Telavancin

Telavancin belongs to the pharmacological class of Glycopeptide Antibiotics.

Telavancin has been approved to relieve symptoms and also for the treatment and maintenance of Bloodstream infection,Pneumonia, hospital-acquired or ventilator-associated,Skin and soft tissue infections.

Telavancin demonstrates linear pharmacokinetics in the dosage range of 1 to 12.5 mg/kg. It remains effective against MRSA and penicillin-resistant Streptococcus pneumoniae even 24 hours after administration. The trough concentration at that time is around 10 μg/mL. However, telavancin has poor bioavailability and requires intravenous administration over 30 to 120 minutes. In healthy subjects receiving a 10 mg/kg dose, the maximum plasma concentration (Cmax) is 93.6 ± 14.2 μg/mL, and the area under the curve (AUC) from 0 to 24 hours is 666 ± 107 μg · h/mL. It takes about 3 days to reach a steady state. Telavancin has a volume of distribution (Vss) of 0.14 L/kg. It binds to serum albumin in a concentration-independent manner (>90%) without affecting its antimicrobial activity. Telavancin is primarily eliminated through urine (>80% as an unchanged drug) and, to a lesser extent, through feces (<1%). Its metabolism does not involve the cytochrome P450 enzyme system, and the primary metabolite is THRX-651540, although the specific pathway is unknown.

The common side effects involved in using Telavancin are Nausea, Vomiting, Diarrhea, Abdominal pain, Gastrointestinal discomfort, Skin rash, Injection site pain, Injection site redness, Injection site swelling, Taste Disturbances.

Telavancin is available in the form of Lyophilized Injections.

Telavancin is approved in Germany, Japan, Malaysia, India, the U.K., the U.S., and China.

Telavancin belongs to the pharmacological class of Glycopeptide Antibiotics

Telavancin is a lipoglycopeptide with bactericidal properties, effectively targeting a wide spectrum of gram-positive bacteria. Its mechanism of action involves inhibiting the polymerization of N-acetylmuramic acid (NAM) and N-acetylglucosamine (NAG), as well as the cross-linking of peptidoglycan, by binding to D-Ala-D-Ala. This binding process hinders the synthesis of the bacterial cell wall, leading to its inhibition. Additionally, telavancin disrupts the membrane potential and increases cell permeability due to its lipophilic side chain component. This unique bactericidal mechanism distinguishes telavancin from vancomycin.

Telavancin has been approved to relieve symptoms and also for the treatment and maintenance of Bloodstream infection,Pneumonia, hospital-acquired or ventilator-associated,Skin and soft tissue infections.

Telavancin exhibits low bioavailability and requires intravenous administration over a period of 30-120 minutes. In healthy subjects receiving a dose of 10 mg/kg, the maximum concentration (Cmax) achieved was 93.6 ± 14.2 μg/mL. The area under the concentration-time curve from 0 to infinity (AUC(0-∞)) was 747 ± 129 μg · h/mL, and the AUC from 0 to 24 hours (AUC(0-24h)) was 666 ± 107 μg · h/mL. It takes approximately 3 days to reach steady-state concentrations.

Telavancin is found to be available in the form of Lyophilized Injections.

Telavancin can be used in the following treatment:

• Bloodstream infection
• Pneumonia, hospital-acquired or ventilator-associated
• Skin and soft tissue infection

Telavancin can help to relieve symptoms and also for the treatment and maintenance of Bloodstream infection,Pneumonia, hospital-acquired or ventilator-associated, Skin, and soft tissue infections.

Telavancin is approved for use in the following clinical indications:

• Bloodstream infection
• Pneumonia, hospital-acquired or ventilator-associated
• Skin and soft tissue infection

Bloodstream infection (off-label use, alternative agent):

For pathogen-directed therapy targeting MRSA, the recommended intravenous dosage is 10 mg/kg once daily. The manufacturer does not provide a maximum dose recommendation, but based on limited pharmacokinetic data in obese patients, doses up to 1 g/day may be safely used. The treatment duration for uncomplicated S. aureus bacteremia should be at least 14 days from the day of the first negative blood culture. Longer treatment courses are warranted for endocarditis or metastatic sites of infection.

Pneumonia, hospital-acquired or ventilator-associated (alternative agent):

Note: In patients with a creatinine clearance (CrCl) of 50 mL/minute or less, increased mortality compared to vancomycin has been observed.

As part of empiric or pathogen-directed therapy for MRSA, the recommended intravenous dosage is 10 mg/kg every 24 hours. The manufacturer does not specify a maximum dose, but based on limited pharmacokinetic data in obese patients, doses up to 1 g/day can be safely used. The duration of therapy varies based on disease severity and response to treatment, typically lasting for 7 days.

