Vibativ

Overdose

In the event of overdosage, VIBATIV 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 VIBATIV 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.

Contraindications

Use of intravenous unfractionated heparin sodium is contraindicated with VIBATIV administration because the activated partial thromboplastin time (aPTT) test results are expected to be artificially prolonged for 0 to 18 hours after VIBATIV administration.

VIBATIV is contraindicated in patients with known hypersensitivity to telavancin.

Undesirable effects

The following serious adverse reactions are also discussed elsewhere in the labeling:

• Nephrotoxicity
• Infusion-related reactions
• Clostridium difficile-associated diarrhea

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 two Phase 3 cSSSI clinical trials (Trial 1 and Trial 2) for VIBATIV included 929 adult patients treated with VIBATIV at 10 mg/kg IV once daily. The mean age of patients treated with VIBATIV was 49 years (range 18-96). There was a slight male predominance (56%) in patients treated with VIBATIV, and patients were predominantly Caucasian (78%).

In the cSSSI clinical trials, <1% (8/929) patients who received VIBATIV died and <1% (8/938) patients treated with vancomycin died. Serious adverse events were reported in 7% (69/929) of patients treated with VIBATIV 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 VIBATIV, 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 VIBATIV-treated patients observed in the VIBATIV Phase 3 cSSSI trials were taste disturbance, nausea, vomiting, and foamy urine.

Table 4 displays the incidence of treatment-emergent adverse drug reactions reported in ≥2% of patients treated with VIBATIV possibly related to the drug.

Table 4: Incidence of Treatment-Emergent Adverse Drug Reactions Reported in ≥2% of VIBATIV or Vancomycin Patients Treated in cSSSI Trial 1 and Trial 2

Two randomized, double-blind Phase 3 trials (Trial 1 and Trial 2) for VIBATIV included 1,503 adult patients treated with VIBATIV at 10 mg/kg IV once daily or vancomycin at 1 g IV twice daily. The mean age of patients treated with VIBATIV was 62 years (range 18-100). In patients treated with VIBATIV, 69% of the patients were white and 65% were male. In the combined VIBATIV 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 (CrCl ≤50 mL/min) who were treated with VIBATIV for HABP/VABP had increased mortality observed versus vancomycin in both the trials.

Table 5: 28-Day Mortality (Kaplan-Meier Estimates ) Stratified by Baseline Creatinine Clearance — All-Treated Analysis Population

Serious adverse events were reported in 31% of patients treated with VIBATIV and 26% of patients who received vancomycin. Treatment discontinuations due to adverse events occurred in 8% (60/751) of patients who received VIBATIV, 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 VIBATIV possibly related to the drug.

Table 6: Incidence of Treatment-Emergent Adverse Drug Reactions Reported in ≥5% of VIBATIV or Vancomycin Patients Treated in HABP/VABP Trial 1 and Trial 2

Complicated Skin and Skin Structure Infections

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 VIBATIVtreated patients compared with 10/938 (1%) of vancomycin-treated patients. In 17 of the 30 VIBATIVtreated 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 VIBATIV-treated patients compared with 3/938 (0.3%) of vancomycintreated patients. Twelve patients treated with VIBATIV 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 VIBATIV-treated patients with normal baseline serum creatinine (15%) compared with vancomycin-treated patients with normal baseline serum creatinine (7%).

Fifteen of 174 (9%) VIBATIV-treated patients ≥65 years of age had adverse events indicative of renal impairment compared with 16 of 755 patients (2%) <65 years of age.

Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia

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 VIBATIV 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 VIBATIV-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 VIBATIV-treated patients (2%) and 7 vancomycin-treated patients (1%).

Increases in serum creatinine to 1.5 times baseline occurred more frequently among VIBATIV-treated patients (16%) compared with vancomycin-treated patients (10%).

Forty-four of 399 (11.0%) VIBATIV-treated patients ≥65 years of age had adverse events indicative of renal impairment compared with 30 of 352 patients (8%) <65 years of age.

The following adverse reactions have been identified during post-approval use of VIBATIV. 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 VIBATIV, including anaphylactic reactions. It is unknown if patients with hypersensitivity reactions to vancomycin will experience cross-reactivity to telavancin.

