Telavancin hydrochloride

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# Black Box Warning

# Overview
Telavancin hydrochloride is an antibiotic that is FDA approved for the treatment of Complicated skin and skin structure infections (cSSSI) and Hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP). There is a Black Box Warning for this drug as shown here.  Common adverse reactions include dysgeusia, nausea, vomiting, and proteinuria.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- Caused by susceptible isolates of the following Gram-positive microorganisms: Staphylococcus aureus (including methicillin-susceptible and -resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus group (includes S. anginosus, S. intermedius, and S. constellatus), or Enterococcus faecalis (vancomycin-susceptible isolates only).
- Dosage: 10 mg/kg administered over a 60-minute period by intravenous infusion once every 24 hours for 7 to 14 days.
- Caused by susceptible isolates of Staphylococcus aureus (including methicillin-susceptible and -resistant isolates). telavancin hydrochloride should be reserved for use when alternative treatments are not suitable.
- Dosage: 10 mg/kg administered over a 60-minute period by intravenous infusion once every 24 hours for 7 to 21 days.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Telavancin hydrochloride in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Telavancin hydrochloride in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness not established in pediatric patients

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Telavancin hydrochloride in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Telavancin hydrochloride in pediatric patients.

# Contraindications
- Intravenous Unfractionated Heparin Sodium because the activated partial thromboplastin time (aPTT) test results are expected to be artificially prolonged for 0 to 18 hours after telavancin hydrochloride administration.
- Known Hypersensitivity to telavancin hydrochloride

