INDICATIONS
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.
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.
COMPLICATED SKIN AND SKIN STRUCTURE INFECTIONS
VIBATIV (TELAVANCIN) 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).
HABP/VABP
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 (INCLUDING METHICILLIN-SUSCEPTIBLE AND -RESISTANT ISOLATES). VIBATIV SHOULD BE RESERVED FOR USE WHEN ALTERNATIVE TREATMENTS ARE NOT SUITABLE.
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
VIBATIV IS SUPPLIED IN SINGLE-USE VIALS CONTAINING EITHER 250 OR 750 MG TELAVANCIN AS A STERILE, LYOPHILIZED POWDER.
STORAGE AND HANDLING
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. MARKETED BY: THERAVANCE BIOPHARMA US, INC., SOUTH SAN FRANCISCO, CA 94080. REVISED: DECEMBER 2014
DOSAGE AND ADMINISTRATION
COMPLICATED SKIN AND SKIN STRUCTURE INFECTIONS
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.
HOSPITAL-ACQUIRED BACTERIAL PNEUMONIA/VENTILATOR-ASSOCIATED BACTERIAL PNEUMONIA (HABP/VABP)
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.
PATIENTS WITH RENAL IMPAIRMENT
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 [SEE CLINICAL PHARMACOLOGY].
TABLE 1: DOSAGE ADJUSTMENT IN ADULT PATIENTS WITH RENAL IMPAIRMENT
CREATININE CLEARANCEA (CRCL) (ML/MIN) VIBATIV DOSAGE REGIMEN
> 50 10 MG/KG EVERY 24 HOURS
30-50 7.5 MG/KG EVERY 24 HOURS
10- < 30 10 MG/KG EVERY 48 HOURS
ACALCULATE USING THE COCKCROFT-GAULT FORMULA AND IDEAL BODY WEIGHT (IBW). USE ACTUAL BODY WEIGHT IF IT IS LESS THAN IBW.
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.
PREPARATION AND ADMINISTRATION
250 MG VIAL
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).
750 MG VIAL
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)
VOLUME OF RECONSTITUTED SOLUTION (ML) = TELAVANCIN DOSE (MG)/ 15 MG/ML
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.
SIDE EFFECTS
THE FOLLOWING SERIOUS ADVERSE REACTIONS ARE ALSO DISCUSSED ELSEWHERE IN THE LABELING:
" NEPHROTOXICITY [SEE WARNINGS AND PRECAUTIONS]
" INFUSION-RELATED REACTIONS [SEE WARNINGS AND PRECAUTIONS]
" CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA [SEE WARNINGS AND PRECAUTIONS]
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 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
VIBATIV
(N=929) VANCOMYCIN
(N=938)
BODY AS A WHOLE
RIGORS 4% 2%
DIGESTIVE SYSTEM
NAUSEA 27% 15%
VOMITING 14% 7%
DIARRHEA 7% 8%
METABOLIC AND NUTRITIONAL
DECREASED APPETITE 3% 2%
NERVOUS SYSTEM
TASTE DISTURBANCE* 33% 7%
RENAL SYSTEM
FOAMY URINE 13% 3%
* DESCRIBED AS A 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). 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
VIBATIV (N=751) VANCOMYCIN (N=752)
NAUSEA 5% 4%
VOMITING 5% 4%
RENAL FAILURE ACUTE 5% 4%
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 VIBATIVTREATED 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].
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].
POSTMARKETING EXPERIENCE
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. [SEE HYPERSENSITIVITY REACTIONS]
READ THE VIBATIV (TELAVANCIN FOR INJECTION) SIDE EFFECTS CENTER FOR A COMPLETE GUIDE TO POSSIBLE SIDE EFFECTS
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 [SEE CLINICAL PHARMACOLOGY].
THE CLEARANCE OF TELAVANCIN BY CONTINUOUS VENOVENOUS HEMOFILTRATION (CVVH) WAS EVALUATED IN AN IN VITRO STUDY [SEE NONCLINICAL TOXICOLOGY]. 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.
CLINICAL PHARMACOLOGY
MECHANISM OF ACTION
TELAVANCIN IS AN ANTIBACTERIAL DRUG [SEE MICROBIOLOGY].
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.