Therapeutic indications

VIBATIV is indicated for the treatment of adult patients with complicated skin and skin structure infections (cSSSI) 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).

VIBATIV is indicated for the treatment of adult patients with hospital-acquired and ventilatorassociated bacterial pneumonia (HABP/VABP), caused by susceptible isolates of Staphylococcus aureus (both methicillin-susceptible and -resistant isolates). VIBATIV should be reserved for use when alternative treatments are not suitable.

Combination therapy may be clinically indicated if the documented or presumed pathogens include Gram-negative organisms.

Appropriate specimens for bacteriological examination should be obtained in order to isolate and identify the causative pathogens and to determine their susceptibility to telavancin. VIBATIV may be initiated as empiric therapy before results of these tests are known.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of VIBATIV and other antibacterial drugs, VIBATIV should be used only to treat infections 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.

Pharmacodynamic properties

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 VIBATIV 7.5 mg/kg, VIBATIV 15 mg/kg, positive control, or placebo infused over 60 minutes once daily for 3 days. Based on interpolation of the data from VIBATIV 7.5 mg/kg and 15 mg/kg, the mean maximum baseline-corrected, placebocorrected QTc prolongation at the end of infusion was estimated to be 12-15 msec for VIBATIV 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 VIBATIV and 15 msec for the positive control.

Table 7: Mean and Maximum QTcF Changes from Baseline Relative to Placebo

ECGs were performed prior to and during the treatment period in patients receiving VIBATIV 10 mg/kg in 3 cSSSI studies to monitor QTc intervals. In these trials, 214 of 1029 (21%) patients allocated to treatment with VIBATIV 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 VIBATIV group and 0.6% (6 patients) in the vancomycin group. Nine of the 15 VIBATIV 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 ( < 1%) who did not receive a concomitant medication known to prolong the QTc interval experienced a prolongation > 60 msec from baseline. In a separate analysis, 1 patient in the VIBATIV 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.

Pharmacokinetic properties

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.

Table 8: Pharmacokinetic Parameters of Telavancin in Healthy Adults, 10 mg/kg

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 VIBATIV 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 (AUC0-2 4hr ratio) after 3 daily doses of 7.5 mg/kg VIBATIV 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.

Date of revision of the text

Name of the medicinal product

Fertility, pregnancy and lactation

Pregnancy Exposure Registry

There is a pregnancy registry that monitors pregnancy outcomes in women exposed to VIBATIV during pregnancy. Physicians are encouraged to register pregnant patients, or pregnant women may enroll themselves in the VIBATIV pregnancy registry by calling 1-855-633-8479.

Fetal Risk Summary

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 VIBATIV use in pregnant women. In 3 animal species, VIBATIV 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).

Clinical Considerations

Given the lack of human data and the risks suggested by animal data, avoid using VIBATIV in pregnant women unless the benefits to the patient outweigh the potential risks to the fetus.

Human Data

There are no data on human pregnancies exposed to VIBATIV.

Animal Data

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.

Qualitative and quantitative composition

VIBATIV is supplied in single-use vials containing either 250 or 750 mg telavancin as a sterile, lyophilized powder.

• 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)

Store original packages at refrigerated temperatures of 2 to 8°C (35 to 46°F). Excursions to ambient temperatures (up to 25 °C (77°F)) are acceptable. Avoid excessive heat.

Manufactured by: Theravance Biopharma Antibiotics, Inc. Revised: May 2016

Special warnings and precautions for use

Included as part of the "PRECAUTIONS" Section

In the analysis of patients (classified by the treatment received) in the two combined HABP/VABP trials with pre-existing moderate/severe renal impairment (CrCl ≤50 mL/min), all-cause mortality within 28 days of starting treatment was 95/241 (39%) in the VIBATIV 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 VIBATIV group and 92/510 (18%) in the vancomycin group. Therefore, VIBATIV use in patients with baseline CrCl ≤50 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 VIBATIV-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.

Table 2: Clinical Cure by Pre-existing Renal Impairment – Clinically Evaluable Population

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 VIBATIV. 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 VIBATIV 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 VIBATIV during pregnancy unless the potential benefit to the patient outweighs the potential risk to the fetus. VIBATIV 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 VIBATIV. If not already pregnant, women of childbearing potential should use effective contraception during VIBATIV 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 VIBATIV 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 VIBATIV. Blood samples for coagulation tests unaffected by VIBATIV may be collected at any time.