# Warnings
In the analysis of patients (classified by the treatment received) in the two combined HABP/VABP trials with pre-existing moderate/severe renal impairment (CrCl50 mL/min), all-cause mortality within 28 days of starting treatment was 95/241 (39%) in the telavancin hydrochloride group, compared with 72/243 (30%) in the vancomycin group.  All-cause mortality at 28 days in patients without pre-existing moderate/severe renal impairment (CrCl>50 mL/min) was 86/510 (17%) in the telavancin hydrochloride group and 92/510 (18%) in the vancomycin group. Therefore, telavancin hydrochloride use in patients with baseline CrCl50 mL/min should be considered only when the anticipated benefit to the patient outweighs the potential risk.
In a subgroup analysis of the combined cSSSI trials,clinical cure rates in the telavancin hydrochloride-treated patients were lower in patients with baseline CrCl 50 mL/min compared with those with CrCl>50 mL/min (TABLE 2). A decrease of this magnitude was not observed in vancomycin-treated patients. Consider these data when selecting antibacterial therapy for use in patients with cSSSI and with baseline moderate/severe renal impairment.
In both the HABP/VABP trials and the cSSSI trials, renal adverse events were more likely to occur in patients with baseline comorbidities known to predispose patients to kidney dysfunction (pre-existing renal disease, diabetes mellitus, congestive heart failure, or hypertension). The renal adverse event rates were also higher in patients who received concomitant medications known to affect kidney function (e.g., non-steroidal anti-inflammatory drugs, ACE inhibitors, and loop diuretics).
Monitor renal function (i.e., serum creatinine, creatinine clearance) in all patients receiving telavancin hydrochloride. Values should be obtained prior to initiation of treatment, during treatment (at 48- to 72-hour intervals or more frequently, if clinically indicated), and at the end of therapy. If renal function decreases, the benefit of continuing telavancin hydrochloride versus discontinuing and initiating therapy with an alternative agent should be assessed.
In patients with renal dysfunction, accumulation of the solubilizer hydroxypropyl-beta-cyclodextrin can occur.
Avoid use of telavancin hydrochloride during pregnancy unless the potential benefit to the patient outweighs the potential risk to the fetus. telavancin hydrochloride caused adverse developmental outcomes in 3 animal species at clinically relevant doses. This raises concern about potential adverse developmental outcomes in humans.
Women of childbearing potential should have a serum pregnancy test prior to administration of telavancin hydrochloride. If not already pregnant, women of childbearing potential should use effective contraception during telavancin hydrochloride treatment.
Although telavancin does not interfere with coagulation, it interfered with certain tests used to monitor coagulation (TABLE 3), when conducted using samples drawn 0 to 18 hours after telavancin hydrochloride administration for patients being treated once every 24 hours. Blood samples for these coagulation tests should be collected as close as possible prior to a patient's next dose of telavancin hydrochloride. Blood samples for coagulation tests unaffected by telavancin hydrochloride may be collected at any time.
For patients who require aPTT monitoring while being treated with telavancin hydrochloride, a non phospholipid dependent coagulation test such as a Factor Xa (chromogenic) assay or an alternative anticoagulant not requiring aPTT monitoring may be considered.
No evidence of increased bleeding risk has been observed in clinical trials with telavancin hydrochloride. Telavancin has no effect on platelet aggregation. Furthermore, no evidence of hypercoagulability has been seen, as healthy subjects receiving telavancin hydrochloride have normal levels of D-dimer and fibrin degradation products.
Serious and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, may occur after first or subsequent doses. Discontinue telavancin hydrochloride at first sign of skin rash, or any other sign of hypersensitivity. Telavancin is a semi-synthetic derivative of vancomycin; it is unknown if patients with hypersensitivity reactions to vancomycin will experience cross-reactivity to telavancin. telavancin hydrochloride should be used with caution in patients with known hypersensitivity to vancomycin.
telavancin hydrochloride is a lipoglycopeptide antibacterial agent and should be administered over a period of 60 minutes to reduce the risk of infusion-related reactions. Rapid intravenous infusions of the glycopeptide class of antimicrobial agents can cause Red-man Syndrome-like reactions including: flushing of the upper body, urticaria, pruritus, or rash. Stopping or slowing the infusion may result in cessation of these reactions.
Clostridium difficile-associated diarrhea (CDAD) has been reported with nearly all antibacterial agents and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the 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. Hyper-toxin-producing strains of C. difficile cause increased morbidity and mortality, since these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
Prescribing telavancin hydrochloride in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
As with other antibacterial drugs, use of telavancin hydrochloride may result in overgrowth of nonsusceptible organisms, including fungi. Patients should be carefully monitored during therapy. If superinfection occurs, appropriate measures should be taken.
In a study involving healthy volunteers, doses of 7.5 and 15 mg/kg of telavancin hydrochloride prolonged the QTc interval. Caution is warranted when prescribing telavancin hydrochloride to patients taking drugs known to prolong the QT interval. Patients with congenital long QT syndrome, known prolongation of the QTc interval, uncompensated heart failure, or severe left ventricular hypertrophy were not included in clinical trials of telavancin hydrochloride. Use of telavancin hydrochloride should be avoided in patients with these conditions.

