Tyzavan

Description for Tyzavan

TYZAVAN (Vancomycin Injection, USP), in single-dose flexible bags contain vancomycin as vancomycin hydrochloride. It is a tricyclic glycopeptide antibacterial drug derived from Amycolatopsis orientalis (formerly Nocardia orientalis). The molecular formula is C₆₆H₇₅Cl₂N₉O₂₄•HCl and the molecular weight is 1,485.71. The chemical name is (S_a)(3S,6R,7R,22R,23S,26S,36R,38aR)-44-{[2-O-(3-amino-2,3,6-trideoxy-3-C-methyl-α-L-lyxohexopyranosyl)-β-D-glucopyranosyl]-oxy}-3-(carbamoylmethyl)-10,19-dichloro2,3,4,5,6,7,23,24,25,26,36,37,38,38a-tetradecahydro-7,22,28,30,32-pentahydroxy-6-[(2R)-4methyl-2-[methylamino]valeramido]-2,5,24,38,39-pentaoxo-22H-8,11:18,21-dietheno23,36(iminometha-no)-13,16:31,35-dimetheno-1H,16H-[1,6,9]-oxadiazacyclohexadecino-[4,5m][10,2,16]-benzoxa-diazacyclotetracosine-26-carboxylic acid, monohydrochloride. Vancomycin hydrochloride has the following structural formula:

TYZAVAN (Vancomycin Injection, USP), in single-dose flexible bags are sterile, nonpyrogenic premixed 100 mL, 150 mL, 200 mL, 250 mL, 300 mL, 350 mL or 400 mL solution containing 500 mg, 750 mg, 1 g, 1.25 g, 1.5 g, 1.75 g or 2 g vancomycin, respectively, as vancomycin hydrochloride. Each 100 mL of solution contains 1.36 g N-acetyl-D-alanine, 1.26 g L-lysine hydrochloride (monochloride) in water for injection. Hydrochloric acid and sodium hydroxide are used for pH adjustment. The pH is 4.5 to 5.5 and the osmolarity is 350 to 475 mOsmol/L.

ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Infusion Reactions [see Warnings and Precautions (5.1)]
• Nephrotoxicity [see Warnings and Precautions (5.2)]
• Ototoxicity [see Warnings and Precautions (5.3)]
• Severe Dermatologic Reactions [see Warnings and Precautions (5.4)]
• Clostridioides difficile-Associated Diarrhea [see Warnings and Precautions (5.5)]
• Hemorrhagic Occlusive Retinal Vasculitis [see Warnings and Precautions (5.6)]
• Neutropenia [see Warnings and Precautions (5.7)]
• Phlebitis and Other Administration Site Reactions[see Warnings and Precautions (5.8)].

Clinical Trials Experience

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 following adverse reactions associated with the use of vancomycin were identified in clinical trials:

Immune System Disorders: Hypersensitivity reactions including anaphylaxis and “vancomycin infusion reactions”
Skin and Subcutaneous Tissue Disorders: Erythema (especially of the face, neck and upper torso) and pruritus which are manifestations of rashes including exfoliative dermatitis. Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), Linear IgA bullous dermatosis (LABD)
Renal and Urinary Disorders: Acute kidney injury and interstitial nephritis
Ear and Labyrinth Disorders: Tinnitus, hearing loss, vertigo
Blood and Lymphatic System Disorders: Agranulocytosis, neutropenia, pancytopenia, leukopenia, thrombocytopenia, eosinophilia
Gastrointestinal Disorders: Pseudomembranous colitis
Cardiac Disorders: Cardiac arrest, chest pain
General Disorders and Administration Site Conditions: General discomfort, fever, chills, phlebitis, injection site irritation, injection site pain and necrosis following intramuscular injection, chemical peritonitis following intraperitoneal administration (TYZAVAN is not approved for intramuscular and intraperitoneal administration)
Laboratory Abnormalities: Elevated blood urea nitrogen, elevated serum creatinine
Musculoskeletal and Connective Tissue Disorders: Muscle pain
Nervous System Disorders: Dizziness
Respiratory, Thoracic and Mediastinal Disorders: Wheezing, dyspnea
Vascular Disorders: Hypotension, shock, vasculitis

Postmarketing Experience

The following adverse reactions have been identified during postmarketing use of vancomycin. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and Subcutaneous Tissue Disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP)

Drug Interactions for Tyzavan

Anesthetic Agents

Concomitant administration of vancomycin and anesthetic agents has been associated with erythema and histamine-like flushing [see Warnings and Precautions (5.1) and Use in Specific Populations (8.4)].

