Prescription Drug Information: SIVEXTRO

SIVEXTRO- tedizolid phosphate tablet, film coated
SIVEXTRO- tedizolid phosphate injection, powder, lyophilized, for solution
Nabriva Therapeutics US, Inc.

1 INDICATIONS AND USAGE

1.1 Acute Bacterial Skin and Skin Structure Infections

SIVEXTRO® is an oxazolidinone-class antibacterial indicated in adult and pediatric patients 12 years of age and older 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 .

1.2 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.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

The recommended dosage of SIVEXTRO is 200 mg administered once daily for six (6) days either orally (with or without food) or as an intravenous (IV) infusion in patients 12 years of age or older.

The recommended dosage and administration of SIVEXTRO are described in Table 1.

Table 1: Dosage of SIVEXTRO
Infection Route Dosage Frequency Infusion Time Duration of Treatment
Acute Bacterial Skin and Skin Structure Infections (ABSSSI) Intravenous 200 mg Once daily 1 hour 6 days
Oral 200 mg Once daily Not Applicable

No dose adjustment is necessary when changing from intravenous to oral SIVEXTRO.

If patients miss a dose, they should take it as soon as possible anytime up to 8 hours prior to their next scheduled dose. If less than 8 hours remain before the next dose, wait until their next scheduled dose.

2.2 Preparation and Administration of Intravenous Solution

SIVEXTRO is supplied as a sterile, lyophilized powder for injection in single-dose vials of 200 mg. Each 200 mg vial must be reconstituted with Sterile Water for Injection and subsequently diluted only with 0.9% Sodium Chloride Injection, USP.

SIVEXTRO vials contain no antimicrobial preservatives and are intended for single dose only. Discard any unused portion.

Preparation

The contents of the vial should be reconstituted using aseptic technique as follows:

Note: To minimize foaming, AVOID vigorous agitation or shaking of the vial during or after reconstitution.

  1. Reconstitute the SIVEXTRO vial with 4 mL of Sterile Water for Injection.
  2. Gently swirl the contents and let the vial stand until the cake has completely dissolved and any foam disperses.
  3. Inspect the vial to ensure the solution contains no particulate matter and no cake or powder remains attached to the sides of the vial. If necessary, invert the vial to dissolve any remaining powder and swirl gently to prevent foaming. The reconstituted solution is clear and colorless to pale-yellow in color; the total storage time should not exceed 24 hours at either room temperature or under refrigeration at 2°C to 8°C (36°F to 46°F).
  4. Tilt the upright vial and insert a syringe with appropriately sized needle into the bottom corner of the vial and remove 4 mL of the reconstituted solution. Do not invert the vial during extraction.
  5. The reconstituted solution must be further diluted in 250 mL of 0.9% Sodium Chloride Injection, USP. Slowly inject the 4 mL of reconstituted solution into a 250 mL bag of 0.9% Sodium Chloride Injection, USP. Invert the bag gently to mix. Do NOT shake the bag as this may cause foaming.

Administration

Administer as an intravenous infusion only.

Do not administer as an intravenous push or bolus. Do not mix SIVEXTRO with other drugs when administering. It is not intended for intra-arterial, intramuscular, intrathecal, intraperitoneal, or subcutaneous administration.

The intravenous bag containing the reconstituted and diluted intravenous solution should be inspected visually for particulate matter prior to administration. Discard if visible particles are observed. The resulting solution is clear and colorless to pale-yellow in color.

After reconstitution and dilution, SIVEXTRO is to be administered via intravenous infusion using a total time of 1 hour.

The total time from reconstitution to administration should not exceed 24 hours at room temperature or under refrigeration at 2°C to 8°C (36°F to 46°F).

Discard unused portion.

2.3 Compatible Intravenous Solutions

SIVEXTRO is compatible with 0.9% Sodium Chloride Injection, USP.

2.4 Incompatibilities

SIVEXTRO for injection is incompatible with any solution containing divalent cations (e.g., Ca2+ , Mg2+), including Lactated Ringer’s Injection and Hartmann’s Solution.

Limited data are available on the compatibility of SIVEXTRO for injection with other intravenous substances, additives or other medications and they should not be added to SIVEXTRO single-dose vials or infused simultaneously. If the same intravenous line is used for sequential infusion of several different drugs, the line should be flushed before and after infusion of SIVEXTRO with 0.9% Sodium Chloride Injection, USP.