For patients who require aPTT monitoring while being treated with VIBATIV, a non phospholipid dependent coagulation test such as a Factor Xa (chromogenic) assay or an alternative anticoagulant not requiring aPTT monitoring may be considered.

Table 3: Coagulation Tests Affected and Unaffected by Telavancin

No evidence of increased bleeding risk has been observed in clinical trials with VIBATIV. Telavancin has no effect on platelet aggregation. Furthermore, no evidence of hypercoagulability has been seen, as healthy subjects receiving VIBATIV 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 VIBATIV 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. VIBATIV should be used with caution in patients with known hypersensitivity to vancomycin.

VIBATIV 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-toxinproducing 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 VIBATIV 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 VIBATIV 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 VIBATIV prolonged the QTc interval. Caution is warranted when prescribing VIBATIV 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 VIBATIV. Use of VIBATIV should be avoided in patients with these conditions.

Advise the patient to read the FDA-approved patient labeling (Medication Guide)

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 VIBATIV is used during pregnancy
• Have a pregnancy test prior to administration of VIBATIV
• If not pregnant, use effective contraceptive methods to prevent pregnancy during VIBATIV treatment
• Notify their prescribing physician/ healthcare provider if they become pregnant during VIBATIV treatment

There is a pregnancy registry that monitors pregnancy outcomes in women exposed to VIBATIV 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.

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

Patients should be informed about the common adverse effects of VIBATIV including diarrhea, taste disturbance, nausea, vomiting, headache, and foamy urine. 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 VIBATIV, including over-the-counter medications.

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.

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.

Pregnancy Exposure Registry

There is a pregnancy registry that monitors pregnancy outcomes in women exposed to VIBATIV during pregnancy. Physicians are encouraged to register pregnant patients, or pregnant women may enroll themselves in the VIBATIV pregnancy registry by calling 1-855-633-8479.

Fetal Risk Summary

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 VIBATIV use in pregnant women. In 3 animal species, VIBATIV 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).

Clinical Considerations

Given the lack of human data and the risks suggested by animal data, avoid using VIBATIV in pregnant women unless the benefits to the patient outweigh the potential risks to the fetus.

Human Data

There are no data on human pregnancies exposed to VIBATIV.

Animal Data

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.

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

The safety and effectiveness of VIBATIV in pediatric patients has not been studied.

Of the 929 patients treated with VIBATIV 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 VIBATIV 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 VIBATIV 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.

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 VIBATIV-treated patients with baseline CrCl ≤50 mL/min. Use of VIBATIV in patients with pre-existing moderate/severe renal impairment should be considered only when the anticipated benefit to the patient outweighs the potential risk.

VIBATIV-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.

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 .

Dosage (Posology) and method of administration

The recommended dosing for VIBATIV is 10 mg/kg administered over a 60-minute period in patients ≥18 years of age by intravenous infusion once every 24 hours for 7 to 14 days. The duration of therapy should be guided by the severity and site of the infection and the patient's clinical progress.

The recommended dosing for VIBATIV is 10 mg/kg administered over a 60-minute period in patients ≥18 years of age by intravenous infusion once every 24 hours for 7 to 21 days. The duration of therapy should be guided by the severity of the infection and the patient's clinical progress.

Because telavancin is eliminated primarily by the kidney, a dosage adjustment is required for patients whose creatinine clearance is ≤50 mL/min, as listed in Table 1.

Table 1: Dosage Adjustment in Adult Patients with 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 undergoing hemodialysis.

Reconstitute the contents of a VIBATIV 250 mg vial with 15 mL of 5% Dextrose Injection, USP; Sterile Water for Injection, USP; or 0.9% Sodium Chloride Injection, USP. The resultant solution has a concentration of 15 mg/mL (total volume of approximately 17.0 mL).

Reconstitute the contents of a VIBATIV 750 mg vial with 45 mL of 5% Dextrose Injection, USP; Sterile Water for Injection, USP; or 0.9% Sodium Chloride Injection, USP. The resultant solution has a concentration of 15 mg/mL (total volume of approximately 50.0 mL).