Piperacillin-Tazobactam

Studies have detected an increased incidence of acute kidney injury in patients administered concomitant piperacillin/tazobactam and vancomycin as compared to vancomycin alone. Monitor kidney function in patients receiving concomitant piperacillin/tazobactam and vancomycin. No pharmacokinetic interactions have been noted between piperacillin/tazobactam and vancomycin.

Ototoxic and/or Nephrotoxic Drugs

Concurrent and/or sequential systemic or topical use of other potentially neurotoxic and/or nephrotoxic drugs requires more frequent monitoring of renal function.

Warnings for Tyzavan

Included as part of the PRECAUTIONS section.

Precautions for Tyzavan

Infusion Reactions

Hypotension, including shock and cardiac arrest, wheezing, dyspnea, urticaria, muscular and chest pain may occur with rapid TYZAVAN administration (e.g., over several minutes). The reactions may be more severe in pediatric patients [see Use in Specific Populations (8.4)].

Rapid intravenous administration of TYZAVAN may also be associated with “vancomycin infusion reactions” which manifests as pruritus and erythema that involves the face, neck and upper body or pain and muscle spasm of the chest and back.

There have been reports that the frequency of infusion-related reactions (including hypotension, flushing, erythema, urticaria, and pruritus) increases with the concomitant administration of anesthetic agents.

Infusion-related adverse reactions are related to both the concentration and the rate of administration of TYZAVAN. Infusion-related adverse reactions may occur, however, at any rate or concentration. Administer TYZAVAN over a period of 60 minutes or greater to reduce the risk of infusion-related adverse reactions. In selected patients in need of fluid restriction, a concentration up to 10 mg/mL may be used; use of such higher concentrations may increase the risk of infusion-related adverse reactions. Administer TYZAVAN as a 60-minute infusion prior to administration of intravenous anesthetic agents when feasible to minimize infusion-related adverse reactions. Stop the infusion if a reaction occurs because this usually results in prompt cessation of these reactions.

Nephrotoxicity

TYZAVAN can result in acute kidney injury (AKI), including acute renal failure, mainly due to interstitial nephritis or less commonly acute tubular necrosis. AKI is manifested by increasing blood urea nitrogen (BUN) and serum creatinine (Cr). The risk of AKI increases with higher vancomycin serum levels, prolonged exposure, concomitant administration of other nephrotoxic drugs, concomitant administration of piperacillin-tazobactam [see Drug Interactions (7.2)], volume depletion, pre-existing renal impairment and in critically ill patients and patients with co-morbid conditions that predispose to renal impairment.

Monitor serum vancomycin concentrations and renal function in all patients receiving TYZAVAN. More frequent monitoring is recommended in patients with comorbidities that predispose to impairment in renal function or are concomitantly receiving other nephrotoxic drugs, in critically ill patients, in patients with changing renal function, and in patients requiring higher therapeutic vancomycin levels. If acute kidney injury occurs, discontinue TYZAVAN or reduce the dose.

Ototoxicity

Ototoxicity has occurred in patients receiving vancomycin. It may be reversible or permanent. Ototoxicity manifests as tinnitus, hearing loss, dizziness or vertigo. The risk is higher in older patients, patients who are receiving higher doses, who have an underlying hearing loss, who are receiving concomitant therapy with another ototoxic agent, such as an aminoglycoside or who have underlying renal impairment. Monitor for signs and symptoms of ototoxicity during therapy. Monitor serum vancomycin concentrations and renal function in all patients receiving parenteral vancomycin. Discontinue TYZAVAN if ototoxicity occurs. Dosage of TYZAVAN must be adjusted for patients with renal impairment [see Dosage and Administration (2.3)]. Serial tests of auditory function may be helpful in order to minimize the risk of ototoxicity [see Dosage and Administration (2.4)].

Severe Dermatologic Reactions

Severe dermatologic reactions such as toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and linear IgA bullous dermatosis (LABD) have been reported in association with the use of vancomycin. Cutaneous signs or symptoms reported include skin rashes, mucosal lesions, and blisters.

Discontinue TYZAVAN at the first appearance of signs and symptoms of TEN, SJS, DRESS, AGEP, or LABD.

Clostridioides difficile-Associated Diarrhea (CDAD)

Clostridioides difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including vancomycin and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to 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 antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

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

Clinically significant serum concentrations have been reported in some patients being treated for active C. difficile-induced pseudomembranous colitis after multiple oral doses of vancomycin. Prolonged use of TYZAVAN may result in the overgrowth of nonsusceptible microorganisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken. In rare instances, there have been reports of pseudomembranous colitis due to C. difficile developing in patients who received intravenous vancomycin.