# Adverse Reactions

## Clinical Trials Experience
The two Phase 3 cSSSI clinical trials (Trial 1 and Trial 2) for telavancin hydrochloride included 929 adult patients treated with telavancin hydrochloride at 10 mg/kg IV once daily. The mean age of patients treated with telavancin hydrochloride was 49 years (range 18-96). There was a slight male predominance (56%) in patients treated with telavancin hydrochloride, and patients were predominantly Caucasian (78%).
In the cSSSI clinical trials, <1% (8/929) patients who received telavancin hydrochloride died and <1% (8/938) patients treated with vancomycin died. Serious adverse events were reported in 7% (69/929) of patients treated with telavancin hydrochloride and most commonly included renal, respiratory, or cardiac events. Serious adverse events were reported in 5% (43/938) of vancomycin-treated patients, and most commonly included cardiac, respiratory, or infectious events. Treatment discontinuations due to adverse events occurred in 8% (72/929) of patients treated with telavancin hydrochloride, the most common events being nausea and rash (~1% each). Treatment discontinuations due to adverse events occurred in 6% (53/938) of vancomycin-treated patients, the most common events being rash and pruritus (~1% each).
The most common adverse events occurring in 10% of telavancin hydrochloride-treated patients observed in the telavancin hydrochloride Phase 3 cSSSI trials were dysgeusia, nausea, vomiting, and proteinuria.
TABLE 4 displays the incidence of treatment-emergent adverse drug reactions reported in 2% of patients treated with telavancin hydrochloride possibly related to the drug.
Two randomized, double-blind Phase 3 trials (Trial 1 and Trial 2) for telavancin hydrochloride included 1,503 adult patients treated with telavancin hydrochloride at 10 mg/kg IV once daily or vancomycin at 1 g IV twice daily. The mean age of patients treated with telavancin hydrochloride was 62 years (range 18-100). In patients treated with telavancin hydrochloride, 69% of the patients were white and 65% were male. In the combined telavancin hydrochloride group, 29% were VAP and 71% were HAP patients.
TABLE 5 summarizes deaths using Kaplan-Meier estimates at Day 28 as stratified by baseline creatinine clearance categorized into four groups. Patients with pre-existing moderate/severe renal impairment (CrCl50 mL/min) who were treated with telavancin hydrochloride for HABP/VABP had increased mortality observed versus vancomycin in both the trials.
Serious adverse events were reported in 31% of patients treated with telavancin hydrochloride and 26% of patients who received vancomycin. Treatment discontinuations due to adverse events occurred in 8% (60/751) of patients who received telavancin hydrochloride, the most common events being acute renal failure and electrocardiogram QTc interval prolonged (~1% each). Treatment discontinuations due to adverse events occurred in 5% (40/752) of vancomycin-patients, the most common events being septic shock and multi-organ failure (<1%).
TABLE 6 displays the incidence of treatment-emergent adverse drug reactions reported in  5% of HABP/VABP patients treated with telavancin hydrochloride possibly related to the drug.
In cSSSI trials, the incidence of renal adverse events indicative of renal impairment (increased serum creatinine, renal impairment, renal insufficiency, and/or renal failure) was 30/929 (3%) of telavancin hydrochloride-treated patients compared with 10/938 (1%) of vancomycin-treated patients. In 17 of the 30 telavancin hydrochloride-treated patients, these adverse events had not completely resolved by the end of the trials, compared with 6 of the 10 vancomycin-treated patients. Serious adverse events indicative of renal impairment occurred in 11/929 (1%) of telavancin hydrochloride-treated patients compared with 3/938 (0.3%) of vancomycin-treated patients. Twelve patients treated with telavancin hydrochloride discontinued treatment due to adverse events indicative of renal impairment compared with 2 patients treated with vancomycin.
Increases in serum creatinine to 1.5 times baseline occurred more frequently among telavancin hydrochloride-treated patients with normal baseline serum creatinine (15%) compared with vancomycin-treated patients with normal baseline serum creatinine (7%).
Fifteen of 174 (9%) telavancin hydrochloride-treated patients 65 years of age had adverse events indicative of renal impairment compared with 16 of 755 patients (2%) <65 years of age.
In the HABP/VABP trials, the incidence of renal adverse events (increased serum creatinine, renal impairment, renal insufficiency, and/or renal failure) was 10% for telavancin hydrochloride vs. 8% for vancomycin. Of the patients who had at least one renal adverse event, 54% in each treatment group recovered completely, recovered with sequelae, or were improving from the renal AE at the last visit.  Three percent of telavancin hydrochloride-treated patients and 2% of vancomycin-treated patients experienced at least one serious renal adverse event. Renal adverse events resulted in discontinuation of study medication in 14 telavancin hydrochloride-treated patients (2%) and 7 vancomycin-treated patients (1%).
Increases in serum creatinine to 1.5 times baseline occurred more frequently among telavancin hydrochloride-treated patients (16%) compared with vancomycin-treated patients (10%).
Forty-four of 399 (11.0%) telavancin hydrochloride-treated patients 65 years of age had adverse events indicative of renal impairment compared with 30 of 352 patients (8%) <65 years of age.

## Postmarketing Experience
The following adverse reactions have been identified during post-approval use of telavancin hydrochloride. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Serious hypersensitivity reactions have been reported after first or subsequent doses of telavancin hydrochloride, including anaphylactic reactions. It is unknown if patients with hypersensitivity reactions to vancomycin will experience cross-reactivity to telavancin.