Skin and soft tissue infection (alternative agent):

Note: In patients with a CrCl of 50 mL/minute or less, decreased efficacy compared to vancomycin has been observed.

For intravenous treatment, the recommended dosage is 10 mg/kg once daily. The manufacturer does not provide a maximum dose recommendation, but based on limited pharmacokinetic data in obese patients, doses up to 1 g/day may be safely used. The total duration of therapy should be at least 5 days (including oral step-down therapy) and can be extended up to 14 days, depending on the severity of the infection and the patient's clinical response.

Lyophilized Injection : 750mg/vial.

There are no specific dietary restrictions related to the use of Telavancin mentioned in the available information. However, it is always advisable to follow a healthy and balanced diet while undergoing any medical treatment.

Telavancin may be contraindicated under the following conditions:

Telavancin should not be used in patients who have a known hypersensitivity to Telavancin.

• Pregnancy Category and Developmental Outcomes:

The use of Telavancin during pregnancy should be avoided unless the potential benefits outweigh the potential risks to the fetus. Studies conducted on three animal species have shown adverse developmental effects at doses comparable to clinical doses, raising concerns about potential adverse outcomes in humans.

• Nephrotoxicity:

An increase in serum creatinine levels to 1.5 times the baseline has been observed more frequently in Telavancin-treated patients with normal baseline levels (15%) compared to vancomycin-treated patients (7%). Renal adverse events indicating impairment occurred in a higher percentage of Telavancin-treated patients (3.1%) compared to vancomycin-treated patients (1.1%). The occurrence of serious adverse events related to renal impairment was also higher in Telavancin-treated patients (1.2%) compared to vancomycin-treated patients (0.3%). Elderly patients and those with pre-existing renal disease or taking medications affecting kidney function were more likely to experience renal adverse events.

• Monitoring of Renal Function:

Regular monitoring of renal function, including serum creatinine and creatinine clearance, is recommended for all patients receiving Telavancin. Baseline values should be obtained prior to initiating treatment, and subsequent measurements should be taken during treatment and at the end of therapy. If a decrease in renal function occurs, the decision to continue Telavancin or switch to an alternative treatment should be carefully evaluated.

• Infusion-Related Reactions:

To minimize the risk of infusion-related reactions, Telavancin should be administered over a period of 60 minutes. Rapid intravenous infusions of Telavancin can lead to reactions such as flushing, urticaria, pruritus, or rash. Slowing down or stopping the infusion can help alleviate these reactions.

• Clostridium difficile-Associated Diarrhea:

The use of Telavancin, like other antibacterial agents, may result in Clostridium difficile-associated diarrhea (CDAD), ranging from mild diarrhea to severe colitis. CDAD should be considered in patients presenting with diarrhea after antibiotic use, and appropriate measures, including discontinuation of non-C. difficile-directed antibiotics should be taken.

• Development of Drug-Resistant Bacteria:

Prescribing Telavancin without a confirmed or strongly suspected bacterial infection is not recommended, as it can increase the risk of developing drug-resistant bacteria. Close monitoring of patients during therapy is important to detect potential superinfections.

• QT Prolongation:

Telavancin has been shown to prolong the QTc interval, particularly at higher doses. Caution is advised when prescribing Telavancin to patients taking medications known to prolong the QT interval. Patients with certain pre-existing conditions should avoid using Telavancin.

• Coagulation Test Interference:

Telavancin, the active ingredient in Telavancin, may interfere with certain coagulation tests when conducted within 0 to 18 hours after administration. These tests should be performed as close as possible to the next Telavancin dose. However, there is no evidence of increased bleeding risk or hypercoagulability associated with Telavancin use based on clinical trials.

While there is no specific food interaction between Telavancin and alcohol, it's generally recommended to avoid alcohol when taking any antibiotic medication. Alcohol can interfere with the effectiveness of the medication and may also exacerbate certain side effects.

The excretion of telavancin in human milk is unknown. Since many drugs are excreted in human milk, caution should be exercised when administering Telavancin to breastfeeding women.

Pregnancy Category C

Registry for Pregnancy Exposure

There is a pregnancy registry available to monitor the outcomes of pregnancies in women who have been exposed to Telavancin.

Summary of Fetal Risk

Regardless of drug exposure, all pregnancies carry a background risk of birth defects (approximately 3%), pregnancy loss (approximately 15%), or other adverse outcomes.

There is a lack of data on the use of Telavancin in pregnant women. However, studies conducted on three animal species have shown that exposure to Telavancin during pregnancy, at clinically relevant doses, led to reduced fetal weights and increased rates of digit and limb malformations in offspring. These animal data raise concerns about potential adverse developmental outcomes in humans.

Clinical Considerations

Due to the absence of human data and the risks indicated by animal data, it is advised to avoid using Telavancin in pregnant women unless the benefits to the patient outweigh the potential risks to the fetus.