Hemorrhagic Occlusive Retinal Vasculitis (HORV)

Hemorrhagic occlusive retinal vasculitis, including permanent loss of vision, occurred in patients receiving intracameral or intravitreal administration of vancomycin during or after cataract surgery. The safety and efficacy of vancomycin administered by the intracameral or the intravitreal route have not been established by adequate and well-controlled trials. Vancomycin is not indicated for the prophylaxis of endophthalmitis.

Neutropenia

Reversible neutropenia has been reported in patients receiving vancomycin [see Adverse Reactions (6.1)]. Patients who will undergo prolonged therapy with vancomycin or those who are receiving concomitant drugs which may cause neutropenia should have periodic monitoring of the leukocyte count.

Phlebitis and Other Administration Site Reactions

Inflammation at the site of injection of vancomycin has been reported. Vancomycin is irritating to tissue and must be given by a secure intravenous route of administration to reduce the risk of local irritation and phlebitis.

Administration of vancomycin by intramuscular (IM), intraperitoneal, intrathecal (intralumbar or intraventricular), or intravitreal routes has not been approved and is not recommended. The safety and efficacy of vancomycin administered by the intrathecal (intralumbar or intraventricular) route or by the intraperitoneal route have not been established by adequate and well controlled trials. Pain, tenderness, and necrosis occur with IM injection of vancomycin or with inadvertent extravasation. Thrombophlebitis may occur, the frequency and severity of which can be minimized by slow infusion of the drug and by rotation of venous access sites.

Intraperitoneal administration during continuous ambulatory peritoneal dialysis (CAPD) can result in chemical peritonitis. Manifestations range from cloudy dialysate alone to a cloudy dialysate accompanied by variable degrees of abdominal pain and fever. This syndrome appears to be resolved after discontinuation of intraperitoneal vancomycin.

About 60% of an intraperitoneal dose of vancomycin administered during peritoneal dialysis is absorbed systemically in 6 hours. Serum concentrations of about 10 mcg/mL are achieved by intraperitoneal injection of 30 mg/kg of vancomycin. However, the safety and efficacy of the intraperitoneal use of vancomycin has not been established in adequate and well-controlled trials.

Development of Drug-Resistant Bacteria

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

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Although no long-term studies in animals have been performed to evaluate carcinogenic potential, no mutagenic potential of vancomycin was found in standard laboratory tests. No definitive fertility studies have been performed.

OVERDOSAGE

Supportive care is advised, with maintenance of glomerular filtration. Vancomycin is poorly removed by dialysis. Hemofiltration and hemoperfusion with polysulfone resin have been reported to result in increased vancomycin clearance.

For current information on the management of overdosage, contact the National Poison Control Center at 1-800-222-1222 or www.poison.org.

Contraindications for Tyzavan

TYZAVAN is contraindicated in patients with known hypersensitivity to vancomycin.

Clinical Pharmacology for Tyzavan

Mechanism of Action

Vancomycin is an antibacterial drug [see Microbiology (12.4)].

Pharmacodynamics

Based on animal models of infection, the antimicrobial activity of vancomycin appears to correlate with the AUC/MIC (area under the concentration-time curve/minimum inhibitory concentration) ratio for certain pathogens, including methicillin resistant Staphylococcus aureus. The principal pharmacokinetic/pharmacodynamic parameter best associated with clinical and microbiological cure has not been elucidated in clinical trials ^2,3.

Pharmacokinetics

General Pharmacokinetics

In subjects with normal kidney function, multiple intravenous dosing of 1 g of vancomycin (15 mg/kg) infused over 60 minutes produces mean plasma concentrations of approximately 63 mcg/mL immediately after the completion of infusion, mean plasma concentrations of approximately 23 mcg/mL 2 hours after infusion, and mean plasma concentrations of approximately 8 mcg/mL 11 hours after the end of the infusion. Multiple dosing of 500 mg infused over 30 minutes produces mean plasma concentrations of about 49 mcg/mL at the completion of infusion, mean plasma concentrations of about 19 mcg/mL 2 hours after infusion, and mean plasma concentrations of about 10 mcg/mL 6 hours after infusion. The plasma concentrations during multiple dosing are like those after a single dose.

In healthy subjects administered a single 1g dose of TYZAVAN, geometric mean (geometric %CV) AUC_0-inf values for NADA and vancomycin were 209 (19.6%) and 219 (13.7%) mcg*h/mL, respectively. Based on a population pharmacokinetic analysis, 1g TYZAVAN administered over 1.5 hours every 12 hours achieves a geometric mean (95% prediction interval) steady state AUC_0-24 exposure of 383 (277-547) and 382 (261-567) mcg*h/mL for NADA and vancomycin in healthy subjects, respectively.