CARDIAC ELECTROPHYSIOLOGY
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
QTCF1 CHANGE FROM BASELINE
MEAN (UPPER 90% CONFIDENCE LIMIT2) MSEC MAXIMUM (UPPER 90% CONFIDENCE LIMIT) MSEC
VIBATIV 7.5 MG/KG 4.1 (7) 11.6 (16)
VIBATIV 15 MG/KG 4.6 (8) 15.1 (20)
POSITIVE CONTROL 9.5 (13) 21.6 (26)
1 FRIDERICIA CORRECTED
2UPPER CL FROM A 2-SIDED 90% CI ON DIFFERENCE FROM PLACEBO (MSEC)
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.
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.
TABLE 8: PHARMACOKINETIC PARAMETERS OF TELAVANCIN IN HEALTHY ADULTS, 10 MG/KG
SINGLE DOSE
(N=42) MULTIPLE DOSE
(N=36)
CMAX (MCG/ML) 93.6 ±14.2 108 ± 26
AUC0-?(MCGoHR/ML) 747 ± 129 -1
AUC0-24H (MCGoHR/ML) 666 ± 107 780 ± 125
T½ (HR) 8.0 ± 1.5 8.1 ± 1.5
CL (ML/HR/KG) 13.9 ± 2.9 13.1 ± 2.0
VSS (ML/KG) 145 ± 23 133 ± 24
CMAX MAXIMUM PLASMA CONCENTRATION
AUC AREA UNDER CONCENTRATION-TIME COURSE
T½ TERMINAL ELIMINATION HALF-LIFE
CL CLEARANCE
VSS APPARENT VOLUME OF DISTRIBUTION AT STEADY STATE
1 DATA NOT AVAILABLE
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.
DISTRIBUTION
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 (AUC0-24HR RATIO) AFTER 3 DAILY DOSES OF 7.5 MG/KG VIBATIV IN HEALTHY YOUNG ADULTS.
METABOLISM
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.
EXCRETION
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.
SPECIFIC POPULATIONS
GERIATRIC PATIENTS
THE IMPACT OF AGE ON THE PHARMACOKINETICS OF TELAVANCIN WAS EVALUATED IN HEALTHY YOUNG (RANGE 21-42 YEARS) AND ELDERLY (RANGE 65-83 YEARS) SUBJECTS. THE MEAN CRCL OF ELDERLY SUBJECTS WAS 66 ML/MIN. AGE ALONE DID NOT HAVE A CLINICALLY MEANINGFUL IMPACT ON THE PHARMACOKINETICS OF TELAVANCIN [SEE USE IN SPECIFIC POPULATIONS].
PEDIATRIC PATIENTS
THE PHARMACOKINETICS OF TELAVANCIN IN PATIENTS LESS THAN 18 YEARS OF AGE HAVE NOT BEEN STUDIED.
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.
RENAL IMPAIRMENT
THE PHARMACOKINETICS OF TELAVANCIN WERE EVALUATED IN SUBJECTS WITH NORMAL RENAL FUNCTION AND SUBJECTS WITH VARYING DEGREES OF RENAL IMPAIRMENT FOLLOWING ADMINISTRATION OF A SINGLE DOSE OF TELAVANCIN 7.5 MG/KG (N=28). THE MEAN AUC0-" VALUES WERE APPROXIMATELY 13%, 29%, AND 118% HIGHER FOR SUBJECTS WITH CRCL > 50 TO 80 ML/MIN, CRCL 30 TO 50 ML/MIN, AND CRCL < 30 ML/MIN, RESPECTIVELY, COMPARED WITH SUBJECTS WITH NORMAL RENAL FUNCTION. DOSAGE ADJUSTMENT IS REQUIRED IN PATIENTS WITH CRCL ? 50 ML/MIN [SEE DOSAGE AND ADMINISTRATION].
CREATININE CLEARANCE WAS ESTIMATED FROM SERUM CREATININE BASED ON THE COCKCROFT-GAULT FORMULA:
MALES: (WEIGHT IN KG) X (140 - AGE)
(72) X SERUM CREATININE (MG/100 ML)
FEMALES (0.85) X (ABOVE VALUE)
*USE ACTUAL BODY WEIGHT IF < IDEAL BODY WEIGHT (IBW)
IBW (MALE) = 50 KG + 0.9 KG/CM OVER 152 CM HEIGHT
IBW (FEMALE) = 45.5 KG + 0.9 KG/CM OVER 152 CM HEIGHT
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. THE EFFECTS OF PERITONEAL DIALYSIS HAVE NOT BEEN STUDIED.