Data

Human Data

There is no available data on human pregnancies exposed to Telavancin.

Animal Data

In studies conducted on rat, rabbit, and minipig embryos, telavancin administered intravenously during organogenesis at doses up to 150 mg/kg/day, 45 mg/kg/day, and 75 mg/kg/day, respectively, resulted in limb and skeletal malformations. These doses corresponded to exposure levels approximately 1- to 2-fold the human exposure (AUC) at the maximum recommended clinical dose. Malformations observed at rates below 1% (but absent or at lower rates in control groups) included brachymelia (rats and rabbits), syndactyly (rats and minipigs), adactyly (rabbits), and polydactyly (minipigs). Additional findings in rabbits included flexed front paws and absent ulna, while in minipigs, misshapen digits, and deformed front leg were observed. Fetal body weights were reduced in rats.

In a study on prenatal/perinatal development, pregnant rats received intravenous telavancin at doses up to 150 mg/kg/day (approximately equivalent to the maximum clinical dose in terms of AUC) from the beginning of organogenesis through lactation. Offspring showed decreased fetal body weight and an increased number of stillborn pups. Brachymelia was also observed. However, developmental milestones and fertility of the pups were unaffected.

No food warning has been identified

The adverse reactions related to Telavancin can be categorized as follows:

Common:

1. Nausea
2. Vomiting
3. Diarrhea
4. Headache
5. Taste disturbance (dysgeusia)
6. Injection site reactions (erythema or redness)

Less common:

1. Rash (macular rash)
2. Dizziness
3. Insomnia
4. Fatigue
5. Abdominal pain
6. Constipation
7. Elevated liver enzymes (transaminases)

Rare:

1. Allergic reactions (hypersensitivity)
2. Severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis)
3. Kidney impairment
4. Changes in blood counts (thrombocytopenia, leukopenia)
5. Neurological effects (seizures, confusion)
6. Hearing loss or tinnitus (ringing in the ears)

Interactions of Telavancin with Laboratory Tests

Telavancin's Impact on Coagulation Test Parameters

Telavancin has an affinity for the artificial phospholipid surfaces added to standard anticoagulation tests, which can disrupt the assembly of coagulation complexes and clotting promotion in vitro. The extent of these effects may vary depending on the reagents used in commercially available assays. Consequently, shortly after completing a Telavancin infusion, there have been reported increases in PT, INR, aPTT, and ACT. However, these effects diminish over time as telavancin plasma concentrations decline.

Urine Protein Tests

Telavancin can interfere with urine qualitative dipstick protein assays and quantitative dye methods, such as pyrogallol red-molybdate. However, it does not affect microalbumin assays, which remain suitable for monitoring urinary protein excretion during Telavancin treatment.

The following are the side effects involving Telavancin:

• Nausea
• Vomiting
• Diarrhea
• Headache
• Dizziness
• Taste disturbances (dysgeusia)
• Injection site reactions (erythema, pain, or swelling)
• Rash (macular rash)
• Red man syndrome (flushing or redness of the upper body, often accompanied by itching or rash)

Pregnancy:

Pregnancy Category C

Registry for Pregnancy Exposure

There is a pregnancy registry available to monitor the outcomes of pregnancies in women who have been exposed to Telavancin.

Summary of Fetal Risk

Regardless of drug exposure, all pregnancies carry a background risk of birth defects (approximately 3%), pregnancy loss (approximately 15%), or other adverse outcomes.

There is a lack of data on the use of Telavancin in pregnant women. However, studies conducted on three animal species have shown that exposure to Telavancin during pregnancy, at clinically relevant doses, led to reduced fetal weights and increased rates of digit and limb malformations in offspring. These animal data raise concerns about potential adverse developmental outcomes in humans.

Clinical Considerations

Due to the absence of human data and the risks indicated by animal data, it is advised to avoid using Telavancin in pregnant women unless the benefits to the patient outweigh the potential risks to the fetus.

Data

Human Data

There is no available data on human pregnancies exposed to Telavancin.

Animal Data

In studies conducted on rat, rabbit, and minipig embryos, telavancin administered intravenously during organogenesis at doses up to 150 mg/kg/day, 45 mg/kg/day, and 75 mg/kg/day, respectively, resulted in limb and skeletal malformations. These doses corresponded to exposure levels approximately 1- to 2-fold the human exposure (AUC) at the maximum recommended clinical dose. Malformations observed at rates below 1% (but absent or at lower rates in control groups) included brachymelia (rats and rabbits), syndactyly (rats and minipigs), adactyly (rabbits), and polydactyly (minipigs). Additional findings in rabbits included flexed front paws and absent ulna, while in minipigs, misshapen digits, and deformed front leg were observed. Fetal body weights were reduced in rats.

