Telithromycin

Telithromycin belongs to the pharmacological class of Macrolide antibiotics.

Telithromycin has been approved to relieve symptoms and also for the treatment and maintenance of Community-acquired pneumonia.

Telithromycin is well-absorbed after oral administration, with an absolute bioavailability of approximately 57%. Peak concentrations are typically reached within 0.5 to 4 hours. The absorption of telithromycin is not affected by food intake. It has a moderate volume of distribution of 2.9 L/kg, indicating widespread distribution throughout the body. The drug exhibits moderate protein binding, with approximately 60-70% bound to human serum albumin. Telithromycin undergoes hepatic metabolism, with approximately 50% of the drug being metabolized by the CYP3A4 enzyme and the remaining 50% being metabolized through other pathways independent of cytochrome P450. The elimination of telithromycin occurs via multiple routes: approximately 7% of the dose is excreted unchanged in feces through biliary and/or intestinal secretion, 13% is excreted unchanged in urine through renal excretion, and 37% is metabolized by the liver.

The common side effects involved in using Telithromycin are nausea, vomiting, diarrhea, urticaria, rashes, irritation , liver abnormalities, etc.

Telithromycin is available in the form of Tablets.

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

Telithromycin belongs to the pharmacological class of Macrolide antibiotics.

Telithromycin exerts its action by specifically binding to domains II and V of the 23S ribosomal RNA (rRNA) within the 50S ribosomal subunit. Its binding to domain II allows it to remain effective against gram-positive cocci, including Streptococcus pneumoniae, even in the presence of resistance caused by methylases (erm genes) that modify the binding site in domain V. Additionally, telithromycin has the ability to interfere with the assembly of newly forming ribosomal units. When compared to erythromycin A, telithromycin exhibits 10 times higher affinity for binding to the 23S rRNA in erythromycin-susceptible organisms and 25 times higher affinity in strains that are resistant to macrolides. This enhanced binding affinity is attributed to the C11-12 carbamate side chain present in telithromycin, which enables it to maintain binding at domain II even in the presence of resistance-related alterations in domain V.

Telithromycin has been approved to relieve symptoms and also for the treatment and maintenance of Community-acquired pneumonia.

Telithromycin achieves its maximum plasma concentration (Cmax) within approximately 2-4 hours after oral administration.

The time taken to reach the maximum plasma concentration (Tmax) of telithromycin is generally observed within 2-4 hours after oral dosing.

Telithromycin is found to be available in the form of Tablets.

Telithromycin can be used in the following treatment:

• Community-acquired pneumonia

Telithromycin can help to relieve symptoms and also for the treatment and maintenance of Community-acquired pneumonia.

Telithromycin is approved for use in the following clinical indications:

• Community-acquired pneumonia

For the treatment of community-acquired pneumonia (CAP), the recommended oral dosage is 800 mg once daily. The duration of treatment is typically 7 to 10 days.

Tablets: 400mg

Tablets

• Dosage Adjustments in Kidney Patients:

For patients with a creatinine clearance (CrCl) of 30 mL/minute or higher, no dosage adjustment is required.

For patients with a CrCl less than 30 mL/minute, a dosage of 600 mg once daily is recommended.

For patients with a CrCl of less than 30 mL/minute and concurrent hepatic impairment, a dosage of 400 mg once daily is recommended.

For patients undergoing hemodialysis, a dosage of 600 mg once daily is recommended. It should be administered after dialysis on dialysis days.

No specific dietary restrictions associated with the use of Telithromycin have been found.

Telithromycin may be contraindicated under the following conditions:

• Myasthenia Gravis: Telithromycin should not be used in patients with myasthenia gravis. Exacerbations of myasthenia gravis have been reported, with some occurring shortly after the first dose of telithromycin. These reports have included cases of fatal and life-threatening acute respiratory failure that had a rapid onset and progression.
  
• Previous History of Hepatitis and/or Jaundice: Telithromycin is contraindicated in patients with a previous history of hepatitis and/or jaundice associated with the use of Telithromycin tablets or any macrolide antibiotic.
  
• Hypersensitivity: Telithromycin should not be used in patients with a history of hypersensitivity to telithromycin, any components of Telithromycin tablets, or any macrolide antibiotic.
  