# Drug Interactions
Telavancin binds to the artificial phospholipid surfaces added to common anticoagulation tests, thereby interfering with the ability of the coagulation complexes to assemble on the surface of the phospholipids and promote clotting in vitro. These effects appear to depend on the type of reagents used in commercially available assays. Thus, when measured shortly after completion of an infusion of telavancin hydrochloride, increases in the PT, INR, aPTT, and ACT have been observed. These effects dissipate over time, as plasma concentrations of telavancin decrease.
Telavancin interferes with urine qualitative dipstick protein assays, as well as quantitative dye methods (e.g., pyrogallol red-molybdate). However, microalbumin assays are not affected and can be used to monitor urinary protein excretion during telavancin hydrochloride treatment.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): C
All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%), or other adverse outcomes regardless of drug exposure.
There are no data on telavancin hydrochloride use in pregnant women. In 3 animal species, telavancin hydrochloride exposure during pregnancy at clinically relevant doses caused reduced fetal weights and increased rates of digit and limb malformations in offspring. These data raise concern about potential adverse developmental outcomes in humans (see DATA).
Given the lack of human data and the risks suggested by animal data, avoid using telavancin hydrochloride in pregnant women unless the benefits to the patient outweigh the potential risks to the fetus.
There are no data on human pregnancies exposed to telavancin hydrochloride.
In embryo-fetal development studies in rats, rabbits, and minipigs, telavancin demonstrated the potential to cause limb and skeletal malformations when given intravenously during the period of organogenesis at doses up to 150, 45, or 75 mg/kg/day, respectively. These doses resulted in exposure levels approximately 1- to 2-fold the human exposure (AUC) at the maximum clinical recommended dose. Malformations observed at <1% (but absent or at lower rates in historical or concurrent controls), included brachymelia (rats and rabbits), syndactyly (rats, minipigs), adactyly (rabbits), and polydactyly (minipigs). Additional findings in rabbits included flexed front paw and absent ulna, and in the minipigs included misshapen digits and deformed front leg. Fetal body weights were decreased in rats.
In a prenatal/perinatal development study, pregnant rats received intravenous telavancin at up to 150 mg/kg/day (approximately the same AUC as observed at the maximum clinical dose) from the start of organogenesis through lactation. Offspring showed decreases in fetal body weight and an increase in the number of stillborn pups. Brachymelia was also observed. Developmental milestones and fertility of the pups were unaffected.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Telavancin hydrochloride in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Telavancin hydrochloride during labor and delivery.

### Nursing Mothers
It is not known whether telavancin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when telavancin hydrochloride is administered to a nursing woman.

### Pediatric Use
The safety and effectiveness of telavancin hydrochloride in pediatric patients has not been studied.

### Geriatic Use
Of the 929 patients treated with telavancin hydrochloride at a dose of 10 mg/kg once daily in clinical trials of cSSSI, 174 (19%) were 65 years of age and 87 (9%) were 75 years of age. In the cSSSI trials, lower clinical cure rates were observed in patients 65 years of age compared with those <65 years of age. Overall, treatment-emergent adverse events occurred with similar frequencies in patients 65 (75% of patients) and <65 years of age (83% of patients). Fifteen of 174 (9%) patients 65 years of age treated with telavancin hydrochloride had adverse events indicative of renal impairment compared with 16 of 755 (2%) patients <65 years of age.
Of the 749 HABP/VABP patients treated with telavancin hydrochloride at a dose of 10 mg/kg once daily in clinical trials of HABP/VABP, 397 (53%) were 65 years of age and 230 (31%) were 75 years of age. Treatment-emergent adverse events as well as deaths and other serious adverse events occurred more often in patients 65 years of age than in those <65 years of age in both treatment groups.
Telavancin is substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in this age group.
The mean plasma AUC values of telavancin were similar in healthy young and elderly subjects. Dosage adjustment for elderly patients should be based on renal function.

### Gender
The impact of gender on the pharmacokinetics of telavancin was evaluated in healthy male (n=8) and female (n=8) subjects. The pharmacokinetics of telavancin were similar in males and females. No dosage adjustment is recommended based on gender.