In a study on prenatal/perinatal development, pregnant rats received intravenous telavancin at doses up to 150 mg/kg/day (approximately equivalent to the maximum clinical dose in terms of AUC) from the beginning of organogenesis through lactation. Offspring showed decreased fetal body weight and an increased number of stillborn pups. Brachymelia was also observed. However, developmental milestones and fertility of the pups were unaffected.

Lactation:

The excretion of telavancin in human milk is unknown. Since many drugs are excreted in human milk, caution should be exercised when administering Telavancin to breastfeeding women.

Pediatric:

The safety and efficacy of Telavancin have not been investigated in pediatric patients.

Geriatric Use:

Among the 929 patients who participated in clinical trials of Telavancin for complicated skin and skin structure infections (cSSSI) and received a once-daily dose of 10 mg/kg, 174 patients (18.7%) were aged 65 years or older, and 87 patients (9.4%) were aged 75 years or older. In the cSSSI trials, patients aged 65 years or older had lower rates of clinical cure compared to those younger than 65 years. The incidence of treatment-emergent adverse events was similar between patients aged 65 years or older (75% of patients) and those younger than 65 years (83% of patients). Among patients aged 65 years or older who were treated with telavancin, 15 out of 174 patients (8.6%) experienced adverse events indicating renal impairment, whereas 16 out of 755 patients (1.9%) younger than 65 years experienced such events [refer to Warnings and Precautions (5.3), Clinical Trials (14.1)].

Telavancin is primarily eliminated through the kidneys, and the risk of adverse reactions may be higher in patients with impaired renal function. Considering that elderly patients are more likely to have reduced renal function, caution should be exercised when selecting the dosage for this age group. The average plasma AUC values of telavancin were similar in healthy young and elderly subjects. Adjustments to the dosage for elderly patients should be based on their renal function.

Physicians should be knowledgeable as well as vigilant about the treatment and identification of overdosage of Telavancin.

In healthy volunteers who received a dose of 15 mg/kg, an increased occurrence of adverse reactions was observed with telavancin, including dysgeusia, nausea, vomiting, injection site erythema, headache, macular rash, and red man syndrome.

In case of an overdose, telavancin should be discontinued, and supportive care should be provided, including maintaining glomerular filtration and closely monitoring renal function. Following the administration of a single dose of 7.5 mg/kg telavancin to individuals with end-stage renal disease, approximately 5.9% of the administered dose was recovered in the dialysate after 4 hours of hemodialysis. However, there is no available information on the use of hemodialysis for treating an overdose.

Pharmacodynamics

Telavancin, a semi-synthetic derivative of vancomycin, exerts its bactericidal action by inhibiting cell wall synthesis, similar to vancomycin. Additionally, telavancin exhibits concentration-dependent bactericidal activity. It is a more potent inhibitor (10-fold) of peptidoglycan synthesis compared to vancomycin, and unlike vancomycin, it disrupts cell membrane integrity through its interaction with lipid II. The ratio of area under the curve (AUC) to minimum inhibitory concentration (MIC) is a reliable indicator of the in-vivo response, with a higher ratio corresponding to greater bactericidal activity. A minimum AUC/MIC ratio of 50 is required to prevent bacterial growth at 24 hours, while maximal bactericidal activity is achieved at an AUC/MIC ratio of 404.

Pharmacokinetics

● Absorption:

Telavancin exhibits linear pharmacokinetics within the dosage range of 1 to 12.5 mg/kg. Notably, even 24 hours after administering a dose of 7.5 to 15 mg/kg, its efficacy against MRSA and penicillin-resistant Streptococcus pneumoniae can still be observed, with a trough concentration of approximately 10 μg/mL. Telavancin has low bioavailability and requires intravenous administration over a period of 30-120 minutes. In healthy subjects receiving a dose of 10 mg/kg, the maximum concentration (Cmax) is 93.6 ± 14.2 μg/mL, the area under the curve (AUC) from 0 to infinity is 747 ± 129 μg · h/mL, the AUC from 0 to 24 hours is 666 ± 107 μg · h/mL, and it takes approximately 3 days to reach steady-state levels.

● The volume of distribution:

The volume of distribution at steady state (Vss) in healthy subjects receiving a dose of 10 mg/kg is 0.14 L/kg.

● Protein binding:

Telavancin binds to serum albumin in a concentration-independent manner, with over 90% protein binding. However, this high protein binding does not affect its antimicrobial activity.

● Metabolism:

Telavancin is not metabolized via the cytochrome P450 enzyme system. The primary metabolite, known as THRX-651540, has been identified, but the specific metabolic pathway has not yet been determined.

● Route of elimination:

Telavancin is primarily eliminated through the urine, with over 80% of the drug excreted unchanged and less than 20% excreted as hydroxylated metabolites (with a dose of 10 mg/kg). Fecal elimination accounts for less than 1% of the total drug excretion.

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