Vibativ (telavancin)

适应症：耐甲氧西林金黄色葡萄球菌造成的皮肤感染

生产商：Theravance and Astellas Pharma

批准日期：09年9月11日

Theravance公司和安斯泰来制药公司互助的Vibativ (telavancin)是一种打针型脂糖肽类杀死病菌抗生素，适用于治疗由下面所开列革兰氏阳性菌致病分离物所引起的成人复杂皮肤感染和皮肤结构感染(cSSSI)：金黄色葡萄球菌(包括甲氧西林敏锐金黄色葡萄球菌[MSSA]和耐甲氧西林金黄色葡萄球菌分离物)；化脓性链球菌；无乳链球菌；咽峡炎链球菌属(包括咽峡炎链球菌、中间链球菌和星座链球菌)；以及粪肠球菌(仅对万古霉素敏锐分离物)。

有2项3期多中间、双盲、随机试验对Vibativ的安全性和有效性做了评估。这些研究旨在比较成人cSSSI(系革兰氏阳性菌而至)患者应用Vibativ (1广普脱敏八联疗法 mg/kg ，静脉给药，1日1次)与万古霉素(1 gm ，静脉给药，每12h 1次)疗效。共1,867例患者到场研究并接管治疗，719例当时患有MRSA感染。在这两项研究中，Vibativ达到其相对于标准治疗药万古霉素的非劣性主要研究终点。在儿童中尚未对Vibativ进行研究。

3期 cSSSI临床试验中最常见的不良反映(发生率在Vibativ治疗组患者中≥1广普脱敏八联疗法%)为味觉障碍、恶心、呕吐、以及泡沫尿。在这些试验中，Vibativ治疗组中7%的患者报告发生严重的不良事件，以肾脏、呼吸系统或心脏事件为至多见。万古霉素治疗组中5%的患者报告了严重不良事件，以心脏、呼吸系统或感染事件为至多见。

Vibativ1日1次用药，以减少输注相关反映的发生风险。快速静脉输注糖苷肽类抗菌药可导致上半身潮红、荨麻疹、瘙痒或皮疹。

 
VIBATIV

(telavancin) for Injection, for Intravenous Use

DRUG DESCRIPTION
VIBATIV contains telavancin hydrochloride, a lipoglycopeptide antibacterial that is a synthetic derivative of vancomycin. The chemical name of telavancin hydrochloride is vancomycin,N3”-[2-(decylamino)ethyl]-29-[[(phosphono-methyl)-amino]-methyl]- hydrochloride.

Telavancin hydrochloride is an off-white to slightly colored amorphous powder with the empirical formula C80H106C12N11O27P•xHCl (where x = 1 to 3) and a free-base molecular weight of 1755.6. It is highly lipophilic and slightly soluble in water.

VIBATIV is a sterile, preservative-free, white to slightly colored lyophilized powder containing telavancin hydrochloride (equivalent to either 250 mg or 750 mg of telavancin as the free base) for intravenous use. The inactive ingredients are Hydroxypropylbetadex, Ph. Eur (hydroxypropyl-beta-cyclodextrin) (2500 mg per 250 mg telavancin, 7500 mg per 750 mg telavancin), mannitol (312.5 mg per 250 mg telavancin, 937.5 mg per 750 mg telavancin), and sodium hydroxide and hydrochloric acid used in minimal quantities for pH adjustment. When reconstituted, it forms a clear to slightly colored solution with a pH of 4.5 (4.0 to 5.0).

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.

Complicated Skin and Skin Structure Infections
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).

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.

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 and bacteriological progress.

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).

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)

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 4 hours when stored at room temperature or within 72 hours under refrigeration at 2 to 8° C (36 to 46° F). The diluted (dosing) solution in the infusion bag should be used within 4 hours when stored at room temperature or used within 72 hours 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 4 hours at room temperature and 72 hours under refrigeration at 2 to 8° C (36 to 46° F).

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.

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 0469-3525-30)

Cartons of 10 individually packaged 750 mg single-dose vials
(NDC 0469-3575-50)

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.

SIDE EFFECTS
The following serious adverse reactions are 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
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 reactions occurring in 10% of VIBATIV-treated patients observed in the VIBATIV Phase 3 cSSSI trials were taste disturbance, nausea, vomiting, and foamy urine.

DRUG INTERACTIONS
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.

WARNINGS
Included as part of the PRECAUTIONS section.

PRECAUTIONS
Women of Childbearing Potential
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.

Pregnancy
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 [see Use in Specific Populations].

Nephrotoxicity
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%).

In 30/929 (3.1%) of VIBATIV-treated patients compared to 10/938 (1.1%) of vancomycin-treated patients, renal adverse events indicative of renal impairment occurred, as defined by the following terms: increased serum creatinine, renal impairment, renal insufficiency, and/or renal failure. 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 (1.2%) of VIBATIV-treated patients compared to 3/938 (0.3%) of vancomycin-treated patients. Twelve patients treated with VIBATIV discontinued treatment due to adverse events indicative of renal impairment compared to 2 patients treated with vancomycin. 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 rate was also higher in patients who received concomitant medications known to affect kidney function (eg, non-steroidal antiinflammatory drugs, ACE inhibitors, and loop diuretics). Fifteen of 174 patients (8.6%) ≥ 65 years of age had adverse events indicative of renal impairment compared to 16 of 755 patients (1.9%) < 65 years of age [see Use in Specific Populations].

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, CLINICAL PHARMACOLOGY].

In patients with renal dysfunction, accumulation of the solubilizer hydroxypropyl-beta-cyclodextrin can occur [see Patients with Renal Impairment and CLINICAL PHARMACOLOGY].

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.

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 over 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.

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.

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]. 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.

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.

Patient Counselling Information
See Medication Guide.

Use during Pregnancy and by Women of Childbearing Potential
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
Pregnancy 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 pregnancy registry by calling 1-888-658-4228.

Diarrhea
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.

Correct Use of Antibacterial Drugs
Patients should be counseled that antibacterial drugs including VIBATIV should only be used to treat bacterial infections. They do not treat viral infections (eg, 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.

Common Adverse Effects
Patients should be informed about the common adverse effects of VIBATIV including 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.

Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
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.

Use In Specific Populations
Pregnancy
Teratogenic effects: Pregnancy Category C
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 1-888-658-4228.

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.

Data
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.

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

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

Geriatric Use
Of the 929 patients treated with VIBATIV at a dose of 10 mg/kg once daily in clinical trials of cSSSI, 174 (18.7%) were ≥ 65 years of age and 87 (9.4%) 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 (8.6%) patients ≥ 65 years of age treated with telavancin had adverse events indicative of renal impairment compared to 16 of 755 (1.9%) patients < 65 years of age [see WARNINGS AND PRECAUTIONS, Clinical Trials].

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, CLINICAL PHARMACOLOGY].

Patients with Renal Impairment
The 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]. Patients with creatinine clearance ≤ 50 mL/min also 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 [see DOSAGE AND ADMINISTRATION]. 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, CLINICAL PHARMACOLOGY].

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, CLINICAL PHARMACOLOGY].

Patients with Hepatic Impairment
The 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].

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.

CONTRAINDICATIONS
None.

中文参考商品译名:
VIBATIV 250毫克/瓶
中文参考药品译名:
盐酸特拉万星
生产厂家中文参考译名:
THERAVANCE INC
生产厂家英文名:
THERAVANCE INC