### Race
There is no FDA guidance on the use of Telavancin hydrochloride with respect to specific racial populations.

### Renal Impairment
The HABP/VABP and cSSSI trials included patients with normal renal function and patients with varying degrees of renal impairment. Patients with underlying renal dysfunction or risk factors for renal dysfunction had a higher incidence of renal adverse events.
In the HABP/VABP studies higher mortality rates were observed in the telavancin hydrochloride-treated patients with baseline CrCl50 mL/min. Use of telavancin hydrochloride in patients with pre-existing moderate/severe renal impairment should be considered only when the anticipated benefit to the patient outweighs the potential risk.
telavancin hydrochloride-treated patients in the cSSSI studies with baseline creatinine clearance 50 mL/min had lower clinical cure rates. Consider these data when selecting antibacterial therapy in patients with baseline moderate/severe renal impairment (CrCl 50 mL/min).
Dosage adjustment is required in patients with 50 mL/min renal impairment. There is insufficient information to make specific dosage adjustment recommendations for patients with end-stage renal disease (CrCl <10 mL/min), including patients receiving hemodialysis.
Hydroxypropyl-beta-cyclodextrin is excreted in urine and may accumulate in patients with renal impairment. Serum creatinine should be closely monitored and, if renal toxicity is suspected, an alternative agent should be considered.

### Hepatic Impairment
The HABP/VABP and cSSSI trials included patients with normal hepatic function and with hepatic impairment. No dosage adjustment is recommended in patients with mild or moderate hepatic impairment.

### Females of Reproductive Potential and Males
Telavancin did not affect the fertility or reproductive performance of adult male rats (exposed to telavancin for at least 4 weeks prior to mating) or female rats (exposed to telavancin for at least 2 weeks prior to mating).
Male rats given telavancin for 6 weeks, at exposures similar to those measured in clinical studies, displayed altered sperm parameters that were reversible following an 8-week recovery period.

### Immunocompromised Patients
There is no FDA guidance one the use of Telavancin hydrochloride in patients who are immunocompromised.

# Administration and Monitoring

### Administration
Intravenous

### Monitoring
There is limited information regarding Telavancin hydrochloride Monitoring in the drug label.

# IV Compatibility
There is limited information regarding the compatibility of Telavancin hydrochloride and IV administrations.

# Overdosage
In the event of overdosage, telavancin hydrochloride should be discontinued and supportive care is advised with maintenance of glomerular filtration and careful monitoring of renal function. Following administration of a single dose of telavancin hydrochloride 7.5 mg/kg to subjects with end-stage renal disease, approximately 5.9% of the administered dose of telavancin was recovered in the dialysate following 4 hours of hemodialysis. However, no information is available on the use of hemodialysis to treat an overdosage.
The clearance of telavancin by continuous venovenous hemofiltration (CVVH) was evaluated in an in vitro study. Telavancin was cleared by CVVH and the clearance of telavancin increased with increasing ultrafiltration rate. However, the clearance of telavancin by CVVH has not been evaluated in a clinical study; thus, the clinical significance of this finding and use of CVVH to treat an overdosage is unknown.

# Pharmacology

## Mechanism of Action
Telavancin inhibits cell wall biosynthesis by binding to late-stage peptidoglycan precursors, including lipid II. Telavancin also binds to the bacterial membrane and disrupts membrane barrier function.