FOLLOWING A SINGLE INTRAVENOUS DOSE OF VIBATIV 7.5 MG/KG, THE CLEARANCE OF HYDROXYPROPYLBETA- CYCLODEXTRIN WAS REDUCED IN SUBJECTS WITH RENAL IMPAIRMENT, RESULTING IN A HIGHER EXPOSURE TO HYDROXYPROPYL-BETA-CYCLODEXTRIN. IN SUBJECTS WITH MILD, MODERATE, AND SEVERE RENAL IMPAIRMENT, THE MEAN CLEARANCE VALUES WERE 38%, 59%, AND 82% LOWER, RESPECTIVELY, COMPARED WITH SUBJECTS WITH NORMAL RENAL FUNCTION. MULTIPLE INFUSIONS OF VIBATIV MAY RESULT IN ACCUMULATION OF HYDROXYPROPYL-BETA-CYCLODEXTRIN.
HEPATIC IMPAIRMENT
THE PHARMACOKINETICS OF TELAVANCIN WERE NOT ALTERED IN SUBJECTS WITH MODERATE HEPATIC IMPAIRMENT (N= 8, CHILD-PUGH B) COMPARED WITH HEALTHY SUBJECTS WITH NORMAL HEPATIC FUNCTION MATCHED FOR GENDER, AGE, AND WEIGHT. THE PHARMACOKINETICS OF TELAVANCIN HAVE NOT BEEN EVALUATED IN PATIENTS WITH SEVERE HEPATIC IMPAIRMENT (CHILD-PUGH C).
DRUG INTERACTIONS
IN VITRO
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).
MIDAZOLAM
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.
AZTREONAM
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.
PIPERACILLIN-TAZOBACTAM
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.
MICROBIOLOGY
TELAVANCIN IS A SEMISYNTHETIC, LIPOGLYCOPEPTIDE ANTIBIOTIC. TELAVANCIN EXERTS CONCENTRATION-DEPENDENT, BACTERICIDAL ACTIVITY AGAINST GRAM-POSITIVE ORGANISMS IN VITRO, AS DEMONSTRATED BY TIME-KILL ASSAYS AND MBC/MIC (MINIMUM BACTERICIDAL CONCENTRATION/MINIMUM INHIBITORY CONCENTRATION) RATIOS USING BROTH DILUTION METHODOLOGY. IN VITRO STUDIES DEMONSTRATED A TELAVANCIN POST-ANTIBIOTIC EFFECT RANGING FROM 1 TO 6 HOURS AGAINST S. AUREUS AND OTHER GRAM-POSITIVE PATHOGENS.
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.
INTERACTIONS WITH OTHER ANTIBACTERIAL DRUGS
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.
CROSS-RESISTANCE
SOME VANCOMYCIN-RESISTANT ENTEROCOCCI HAVE A REDUCED SUSCEPTIBILITY TO TELAVANCIN. THERE IS NO KNOWN CROSS-RESISTANCE BETWEEN TELAVANCIN AND OTHER CLASSES OF ANTIBACTERIAL DRUGS.
ANTIBACTERIAL ACTIVITY
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 [SEE INDICATIONS AND USAGE]:
FACULTATIVE GRAM-POSITIVE MICROORGANISMS
STAPHYLOCOCCUS AUREUS (INCLUDING METHICILLIN-RESISTANT ISOLATES)
ENTEROCOCCUS 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
SUSCEPTIBILITY TEST METHODS
WHEN AVAILABLE, THE CLINICAL MICROBIOLOGY LABORATORY SHOULD PROVIDE CUMULATIVE RESULTS OF THE IN VITRO SUSCEPTIBILITY TEST RESULTS FOR ANTIMICROBIAL DRUGS USED IN LOCAL HOSPITALS AND PRACTICE AREAS TO THE PHYSICIAN AS PERIODIC REPORTS THAT DESCRIBE THE SUSCEPTIBILITY PROFILE OF NOSOCOMIAL AND COMMUNITY-ACQUIRED PATHOGENS. THESE REPORTS SHOULD AID THE PHYSICIAN IN SELECTING AN ANTIMICROBIAL DRUG.
