VIBATIV Powder for solution for injection Ref.[27433] Active ingredients: Telavancin

5.1 Increased Mortality in Patients with HABP/VABP and Pre-existing Moderate to Severe Renal Impairment (CrCl ≤50 mL/min)

In the analysis of patients (classified by the treatment received) in the two combined HABP/VABP trials with preexisting 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. Allcause 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 [see Adverse Reactions (6.1), Use in Specific Populations (8.4) and Clinical Studies (14.2)].

5.2 Decreased Clinical Response in Patients with cSSSI and Pre-existing Moderate/Severe Renal Impairment (CrCl ≤50 mL/min)

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:

5.3 Nephrotoxicity

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 [see Dosage and Administration (2), Adverse Reactions (6), and Clinical Pharmacology (12.3)].

In patients with renal dysfunction, accumulation of the solubilizer hydroxypropyl-beta-cyclodextrin can occur [see Patients with Renal Impairment (8.6) and Clinical Pharmacology (12.3)].

5.4 Embryo-Fetal Toxicity

Based on findings in animal reproduction studies, VIBATIV may cause fetal harm. VIBATIV caused adverse developmental outcomes in 3 animal species at clinically relevant doses. Verify pregnancy status in females of reproductive potential prior to initiating VIBATIV. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with VIBATIV and for 2 days after the final dose [see Use in Specific Populations (8.1, 8.3)].

5.5 Coagulation Test Interference

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 [see Drug Interactions (7.1)].

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.

5.6 Hypersensitivity Reactions

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 [see Postmarketing Experience (6.2)].

5.7 Infusion-Related Reactions

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.

5.8 Clostridium difficile-Associated Diarrhea

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.

5.9 Development of Drug-Resistant Bacteria

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.

5.10 QTc Prolongation

In a study involving healthy volunteers, doses of 7.5 and 15 mg/kg of VIBATIV prolonged the QTc interval [see Clinical Pharmacology (12.2)]. 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.

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

• Nephrotoxicity [see Warnings and Precautions (5.3)]
• Infusion-related reactions [see Warnings and Precautions (5.7)]
• Clostridium difficile-associated diarrhea [see Warnings and Precautions (5.8)]

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.

Complicated Skin and Skin Structure Infections

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 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 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) with 69% of the patients white and 65% 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* Stratified by Baseline Creatinine Clearance- All-Treated Analysis Population:

^* (Kaplan-Meier Estimates)

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 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 VIBATIV-treated patients compared with 10/938 (1%) of vancomycin-treated patients. In 17 of the 30 VIBATIV-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 VIBATIV-treated patients compared with 3/938 (0.3%) of vancomycin-treated 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 [see Use in Specific Populations (8.5)].

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 vancomycintreated 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 [see Use in Specific Populations (8.5)].

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 crossreactivity to telavancin [see Hypersensitivity Reactions (5.6)].

7.1 Drug-Laboratory Test Interactions

Effects of Telavancin on Coagulation Test Parameters

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 VIBATIV, increases in the PT, INR, aPTT, and ACT have been observed. These effects dissipate over time, as plasma concentrations of telavancin decrease.

Urine Protein Tests

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 VIBATIV treatment.

Risk Summary

Based on findings in animal reproduction studies, VIBATIV may cause fetal harm. There are no available data on VIBATIV 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 VIBATIV and any potential adverse effects on the breastfed child from VIBATIV or from the underlying maternal conditions.

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating VIBATIV.

Contraception

Females

VIBATIV may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment and for 2 days after the final dose.

Infertility

Males

Based on findings in rats, VIBATIV may impair male fertility [see Nonclinical Toxicology (13.1)]. The effect on fertility was reversible in rats.

The safety and effectiveness of VIBATIV have not been established in pediatric patients. In particular, there is a concern for poor clinical outcomes in pediatric patients less than one year of age due to immature renal function. Increased mortality in adult patients with HABP/VABP and renal impairment and decreased clinical response in adults with cSSSI and renal impairment were observed [see Boxed Warning and Warnings and Precautions (5.1, 5.2)].

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 [see Warnings and Precautions (5.3), Clinical Trials (14.1)].

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 [see Dosage and Administration (2), Clinical Pharmacology (12.3)].

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 [see Warnings and Precautions (5.3)].

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 [see Warnings and Precautions (5.1)].

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) [see Warnings and Precautions (5.2)].

Dosage adjustment is required in patients with ≤50 mL/min renal impairment [see Dosage and Administration (2)]. 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 [see Overdosage (10), Clinical Pharmacology (12.3)].

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 [see Warnings and Precautions (5.3), Clinical Pharmacology (12.3)].

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 [see Clinical Pharmacology (12.3)].