Sivextro tablet, film coated; lyophilized powder for injection

Acute Bacterial Skin and Skin Structure Infections

Sivextro® is an oxazolidinone-class antibacterial indicated for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of the following Gram-positive microorganisms: Staphylococcus aureus (including methicillin-resistant [MRSA] and methicillin-susceptible [MSSA] isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus Group (including Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus), and Enterococcus faecalis.

Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Sivextro and other antibacterial drugs, Sivextro should be used only to treat ABSSSI that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

None

Orally administered Sivextro inhibits Breast Cancer Resistance Protein (BCRP) in the intestine, which can increase the plasma concentrations of orally administered BCRP substrates, and the potential for adverse reactions. If possible, an interruption in the treatment of the co-administered BCRP substrate medicinal product should be considered during treatment with Sivextro, especially for BCRP substrates with a narrow therapeutic index (e.g., methotrexate or topotecan). If coadministration cannot be avoided, monitor for adverse reactions related to the concomitantly administered BCRP substrates, including rosuvastatin. [See Clinical Pharmacology (12.3).]

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity studies have not been conducted with tedizolid phosphate.

Tedizolid phosphate was negative for genotoxicity in all in vitro assays (bacterial reverse mutation (Ames), Chinese hamster lung (CHL) cell chromosomal aberration) and in all in vivo tests (mouse bone marrow micronucleus, rat liver unscheduled DNA synthesis). Tedizolid, generated from tedizolid phosphate after metabolic activation (in vitro and in vivo), was also tested for genotoxicity. Tedizolid was positive in an in vitro CHL cell chromosomal aberration assay, but negative for genotoxicity in other in vitro assays (Ames, mouse lymphoma mutagenicity) and in vivo in a mouse bone marrow micronucleus assay.

In a fertility study, oral tedizolid phosphate had no adverse effects on the fertility or reproductive performance, including spermatogenesis, of male rats at the maximum tested dose (50 mg/kg/day) with a plasma tedizolid AUC approximately 5-fold greater than the plasma AUC value in humans at the oral therapeutic dose. Tedizolid phosphate also had no adverse effects on the fertility or reproductive performance of adult female rats at doses up to the maximum tested (15 mg/kg/day). Plasma tedizolid exposure (AUC) at this NOAEL in female rats was approximately 4-fold higher than that in humans at the oral therapeutic dose.

Animal Toxicology and/or Pharmacology

Repeated-oral and intravenous dosing of tedizolid phosphate in rats in 1-month and 3-month toxicology studies produced dose- and time-dependent bone marrow hypocellularity (myeloid, erythroid, and megakaryocyte), with associated reduction in circulating RBCs, WBCs, and platelets. These effects showed evidence of reversibility and occurred at plasma tedizolid exposure levels (AUC) ≥6-fold greater than the plasma exposure associated with the human therapeutic dose. In a 1-month immunotoxicology study in rats, repeated oral dosing of tedizolid phosphate was shown to significantly reduce splenic B cells and T cells and reduce plasma IgG titers. These effects occurred at plasma tedizolid exposure levels (AUC) ≥3-fold greater than the expected human plasma exposure associated with the therapeutic dose.

Acute Bacterial Skin and Skin Structure Infections

A total of 1333 adults with acute bacterial skin and skin structure infections (ABSSSI) were randomized in two multicenter, multinational, double-blind, non-inferiority trials. Both trials compared Sivextro 200 mg once daily for 6 days versus linezolid 600 mg every 12 hours for 10 days. In Trial 1, patients were treated with oral therapy, while in Trial 2, patients could receive oral therapy after a minimum of one day of intravenous therapy. Patients with cellulitis/erysipelas, major cutaneous abscess, or wound infection were enrolled in the trials. Patients with wound infections could have received aztreonam and/or metronidazole as adjunctive therapy for gram-negative bacterial coverage, if needed. The intent-to-treat (ITT) patient population included all randomized patients.

In Trial 1, 332 patients with ABSSSI were randomized to Sivextro and 335 patients were randomized to linezolid. The majority (91%) of patients treated with Sivextro in Trial 1 were less than 65 years old with a median age of 43 years (range: 18 to 86 years). Patients treated with Sivextro were predominantly male (61%) and White (84%); 13% had BMI ≥35 kg/m2, 8% had diabetes mellitus, 35% were current or recent intravenous drug users, and 2% had moderate to severe renal impairment. The overall median surface area of infection was 188 cm2. The types of ABSSSI included were cellulitis/erysipelas (41%), wound infection (29%), and major cutaneous abscess (30%). In addition to local signs and symptoms of infection, patients were also required to have at least one regional or systemic sign of infection at baseline, defined as lymphadenopathy (87% of patients), temperature 38°C or higher (16% of patients), white blood cell count greater than 10,000 cells/mm3 or less than 4000 cells/mm3 (42%), or 10% or more band forms on white blood cell differential (4%).