## Structure
Telavancin hydrochloride has the following chemical structure:

## Pharmacodynamics
The antimicrobial activity of telavancin appears to best correlate with the ratio of area under the concentration-time curve to minimum inhibitory concentration (AUC/MIC) for Staphylococcus aureus based on animal models of infection. Exposure-response analyses of the clinical trials support the dose of 10 mg/kg every 24 hours.
The effect of telavancin on cardiac repolarization was assessed in a randomized, double-blind, multiple-dose, positive-controlled, and placebo-controlled, parallel study (n=160). Healthy subjects received telavancin hydrochloride 7.5 mg/kg, telavancin hydrochloride 15 mg/kg, positive control, or placebo infused over 60 minutes once daily for 3 days. Based on interpolation of the data from telavancin hydrochloride 7.5 mg/kg and 15 mg/kg, the mean maximum baseline-corrected, placebo-corrected QTc prolongation at the end of infusion was estimated to be 12-15 msec for telavancin hydrochloride 10 mg/kg and 22 msec for the positive control (TABLE 7). By 1 hour after infusion the maximum QTc prolongation was 6-9 msec for telavancin hydrochloride and 15 msec for the positive control.
ECGs were performed prior to and during the treatment period in patients receiving telavancin hydrochloride 10 mg/kg in 3 cSSSI studies to monitor QTc intervals. In these trials, 214 of 1029 (21%) patients allocated to treatment with telavancin hydrochloride and 164 of 1033 (16%) allocated to vancomycin received concomitant medications known to prolong the QTc interval and known to be associated with definite or possible risk of torsades de pointes. The incidence of QTc prolongation >60 msec was 1.5% (15 patients) in the telavancin hydrochloride group and 0.6% (6 patients) in the vancomycin group. Nine of the 15 telavancin hydrochloride patients received concomitant medications known to prolong the QTc interval and definitely or possibly associated with a risk of torsades de pointes, compared with 1 of the 6 patients who received vancomycin. A similar number of patients in each treatment group (60 msec from baseline. In a separate analysis, 1 patient in the telavancin hydrochloride group and 2 patients in the vancomycin group experienced QTc >500 msec. No cardiac adverse events were ascribed to prolongation of the QTc interval. In the Phase 3 HABP/VABP studies, the incidence of QTc prolongation >60 msec or mean value >500 msec was 8% (52 patients) in the telavancin group and 7% (48 patients) in the vancomycin group.

## Pharmacokinetics
The mean pharmacokinetic parameters of telavancin (10 mg/kg) after a single and multiple 60-minute intravenous infusions (10 mg/kg every 24 hours) are summarized in TABLE 8.
In healthy young adults, the pharmacokinetics of telavancin administered intravenously were linear following single doses from 5 to 12.5 mg/kg and multiple doses from 7.5 to 15 mg/kg administered once daily for up to 7 days. Steady-state concentrations were achieved by the third daily dose.
Telavancin binds to human plasma proteins, primarily to serum albumin, in a concentration-independent manner. The mean binding is approximately 90% and is not affected by renal or hepatic impairment.
Concentrations of telavancin in pulmonary epithelial lining fluid (ELF) and alveolar macrophages (AM) were measured through collection of bronchoalveolar lavage fluid at various times following administration of telavancin hydrochloride 10 mg/kg once daily for 3 days to healthy adults. Telavancin concentrations in ELF and AM exceeded the MIC90 for S. aureus (0.5 mcg/mL) for at least 24 hours following dosing.
Concentrations of telavancin in skin blister fluid were 40% of those in plasma (AUC0-24hr ratio) after 3 daily doses of 7.5 mg/kg telavancin hydrochloride in healthy young adults.
No metabolites of telavancin were detected in in vitro studies using human liver microsomes, liver slices, hepatocytes, and kidney S9 fraction. None of the following recombinant CYP 450 isoforms were shown to metabolize telavancin in human liver microsomes: CYP 1A2, 2C9, 2C19, 2D6, 3A4, 3A5, 4A11. The clearance of telavancin is not expected to be altered by inhibitors of any of these enzymes.
In a mass balance study in male subjects using radiolabeled telavancin, 3 hydroxylated metabolites were identified with the predominant metabolite (THRX-651540) accounting for <10% of the radioactivity in urine and <2% of the radioactivity in plasma. The metabolic pathway for telavancin has not been identified.
Telavancin is primarily eliminated by the kidney. In a mass balance study, approximately 76% of the administered dose was recovered from urine and <1% of the dose was recovered from feces (collected up to 216 hours) based on total radioactivity.

