment; technological advances, new
products and patents attained by competitors; challenges inherent
in new product development, including obtaining regulatory
approval; the company’s ability to accurately predict future market
conditions; manufacturing difficulties or delays; financial
instability of international economies and sovereign risk;
dependence on the effectiveness of the company’s patents and other
protections for innovative products; and the exposure to
litigation, including patent litigation, and/or regulatory
actions.
The company undertakes no obligation to publicly update any
forward-looking statement, whether as a result of new information,
future events or otherwise. Additional factors that could cause
results to differ materially from those described in the
forward-looking statements can be found in the company’s 2018
Annual Report on Form 10-K and the company’s other filings with the
Securities and Exchange Commission (SEC) available at the SEC’s
Internet site (www.sec.gov).
Please see U.S. Prescribing Information for DIFICID
(fidaxomicin) at
https://www.merck.com/product/usa/pi_circulars/d/dificid/dificid_pi.pdf,
and Patient Information for DIFICID (fidaxomicin) at
https://www.merck.com/product/usa/pi_circulars/d/dificid/dificid_ppi.pdf.
1 DIFICID in the US and Canada is a trademark of Cubist
Pharmaceuticals LLC, an indirect wholly-owned subsidiary of Merck
Sharp & Dohme Corp.
2 Lessa, Fernanda. “Burden of Clostridium difficile Infection in
the United States.” The New England Journal of Medicine, vol. 372,
Feb. 2015, pp.825-834.
3 Ibid.
4 “Antibiotic Resistance Threats in the United States, 2019.”
U.S. Centers for Disease Control and Prevention, 2019, p. 65.
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