The primary endpoint in Trial 1 was early clinical response defined as no increase from baseline lesion area at 48-72 hours after the first dose and oral temperature of ≤37.6°C, confirmed by a second temperature measurement within 24 hours in the ITT population.

In Trial 2, 332 patients with ABSSSI were randomized to Sivextro and 334 patients were randomized to linezolid. The majority (87%) of patients treated with Sivextro in Trial 2 were less than 65 years old with a median age of 46 years (range: 17 to 86 years). Patients treated with Sivextro were predominantly male (68%) and White (86%); 16% had BMI ≥35 kg/m2, 10% had diabetes mellitus, 20% were current or recent intravenous drug users, and 4% had moderate to severe renal impairment. The overall median surface area of infection was 231 cm2. The types of ABSSSI included were cellulitis/erysipelas (50%), wound infection (30%), and major cutaneous abscess (20%). In addition to local signs and symptoms of infection, patients were also required to have at least one regional or systemic sign of infection at baseline, defined as lymphadenopathy (71% of patients), temperature 38°C or higher (31% of patients), white blood cell count greater than 10,000 cells/mm3 or less than 4000 cells/mm3 (53%), or 10% or more band forms on white blood cell differential (16%).

The primary endpoint in Trial 2 was early clinical response defined as at least a 20% decrease from baseline lesion area at 48-72 hours after the first dose in the ITT population (Table 7).

An investigator assessment of clinical response was made at the post-therapy evaluation (PTE) (7 - 14 days after the end of therapy) in the ITT and CE (Clinically Evaluable) populations. Clinical success was defined as resolution or near resolution of most disease-specific signs and symptoms, absence or near resolution of systemic signs of infection if present at baseline (lymphadenopathy, fever, >10% immature neutrophils, abnormal WBC count), and no new signs, symptoms, or complications attributable to the ABSSSI requiring further treatment of the primary lesion (Table 8).

Clinical success by baseline pathogens from the primary infection site or blood cultures for the microbiological intent-to-treat (MITT) patient population for two integrated Phase 3 ABSSSI studies are presented in Table 9 and Table 10.

Baseline bacteremia in the tedizolid arm with relevant pathogens included two subjects with MRSA, four subjects with MSSA, two subjects with S. pyogenes, one subject with S. agalactiae, and one subject with S. constellatus. All of these subjects were Responders at the 48-72 hour evaluation. At the Post-therapy Evaluation (PTE), 8 of 10 subjects were considered clinical successes.

Baseline bacteremia in the tedizolid arm with relevant pathogens included two subjects with MRSA, four subjects with MSSA, two subjects with S. pyogenes, one subject with S. agalactiae, and one subject with S. constellatus. All of these subjects were Responders at the 48-72 hour evaluation. At the Post-therapy Evaluation (PTE) 8 of 10 subjects were considered clinical successes.

Administration with Food

Patients should be informed that Sivextro tablets may be taken with or without food and without any dietary restrictions [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].

Usage Safeguards

Patients should be advised that antibacterial drugs including Sivextro should only be used to treat bacterial infections. Sivextro does not treat viral infections (e.g., the common cold). When Sivextro is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Sivextro or other antibacterial drugs in the future [see Indications and Usage (1.2)].

Patients should be informed that if they miss a dose, they should take the dose as soon as possible anytime up to 8 hours prior to their next scheduled dose. If less than 8 hours remains before the next dose, then they should wait until their next scheduled dose. Patients should take the prescribed number of doses [see Dosage and Administration (2.1)].

Keep Sivextro and all medications out of reach of children.

Potentially Serious Adverse Reactions

Patients should be advised that diarrhea is a common problem caused by antibacterial drugs including Sivextro and usually resolves when the drug is discontinued. Sometimes after starting treatment with antibiotics, patients can develop frequent watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic and may be a sign of a more serious intestinal infection [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)]. If this occurs, patients should contact their healthcare provider as soon as possible.

Manuf. for: Merck Sharp & Dohme Corp., a subsidiary of
MERCK & CO., INC., Whitehouse Station, NJ 08889, USA

Sivextro tablets
Manufactured by: Patheon Inc.
Whitby, Ontario, L1N 5Z5 Canada

Sivextro for injection
Manufactured by: Patheon Italia S.p.A.
03013, Ferentino, FR Italy

For patent information: www.merck.com/product/patent/home.html

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