## Nonclinical Toxicology
In vitro investigations demonstrated no antagonism between telavancin and amikacin, aztreonam, cefepime, ceftriaxone, ciprofloxacin, gentamicin, imipenem, meropenem, oxacillin, piperacillin/tazobactam, rifampin, and trimethoprim/sulfamethoxazole when tested in various combinations against telavancin-susceptible staphylococci, streptococci, and enterococci. This information is not available for other bacteria.
Some vancomycin-resistant enterococci have a reduced susceptibility to telavancin. There is no known cross-resistance between telavancin and other classes of antibacterial drugs.
Telavancin has been shown to be active against most isolates of the following microorganisms both in vitro and in clinical infections as described in the Indications and Usage section:
- Facultative Gram-Positive Microorganisms
- Staphylococcus aureus (including methicillin-resistant isolates)
- Enteroc occus faecalis (vancomycin-susceptible isolates only)
- Streptococcus agalactiae
- Streptococcus anginosus group (includes S. anginosus, S. intermedius, and S. constellatus)
- Streptococcus pyogenes
Greater than 90% of the following microorganisms exhibit an in vitro MIC less than or equal to the telavancin-susceptible breakpoint for organisms of similar genus shown in TABLE 9. The safety and effectiveness of telavancin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.
- Facultative Gram-Positive Microorganisms
- Enterococcus faecium (vancomycin-susceptible isolates only)
- Staphylococcus haemolyticus
- Streptococcus dysgalactiae subsp. equisimilis
- Staphylococcus epidermidis
Long-term studies in animals to determine the carcinogenic potential of telavancin have not been performed.
Neither mutagenic nor clastogenic potential of telavancin was found in a battery of tests including: assays for mutagenicity (Ames bacterial reversion), an in vitro chromosome aberration assay in human lymphocytes, and an in vivo mouse micronucleus assay.
Two-week administration of telavancin in rats produced minimal renal tubular vacuolization with no changes in BUN or creatinine. These effects were not seen in studies conducted in dogs for similar duration. Four weeks of treatment resulted in reversible elevations in BUN and/or creatinine in association with renal tubular degeneration that further progressed following 13 weeks of treatment.
These effects occurred at exposures (based on AUCs) that were similar to those measured in clinical trials.
The potential effects of continuous venovenous hemofiltration (CVVH) on the clearance of telavancin were examined in an in vitro model using bovine blood. Telavancin was cleared by CVVH and the clearance of telavancin increased with increasing ultrafiltration rate.