Distribution

The volume of distribution ranges from 0.3 to 0.43 L/kg after intravenous administration. Vancomycin is approximately 55% serum protein bound as measured by ultrafiltration at vancomycin serum concentrations of 10 to 100 mcg/mL. After intravenous administration of vancomycin, inhibitory concentrations are present in pleural, pericardial, ascitic, and synovial fluids; in urine; in peritoneal dialysis fluid; and in atrial appendage tissue. Vancomycin does not readily diffuse across normal meninges into the spinal fluid; but, when the meninges are inflamed, penetration into the spinal fluid occurs.

Elimination

Mean plasma clearance is about 0.058 L/kg/h, and mean renal clearance is about 0.048 L/kg/h. The mean elimination half-life of vancomycin from plasma is 4 to 6 hours in subjects with normal renal function. In anephric patients, the mean elimination half-life is 7.5 days. Total body and renal clearance of vancomycin may be reduced in the elderly.

Metabolism
There is no apparent metabolism of the vancomycin.

Excretion
In the first 24 hours after intravenous administration, about 75% of an administered dose of vancomycin is excreted in urine by glomerular filtration. Renal impairment slows excretion of vancomycin.

In the first 48 hours after intravenous administration of a single 1 g dose of TYZAVAN, the percent excreted unchanged in urine was approximately 80% for NADA.

Microbiology

Mechanism of Action

The bactericidal action of vancomycin results primarily from inhibition of cell-wall biosynthesis. In addition, vancomycin alters bacterial-cell-membrane permeability and RNA synthesis.

Resistance

Vancomycin is not active in vitro against gram-negative bacilli, mycobacteria, or fungi. There is no cross-resistance between vancomycin and other antibacterials.

Interaction with Other Antimicrobials

The combination of vancomycin and an aminoglycoside acts synergistically in vitro against many isolates of Staphylococcus aureus, Streptococcus gallolyticus (previously known as Streptococcus bovis), Enterococcus spp, and the viridans group streptococci.

Antimicrobial Activity

Vancomycin has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections [see Indications and Usage (1)].

Aerobic bacteria

Gram-positive bacteria
Corynebacterium spp.
Enterococcus spp. (including Enterococcus faecalis)
Staphylococcus aureus (including methicillin-resistant and methicillin-susceptible isolates)
Coagulase negative staphylococci (including S.epidermidis and methicillin-resistant isolates)
Streptococcus gallolyticus (previously known as Streptococcus bovis)
Viridans group streptococci

The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for vancomycin against isolates of similar genus or organism group. However, the efficacy of vancomycin in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials.

Aerobic bacteria

Gram-positive bacteria
Listeria monocytogenes
Streptococcus pyogenes
Streptococcus pneumoniae
Streptococcus agalactiae

Anaerobic bacteria

Gram-positive bacteria
Actinomyces species
Lactobacillus species

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

PATIENT COUNSELING INFORMATION

Infusion Reactions During or After Intravenous Use

Advise patients that generalized skin redness, skin rash, itching, flushing, muscle pain, chest pain, shortness of breath, wheezing, or dizziness may occur during TYZAVAN infusion. These reactions can be lessened or prevented by infusing the drug over at least 60 minutes [see Warnings and Precautions (5.1)].

Acute Kidney Injury

Advise patients that TYZAVAN can result in kidney damage and that blood tests are required to monitor vancomycin blood levels and kidney function during therapy [see Warnings and Precautions (5.2)].

Hearing Loss or Balance Problems

Advise patients that TYZAVAN may result in decreased hearing and to report hearing loss or balance problems to their health care provider [see Warnings and Precautions (5.3)].

Severe Dermatologic Reactions

Advise patients about the signs and symptoms of serious skin manifestations. Instruct patients to stop TYZAVAN immediately and promptly report the first signs or symptoms of skin rash, mucosal lesions or blisters to their healthcare provider [see Warnings and Precautions (5.4)].

Diarrhea

Diarrhea is a common problem caused by antibacterial drugs, including vancomycin, which usually ends when the antibacterial drug is discontinued. Sometimes after starting treatment with antibacterial drugs, patients can develop 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 antibacterial drug. If this occurs, patients should contact their physician as soon as possible [see Warnings and Precautions (5.1)].

Antibacterial Resistance

Patients should be counseled that antibacterial drugs including TYZAVAN, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When TYZAVAN 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 TYZAVAN or other antibacterial drugs in the future.