3 DOSAGE FORMS AND STRENGTHS

SIVEXTRO 200 mg tablet is a yellow film-coated oval tablet; each tablet is debossed with “TZD” on one side and “200” on the other side.

SIVEXTRO for injection is a sterile, white to off-white lyophilized powder for injection in single-dose vials of 200 mg. Each 200 mg vial must be reconstituted with Sterile Water for Injection and subsequently diluted only with 0.9% Sodium Chloride Injection, USP.

4 CONTRAINDICATIONS

None

5 WARNINGS AND PRECAUTIONS

5.1 Patients with Neutropenia

The safety and efficacy of SIVEXTRO in patients with neutropenia (neutrophil counts <1000 cells/mm3) have not been adequately evaluated. In an animal model of infection, the antibacterial activity of SIVEXTRO was reduced in the absence of granulocytes [see Clinical Pharmacology (12.2)]. Alternative therapies should be considered when treating patients with neutropenia and ABSSSI.

5.2 Clostridioides difficile -Associated Diarrhea

Clostridioides difficile -associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents including SIVEXTRO, with severity ranging from mild diarrhea to fatal colitis. Treatment with antibacterial agents can alter the normal flora of the colon and may permit overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antibacterial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary because CDAD has been reported to occur more than two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, antibacterial use not directed against C. difficile should be discontinued, if possible. Appropriate measures such as fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated.

5.3 Development of Drug-Resistant Bacteria

Prescribing SIVEXTRO in the absence of a proven or strongly suspected bacterial infection or prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be compared directly to rates from clinical trials of another drug and may not reflect rates observed in practice.

Adult Patients

Adverse reactions were evaluated for 1425 adult patients treated with SIVEXTRO in two Phase 2 and four Phase 3 clinical trials (three Phase 3 trials for 6 days of therapy and one Phase 3 trial for 7-21 days of therapy). The median age of adult patients treated with SIVEXTRO in the Phase 2 and Phase 3 trials was 44 years, ranging between 17 and 94 years old. The majority of adult patients treated with SIVEXTRO were male (66%) and White (67%).

Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation in Adults

Serious adverse reactions occurred in 37/1425 (2.6%) of adult patients treated with SIVEXTRO and in 25/1000 (2.5%) of adult patients treated with the comparator. SIVEXTRO was discontinued due to an adverse reaction in 14/1425 (1%) of adult patients and the comparator was discontinued due to an adverse reaction in 13/1000 (1.3%) of adult patients.

Most Common Adverse Reactions in Adults

The most common adverse reactions in adult patients treated with SIVEXTRO were nausea (7.1%), headache (4.5%), diarrhea (3.6%), vomiting (2.7%), and dizziness (1.6%). The median time of onset of adverse reactions was 5 days for both SIVEXTRO and linezolid with 12% occurring on the second day of treatment in both treatment groups.

Table 2 lists selected adverse reactions occurring in at least 2% of adult patients treated with SIVEXTRO in clinical trials.

Table 2: Selected Adverse Reactions Occurring in ≥2% of Adult Patients Receiving SIVEXTRO in the Pooled Phase 3 ABSSSI Clinical Trials
Adverse Reactions Pooled Phase 3 ABSSSI Clinical Trials
SIVEXTRO(200 mg oral/intravenous once daily for 6 days)(N=1037) Linezolid(600 mg oral/intravenous twice daily for 10 days)(N=1000)
*
Includes adverse reactions in the following body system or organ classes: General disorders and administration site conditions, infections and infestations, injury, poisoning and procedural complications, and vascular disorders, including but not limited to, phlebitis, injection- or infusion-site pain, injection- or infusion-site swelling, injection-site reaction, injection-site erythema, injection-site induration, and infusion-related reaction.
Gastrointestinal Disorders
Nausea 7% 10%
Diarrhea 4% 5%
Vomiting 3% 5%
Nervous System Disorder
Headache 5% 5%
Dizziness 2% 2%
Infusion- or Injection-Related Adverse Reactions *
4% 2%

The following selected adverse reactions were reported in SIVEXTRO-treated adult patients at a rate of less than 2% in these clinical trials:

Blood and Lymphatic System Disorders: anemia

Cardiovascular: palpitations, tachycardia

Eye Disorders: asthenopia, vision blurred, visual impairment, vitreous floaters

Immune System Disorders: drug hypersensitivity

Infections and Infestations: Clostridioides difficile colitis, oral candidiasis, vulvovaginal mycotic infection