To minimize foaming during product reconstitution, allow the vacuum of the vial to pull the diluent from the syringe into the vial. Do not forcefully inject the diluent into the vial. Do not forcefully shake the vial and do not shake final infusion solution.

The following formula can be used to calculate the volume of reconstituted VIBATIV solution required to prepare a dose:

Telavancin dose (mg) = 10 mg/kg or 7.5 mg/kg x patient weight (in kg) (see Table 1)

For doses of 150 to 800 mg, the appropriate volume of reconstituted solution must be further diluted in 100 to 250 mL prior to infusion. Doses less than 150 mg or greater than 800 mg should be further diluted in a volume resulting in a final concentration of 0.6 to 8 mg/mL. Appropriate infusion solutions include: 5% Dextrose Injection, USP; 0.9% Sodium Chloride Injection, USP; or Lactated Ringer’s Injection, USP. The dosing solution should be administered by intravenous infusion over a period of 60 minutes.

Reconstitution time is generally under 2 minutes, but can sometimes take up to 20 minutes. Mix thoroughly to reconstitute and check to see if the contents have dissolved completely. Parenteral drug products should be inspected visually for particulate matter prior to administration. Discard the vial if the vacuum did not pull the diluent into the vial.

Since no preservative or bacteriostatic agent is present in this product, aseptic technique must be used in preparing the final intravenous solution. Studies have shown that the reconstituted solution in the vial should be used within 12 hours when stored at room temperature or within 7 days under refrigeration at 2 to 8°C (36 to 46°F). The diluted (dosing) solution in the infusion bag should be used within 12 hours when stored at room temperature or used within 7 days when stored under refrigeration at 2 to 8°C (36 to 46°F). However, the total time in the vial plus the time in the infusion bag should not exceed 12 hours at room temperature and 7 days under refrigeration at 2 to 8°C (36 to 46°F). The diluted (dosing) solution in the infusion bag can also be stored at -30 to -10°C (-22 to 14°F) for up to 32 days.

VIBATIV is administered intravenously. Because only limited data are available on the compatibility of VIBATIV with other IV substances, additives or other medications should not be added to VIBATIV single-use vials or infused simultaneously through the same IV line. If the same intravenous line is used for sequential infusion of additional medications, the line should be flushed before and after infusion of VIBATIV with 5% Dextrose Injection, USP; 0.9% Sodium Chloride Injection, USP; or Lactated Ringer's Injection, USP.

Interaction with other medicinal products and other forms of interaction

The inhibitory activity of telavancin against the following CYP 450 enzymes was evaluated in human liver microsomes: CYP 1A2, 2C9, 2C19, 2D6, and 3A4/5. Telavancin inhibited CYP 3A4/5 at potentially clinically relevant concentrations. Upon further evaluation in a Phase 1 clinical trial, telavancin was found not to inhibit the metabolism of midazolam, a sensitive CYP3A substrate (see below).

The impact of telavancin on the pharmacokinetics of midazolam (CYP 3A4/5 substrate) was evaluated in 16 healthy adult subjects following administration of a single dose of VIBATIV 10 mg/kg, intravenous midazolam 1 mg, and both. The results showed that telavancin had no impact on the pharmacokinetics of midazolam and midazolam had no effect on the pharmacokinetics of telavancin.

The impact of telavancin on the pharmacokinetics of aztreonam was evaluated in 11 healthy adult subjects following administration of a single dose of VIBATIV 10 mg/kg, aztreonam 2 g, and both. Telavancin had no impact on the pharmacokinetics of aztreonam and aztreonam had no effect on the pharmacokinetics of telavancin. No dosage adjustment of telavancin or aztreonam is recommended when both drugs are coadministered.

The impact of telavancin on the pharmacokinetics of piperacillin-tazobactam was evaluated in 12 healthy adult subjects following administration of a single dose of VIBATIV 10 mg/kg, piperacillin-tazobactam 4.5 g, and both. Telavancin had no impact on the pharmacokinetics of piperacillin-tazobactam and piperacillin-tazobactam had no effect on the pharmacokinetics of telavancin. No dosage adjustment of telavancin or piperacillintazobactam is recommended when both drugs are coadministered.