DILUTION TECHNIQUE
QUANTITATIVE METHODS ARE USED TO DETERMINE ANTIMICROBIAL MINIMUM INHIBITORY CONCENTRATIONS (MICS). THESE MICS PROVIDE ESTIMATES OF THE SUSCEPTIBILITY OF BACTERIA TO ANTIMICROBIAL COMPOUNDS. THE MICS SHOULD BE DETERMINED USING A STANDARDIZED PROCEDURE [SEE REFERENCES]. STANDARDIZED PROCEDURES ARE BASED ON A BROTH DILUTION METHOD OR EQUIVALENT WITH STANDARDIZED INOCULUM CONCENTRATIONS AND STANDARDIZED CONCENTRATIONS OF TELAVANCIN POWDER. THE TEST METHOD TREATS TELAVANCIN AS A WATER-INSOLUBLE AGENT. DIMETHYL SULFOXIDE IS USED AS SOLVENT AND DILUENT, AND THE CATION-ADJUSTED MUELLER HINTON BROTH TEST MEDIUM IS SUPPLEMENTED WITH POLYSORBATE 80 TO A FINAL CONCENTRATION OF 0.002%. TELAVANCIN SHOULD NOT BE TESTED BY THE AGAR DILUTION METHOD. THE MIC VALUES SHOULD BE INTERPRETED ACCORDING TO THE CRITERIA PROVIDED IN TABLE 9.
DIFFUSION TECHNIQUE
QUANTITATIVE METHODS THAT REQUIRE MEASUREMENT OF ZONE DIAMETERS ALSO PROVIDE REPRODUCIBLE ESTIMATES OF THE SUSCEPTIBILITY OF BACTERIA TO ANTIMICROBIAL COMPOUNDS. ONE SUCH STANDARDIZED PROCEDURE REQUIRES THE USE OF STANDARDIZED INOCULUM CONCENTRATIONS [SEE REFERENCES]. THIS PROCEDURE USES PAPER DISKS IMPREGNATED WITH 30 MCG OF TELAVANCIN TO TEST THE SUSCEPTIBILITY OF MICROORGANISMS TO TELAVANCIN. THE DISK DIFFUSION INTERPRETIVE CRITERIA ARE PROVIDED IN TABLE 9.
TABLE 9: SUSCEPTIBILITY INTERPRETIVE CRITERIA FOR TELAVANCIN
SUSCEPTIBILITY INTERPRETIVE CRITERIA1
MINIMUM INHIBITORY CONCENTRATION (MCG/ML) DISK DIFFUSION ZONE DIAMETER (MM)
S I R S I R
STAPHYLOCOCCUS AUREUS (INCLUDING METHICILLIN-RESISTANT ISOLATES) ? 0.12 -- -- ? 15 -- --
STREPTOCOCCUS PYOGENES STREPTOCOCCUS AGALACTIAE ? 0.12 -- -- ? 15 -- --
STREPTOCOCCUS ANGINOSUS GROUP ? 0.06 ? 15
ENTEROCOCCUS FAECALIS (VANCOMYCIN-SUSCEPTIBLE ISOLATES ONLY) ? 0.25 -- -- ? 15 -- --
1 THE CURRENT ABSENCE OF RESISTANT ISOLATES PRECLUDES DEFINING ANY RESULTS OTHER THAN "SUSCEPTIBLE." ISOLATES YIELDING RESULTS OTHER THAN SUSCEPTIBLE SHOULD BE SUBJECTED TO ADDITIONAL TESTING.
A REPORT OF "SUSCEPTIBLE" INDICATES THAT THE ANTIMICROBIAL IS LIKELY TO INHIBIT GROWTH OF THE PATHOGEN IF THE ANTIMICROBIAL COMPOUND IN THE BLOOD REACHES THE CONCENTRATIONS USUALLY ACHIEVABLE.