Investigations: hepatic transaminases increased (ALT increased, AST increased), gamma-glutamyltransferase (GGT) increased, white blood cell count decreased

Nervous System Disorders: hypoesthesia, paresthesia, VIIth nerve paralysis

Psychiatric Disorders: insomnia

Skin and Subcutaneous Tissue Disorders: pruritus, urticaria, dermatitis

Vascular Disorders: flushing, hypertension

Laboratory Parameters

Hematology laboratory abnormalities that were determined to be potentially clinically significant in the pooled Phase 3 ABSSSI clinical trials are provided in Table 3.

Table 3: Potentially Clinically Significant Lowest Laboratory Values in the Pooled Phase 3 ABSSSI Clinical Trials in Adults
Laboratory Assay Potentially Clinically Significant Values *,
SIVEXTRO(200 mg oral/intravenous once daily for 6 days)(N) Linezolid(600 mg oral/intravenous twice daily for 10 days)(N)
M = male; F = female
*
<75% (<50% for absolute neutrophil count) of lower limit of normal (LLN) for post-baseline measurements
Represents laboratory values within two days after the last dose of active drug
Number of subjects with at least one post-baseline test result that are within two days after the last dose of active drug
Hemoglobin (<10.1 g/dL [M]) (<9 g/dL [F]) (994)3.4% (957)3.4%
Platelet count (<112 × 103 /mm3) (989)2.1% (950)3.8%
Absolute neutrophil count (<0.8 × 103 /mm3) (980)0.4% (941)0.6%

Myelosuppression

Phase 1 studies conducted in healthy adults exposed to SIVEXTRO for 21 days showed a possible dose and duration effect on hematologic parameters beyond 6 days of treatment. In the Phase 3 trials, clinically significant changes in these parameters were generally similar for both treatment arms (see Table 3).

Peripheral and Optic Neuropathy

Peripheral and optic neuropathy have been described in patients treated with another member of the oxazolidinone class for longer than 28 days. In Phase 3 trials in adults, reported adverse reactions for peripheral neuropathy and optic nerve disorders were similar between both treatment arms (peripheral neuropathy 1.2% vs. 0.7% for tedizolid phosphate and linezolid, respectively; optic nerve disorders 0.3% vs. 0.1%, respectively).

Pediatric Patients

Adverse reactions were evaluated in 91 pediatric patients with ABSSSI ranging from 12 to <18 years of age treated with IV and/or oral SIVEXTRO 200 mg for 6 days and 29 patients treated with comparator agents for 10 days. The majority of pediatric patients treated with SIVEXTRO were male (64%) and white (88%).

Serious adverse reactions occurred in 1/91 (1%) of pediatric patients treated with SIVEXTRO and in none of the 29 patients treated with the comparator. Adverse reactions leading to discontinuation occurred in 1 (1%) pediatric patient in the SIVEXTRO arm and in none in the comparator arm.

The most common adverse reactions occurring in pediatric patients receiving SIVEXTRO in the ABSSSI clinical trial were phlebitis (3%), increased hepatic transaminases (alanine aminotransferase, aspartate aminotransferase) (3%), anemia, and vomiting (1%).

Safety has not been evaluated in pediatric patients under 12 years of age.

Laboratory Parameters

Table 4: Potentially Clinically Significant Lowest Laboratory Values in the ABSSSI Clinical Trial in Pediatric Patients (12-<18 years)
Laboratory Assay Potentially Clinically Significant Values *,
SIVEXTRO(200 mg oral/intravenousonce daily for 6 days) (N) Comparators §(for 10 days)(N)
M = male; F = female
*
<75% (<50% for absolute neutrophil count) of lower limit of normal (LLN) for post-baseline measurements
Represents laboratory values within two days after the last dose of active drug
Number of subjects with at least one post-baseline test result that are within two days after the last dose of active drug
§
5 IV and 4 oral comparators selected per local standard of care
Hemoglobin (<10.1 g/dL [M]) (<9 g/dL [F]) (85)2.4% (26)0.0%
Platelet count (<112 × 103 /mm3) (82)1.2% (26)0.0%
Absolute neutrophil count (<0.8 × 103 /mm3) (85)0.0% (26)0.0%

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