Telavancin

Risk Summary

Based on findings in animal reproduction studies, telavancin may cause fetal harm. There are no available data on telavancin use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. 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 providing approximately 1- to 2-fold the human exposure at the maximum recommended clinical dose (see Data). Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

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 recommended clinical 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.

Risk Summary

There are no data on the presence of telavancin in human milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for telavancin and any potential adverse effects on the breastfed child from telavancin or from the underlying maternal conditions.

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 (up to 100 mg/kg/day for at least 4 weeks prior to mating) or female rats (up to 150 mg/kg/day for at least 2 weeks prior to mating).

Male rats given 50 or 100 mg/kg/day telavancin for 6 weeks, at exposure levels similar to those measured in clinical studies, displayed altered sperm parameters that were reversible following an 8-week recovery period. A longer dosing period showed that telavancin caused histopathological changes in the seminiferous tubules and epididymides of the rat testis after 13 weeks of administration at 50 or 100 mg/kg/day. These changes were reversible at the end of a 4 week recovery period.

• 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.

Clinical Trials Experience

Complicated Skin and Skin Structure Infections

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

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

Table 1 displays the incidence of treatment-emergent adverse drug reactions reported in ≥2% of patients treated with telavancin possibly related to the drug.

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

^* Described as metallic or soapy taste.

HABP/VABP

Two randomized, double-blind Phase 3 trials (Trial 1 and Trial 2) for telavancin included 1,503 adult patients treated with telavancin at 10 mg/kg IV once daily or vancomycin at 1 g IV twice daily. The mean age of patients treated with telavancin was 62 years (range 18-100) with 69% of the patients white and 65% male. In the combined telavancin group, 29% were VAP and 71% were HAP patients.

Table 2 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 telavancin for HABP/VABP had increased mortality observed versus vancomycin in both the trials.

Table 2. 28-Day Mortality* Stratified by Baseline Creatinine Clearance- All-Treated Analysis Population:

^* (Kaplan-Meier Estimates)

Serious adverse events were reported in 31% of patients treated with telavancin and 26% of patients who received vancomycin. Treatment discontinuations due to adverse events occurred in 8% (60/751) of patients who received telavancin, 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 3 displays the incidence of treatment-emergent adverse drug reactions reported in ≥5% of HABP/VABP patients treated with telavancin possibly related to the drug.

Table 3. Incidence of Treatment Emergent Adverse Drug Reactions Reported in ≥5% of Patients Treated in HABP/VABP Trial 1 and Trial 2:

Nephrotoxicity

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

Fifteen of 174 (9%) telavancin-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 telavancin 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-treated patients and 2% of vancomycintreated patients experienced at least one serious renal adverse event. Renal adverse events resulted in discontinuation of study medication in 14 telavancin-treated patients (2%) and 7 vancomycin-treated patients (1%).

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

Forty-four of 399 (11.0%) telavancin-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. 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, including anaphylactic reactions. It is unknown if patients with hypersensitivity reactions to vancomycin will experience crossreactivity to telavancin.