QUALITY CONTROL
STANDARDIZED SUSCEPTIBILITY TEST PROCEDURES REQUIRE THE USE OF LABORATORY CONTROL MICROORGANISMS TO MONITOR THE PERFORMANCE OF THE SUPPLIES AND REAGENTS USED IN THE ASSAY, AND THE TECHNIQUES OF THE INDIVIDUALS PERFORMING THE TEST [SEE REFERENCES]. STANDARD TELAVANCIN POWDER SHOULD PROVIDE THE RANGE OF VALUES NOTED IN TABLE 10.
QUALITY CONTROL MICROORGANISMS ARE SPECIFIC STRAINS OF ORGANISMS WITH INTRINSIC BIOLOGICAL PROPERTIES RELATING TO RESISTANCE MECHANISMS AND THEIR GENETIC EXPRESSION WITHIN BACTERIA; THE SPECIFIC STRAINS USED FOR MICROBIOLOGICAL QUALITY CONTROL ARE NOT CLINICALLY SIGNIFICANT.
TABLE 10: ACCEPTABLE QUALITY CONTROL RANGES FOR TELAVANCIN TO BE USED IN VALIDATION OF SUSCEPTIBILITY TEST RESULTS
ACCEPTABLE QUALITY CONTROL RANGES
MINIMUM INHIBITORY CONCENTRATION (MCG/ML) DISK DIFFUSION ZONE DIAMETER (MM)
ENTEROCOCCUS FAECALIS ATCC 29212 0.03 - 0.12 NOT APPLICABLE
STAPHYLOCOCCUS AUREUS ATCC 29213 0.03 - 0.12 NOT APPLICABLE
STAPHYLOCOCCUS AUREUS ATCC 25923 NOT APPLICABLE 16-20
STREPTOCOCCUS PNEUMONIAE ATCC 496191 0.004 - 0.015 17-24
1 THIS ORGANISM MAY BE USED FOR VALIDATION OF SUSCEPTIBILITY TEST RESULTS WHEN TESTING STREPTOCOCCUS SPP. OTHER THAN S. PNEUMONIAE
ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY
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 [SEE OVERDOSAGE].
CLINICAL TRIALS
COMPLICATED SKIN AND SKIN STRUCTURE INFECTIONS
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 VIBATIV (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.
TABLE 11: BASELINE INFECTION TYPES IN PATIENTS IN CSSSI TRIALS 1 AND 2 - ATE POPULATION
VIBATIV
(N=884)1 VANCOMYCIN
(N=910)1
TYPE OF INFECTION
MAJOR ABSCESS 375 (42.4%) 397 (43.6%)
DEEP/EXTENSIVE CELLULITIS 309 (35.0%) 337 (37.0%)
WOUND INFECTION 139 (15.7%) 121 (13.3%)
INFECTED ULCER 45 (5.1%) 46 (5.1%)
INFECTED BURN 16 (1.8%) 9 (1.0%)
1 INCLUDES ALL PATIENTS RANDOMIZED, TREATED, AND EVALUATED FOR EFFICACY
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.
TABLE 12: CLINICAL CURE AT TEST-OF-CURE IN CSSSI TRIALS 1 AND 2 - ATE AND CE POPULATIONS
THE CURE RATES BY PATHOGEN FOR THE MICROBIOLOGICALLY EVALUABLE (ME) POPULATION ARE PRESENTED IN TABLE 13.
TABLE 13: CLINICAL CURE RATES AT THE TEST-OF-CURE FOR THE MOST COMMON PATHOGENS IN CSSSI TRIALS 1 AND 2 - ME POPULATION1
VIBATIV
% (N/N) VANCOMYCIN
% (N/N)
STAPHYLOCOCCUS AUREUS(MRSA) 87.0% (208/239) 85.9% (225/262)
STAPHYLOCOCCUS AUREUS(MSSA) 82.0% (132/161) 85.1% (131/154)
ENTEROCOCCUS FAECALIS 95.6% (22/23) 80.0% (28/35)
STREPTOCOCCUS PYOGENES 84.2% (16/19) 90.5% (19/21)
STREPTOCOCCUS AGALACTIAE 73.7% (14/19) 86.7% (13/15)
STREPTOCOCCUS ANGINOSUS GROUP 76.5% (13/17) 100.0% (9/9)
1 THE ME POPULATION INCLUDED PATIENTS IN THE CE POPULATION WHO HAD GRAM-POSITIVE PATHOGENS ISOLATED AT BASELINE AND HAD CENTRAL IDENTIFICATION AND SUSCEPTIBILITY OF THE MICROBIOLOGICAL ISOLATE(S).