# Clinical Studies
Adult patients with clinically documented complicated skin and skin structure infections (cSSSI) were enrolled in two randomized, multinational, multicenter, double-blinded trials (Trial 1 and Trial 2) comparing telavancin hydrochloride (10 mg/kg IV every 24 hours) with vancomycin (1 g IV every 12 hours) for 7 to 14 days. Vancomycin dosages could be adjusted per site-specific practice. Patients could receive concomitant aztreonam or metronidazole for suspected Gram-negative and anaerobic infection, respectively. These trials were identical in design, enrolling approximately 69% of their patients from the United States.
The trials enrolled adult patients with cSSSI with suspected or confirmed MRSA as the primary cause of infection. The all-treated efficacy (ATe) population included all patients who received any amount of study medication according to their randomized treatment group and were evaluated for efficacy. The clinically evaluable population (CE) included patients in the ATe population with sufficient adherence to the protocol.
The ATe population consisted of 1,794 patients. Of these, 1,410 (79%) patients were clinically evaluable (CE). Patient baseline infection types were well-balanced between treatment groups and are presented in TABLE 11.
The primary efficacy endpoints in both trials were the clinical cure rates at a follow-up (Test of Cure) visit in the ATe and CE populations. Clinical cure rates in Trials 1 and 2 are displayed for the ATe and CE population in TABLE 12.
The cure rates by pathogen for the microbiologically evaluable (ME) population are presented in TABLE 13.
In the two cSSSI trials, clinical cure rates were similar across gender and race. Clinical cure rates in the telavancin hydrochloride clinically evaluable (CE) population were lower in patients 65 years of age compared with those 50 mL/min. A decrease of this magnitude was not observed in the vancomycin-treated patients .
Adult patients with hospital-acquired and ventilator-associated pneumonia were enrolled in two randomized, parallel-group, multinational, multicenter, double-blinded trials of identical design comparing telavancin hydrochloride (10 mg/kg IV every 24 hours) with vancomycin (1 g IV every 12 hours) for 7 to 21 days. Vancomycin dosages could be adjusted for body weight and/or renal function per local guidelines. Patients could receive concomitant aztreonam or metronidazole for suspected Gram-negative and anaerobic infection, respectively. The addition of piperacillin/tazobactam was also permitted for coverage of Gram-negative organisms if resistance to aztreonam was known or suspected. Patients with known or suspected infections due to methicillin-resistant Staphylococcus aureus were enrolled in the studies.
Of the patients enrolled across both trials, 64% were male and 70% were white.The mean age was 63 years. At baseline, more than 50% were admitted to an intensive care unit, about 23% had chronic obstructive pulmonary disease, about 29% had ventilator-associated pneumonia and about 6% had bacteremia. Demographic and baseline characteristics were generally well-balanced between treatment groups; however, there were differences between HABP/VABP Trial 1 and HABP/VABP Trial 2 with respect to a baseline history of diabetes mellitus (31% in Trial 1, 21% in Trial 2) and baseline renal insufficiency (CrCl  50 mL/min) (36% in Trial 1, 27% in Trial 2).
All-cause mortality was evaluated because there is historical evidence of treatment effect for this endpoint. This was a protocol pre-specified secondary endpoint. The 28-day all-cause mortality outcomes(overall and by baseline creatinine clearance categorization) in the group of patients who had at least one baseline Gram-positive respiratory pathogen are shown in TABLE 14. This group of patients included those who had mixed Gram-positive/Gram-negative infections.
The protocol-specified analysis included clinical cure rates at the TOC (7 to 14 days after the last dose of study drug) in the co-primary All-Treated (AT) and Clinically Evaluable (CE) populations (TABLE 15). Clinical cure was determined by resolution of signs and symptoms, no further antibacterial therapy for HABP/VABP after end-of-treatment, and improvement or no progression of baseline radiographic findings. However, the quantitative estimate of treatment effect for this endpoint has not been established.

# How Supplied
- Cartons of 10 individually packaged 250 mg single-dose vials (NDC 62847-002-01)
- Cartons of 10 individually packaged 750 mg single-dose vials (NDC 62847-001-01)

## Storage
Store at refrigerated temperatures of 2 to 8C (35 to 46 F).

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
Women of childbearing potential (those who have not had: complete absence of menses for at least 24 months or medically confirmed menopause, medically confirmed primary ovarian failure, a history of hysterectomy, bilateral oophorectomy, or tubal ligation) should:
- Be informed about the potential risk of fetal harm if telavancin hydrochloride is used during pregnancy
- Have a pregnancy test prior to administration of telavancin hydrochloride
- If not pregnant, use effective contraceptive methods to prevent pregnancy during telavancin hydrochloride treatment
- Notify their prescribing physician/ healthcare provider if they become pregnant during telavancin hydrochloride treatment
There is a pregnancy registry that monitors pregnancy outcomes in women exposed to telavancin hydrochloride during pregnancy. Physicians are encouraged to register pregnant patients, or pregnant women may enroll themselves in the pregnancy registry by calling 1-855-633-8479 FREE.
Diarrhea is a common problem caused by antibiotics that usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as 2 or more months after having received the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.
Patients should be counseled that antibacterial drugs including telavancin hydrochloride should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When telavancin hydrochloride 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 immediate treatment, and (2) increase the likelihood that the bacteria will develop resistance and will not be treatable by telavancin hydrochloride or other antibacterial drugs in the future.
Patients should be informed about the common adverse effects of telavancin hydrochloride including diarrhea, dysgeusia, nausea, vomiting, headache, and proteinuria. Patients should be instructed to inform their healthcare provider if they develop any unusual symptom, or if any known symptom persists or worsens. Patients should be instructed to inform their healthcare provider of any other medications they are currently taking with telavancin hydrochloride, including over-the-counter medications.

# Precautions with Alcohol
Alcohol-Telavancin hydrochloride interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- Vibativ 

# Look-Alike Drug Names
There is limited information regarding Telavancin hydrochloride Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price