IN THE TWO CSSSI TRIALS, CLINICAL CURE RATES WERE SIMILAR ACROSS GENDER AND RACE. CLINICAL CURE RATES IN THE VIBATIV CLINICALLY EVALUABLE (CE) POPULATION WERE LOWER IN PATIENTS ? 65 YEARS OF AGE COMPARED WITH THOSE < 65 YEARS OF AGE. A DECREASE OF THIS MAGNITUDE WAS NOT OBSERVED IN THE VANCOMYCIN CE POPULATION. CLINICAL CURE RATES IN THE VIBATIV CE POPULATION < 65 YEARS OF AGE WERE 503/581 (87%) AND IN THOSE ? 65 YEARS WERE 88/122 (72%). IN THE VANCOMYCIN CE POPULATION CLINICAL CURE RATES IN PATIENTS < 65 YEARS OF AGE WERE 492/570 (86%) AND IN THOSE ? 65 YEARS WAS 111/137 (82%). 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. A DECREASE OF THIS MAGNITUDE WAS NOT OBSERVED IN THE VANCOMYCIN-TREATED PATIENTS [SEE WARNINGS AND PRECAUTIONS].
HABP/VABP
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 VIBATIV (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/GRAMNEGATIVE INFECTIONS.
TABLE 14: ALL-CAUSE MORTALITY AT DAY 28 IN PATIENTS WITH AT LEAST ONE BASELINE GRAM- POSITIVE PATHOGEN
TRIAL 1 TRIAL 2
VIBATIV VANCOMYCIN VIBATIV VANCOMYCIN
ALL PATIENTS MORTALITYA 28.7% 24.3% 24.3% 22.3%
N=187 N=180 N=224 N=206
DIFFERENCE (95% CI) 4.4% (-4.7%, 13.5%) 2.0% (-6.1%, 10%)
CRCL ? 50 ML/MIN MORTALITYA 41.8% 35.4% 43.9% 29.6%
N=63 N=68 N=53 N=58
DIFFERENCE (95% CI) 6.4% (-10.4, 23.2) 14.3% (-3.6, 32.2)
CRCL > 50 ML/MIN MORTALITYA 22.0% 17.6% 18.2% 19.3%
N=124 N=112 N=171 N=148
DIFFERENCE (95% CI) 4.4% (-5.9, 14.7) -1.1% (-9.8, 7.6)
AMORTALITY RATES ARE BASED ON KAPLAN-MEIER ESTIMATES AT STUDY DAY 28. THERE WERE 84 PATIENTS (5.6%) WHOSE SURVIVAL STATUSES WERE NOT KNOWN UP TO 28 DAYS AFTER INITIATION OF STUDY DRUG AND WERE CONSIDERED CENSORED AT THE LAST DAY KNOWN TO BE ALIVE. THIRTY-FIVE OF THESE PATIENTS WERE TREATED WITH VIBATIV AND 45 WERE TREATED WITH VANCOMYCIN.
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.
TABLE 15: CLINICAL RESPONSE RATES IN TRIALS 1 AND 2 - AT AND CE POPULATIONS
TRIAL 1 TRIAL 2
VIBATIV VANCOMYCIN VIBATIV VANCOMYCIN
ATA 57.5% (214/372) 59.1% (221/374) 60.2% (227/377) 60.0% (228/380)
DIFFERENCE (95% CI) -1.6% (-8.6%, 5.5%) 0.2% (-6.8%, 7.2%)
CEB 83.7% (118/141) 80.2% (138/172) 81.3% (139/171) 81.2% (138/170)
DIFFERENCE (95% CI) 3.5% (-5.1%, 12.0%) 0.1% (-8.2%, 8.4%)
AALL-TREATED (AT) POPULATION: PATIENTS WHO RECEIVED AT LEAST ONE DOSE OF STUDY MEDICATION
BCLINICALLY EVALUABLE (CE) POPULATION: PATIENTS WHO WERE CLINICALLY EVALUABLE
REFERENCES
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