Hepatotoxicity

• Severe Liver Injury: Cases of acute hepatic failure and severe liver injury, including fulminant hepatitis and hepatic necrosis leading to liver transplant, have been reported in patients treated with Telithromycin. Some of these cases occurred during or immediately after treatment, with liver injury progressing rapidly even after a few doses of Telithromycin. Physicians and patients should monitor for signs or symptoms of hepatitis, such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness, or hepatomegaly. If signs of hepatitis or transaminase elevations along with other systemic symptoms occur, Telithromycin should be discontinued, and immediate medical evaluation, including liver function tests, should be sought.
  
• Previous History of Hepatitis: Telithromycin must not be re-administered to patients with a previous history of hepatitis and/or jaundice associated with the use of Telithromycin tablets or any macrolide antibiotic.
  
• Less Severe Hepatic Dysfunction: Less severe forms of liver toxicity, including increased liver enzymes, hepatitis, and jaundice, have been reported with the use of Telithromycin. These events associated with less severe liver toxicity were reversible.
  

QTc Prolongation

• Risk of Ventricular Arrhythmias: Telithromycin has the potential to prolong the QTc interval of the electrocardiogram, which may increase the risk of ventricular arrhythmias, including torsades de pointes. Patients with congenital prolongation of the QTc interval, ongoing proarrhythmic conditions, or receiving certain antiarrhythmic agents should avoid telithromycin.
• Cases of Torsades de Pointes: Post-marketing reports have indicated cases of torsades de Pointes associated with Telithromycin. In clinical trials, no cardiovascular morbidity or mortality attributable to QTc prolongation occurred with telithromycin treatment.
  

Visual Disturbances

• Slowed Ability to Accommodate: Telithromycin may cause visual disturbances, particularly affecting the ability to accommodate and release accommodation. These disturbances include blurred vision, difficulty focusing, and diplopia. Most events are mild to moderate, but severe cases have been reported.
  

Loss of Consciousness

• Transient Loss of Consciousness: Post-marketing adverse event reports have described transient loss of consciousness, including some cases associated with vagal syndrome. Patients should minimize activities such as driving or operating machinery if they experience visual disorders or loss of consciousness while taking Telithromycin.
  

Pseudomembranous Colitis

• Risk of Clostridium difficile Associated Diarrhea: Use of antibacterial agents, including Telithromycin, has been associated with Clostridium difficile-associated diarrhea (CDAD), ranging from mild diarrhea to fatal colitis. CDAD should be considered in patients presenting with diarrhea after antibiotic use. Discontinuation of antibiotics not directed against C. difficile may be necessary, and appropriate management should be initiated, including fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation if clinically indicated.
  

There is no specific warning against the consumption of alcohol while taking Telithromycin. However, it is generally advisable to avoid or limit alcohol consumption during antibiotic treatment. Alcohol can interfere with the effectiveness of antibiotics and may also increase the risk of certain side effects.

The excretion of telithromycin in human milk is currently unknown. However, studies in lactating animals have shown that telithromycin is excreted in milk at concentrations approximately five times higher than those found in maternal plasma. In experiments involving preweaned rats, who were indirectly exposed to telithromycin through consumption of milk from dams treated with 200 mg/kg/day for 3 weeks, no adverse effects were observed despite the higher levels of the drug in milk compared to plasma. However, it is important to note that animal data may not always accurately predict the response in humans.

Considering the uncertainty surrounding the excretion of telithromycin in human milk and the potential risks involved, Telithromycin should generally be avoided during lactation unless the expected benefits for the mother clearly outweigh any possible risks to the baby.

Pregnancy C

There is a lack of sufficient and well-controlled studies involving pregnant women. However, animal studies have indicated embryofetal toxicity only at doses that caused toxicity in the mothers. In rats, these effects were observed at doses of 300 mg/kg/day, which is approximately 18.8 times the recommended human clinical dose. In rabbits, similar effects were seen at doses of 60 mg/kg/day, approximately 3.75 times the recommended human clinical dose. The potential risk to humans is currently unknown. Therefore, Telithromycin should generally be avoided during pregnancy unless the anticipated benefits to the mother clearly outweigh any potential risks to the fetus.

It is recommended to take Telithromycin with or without food. No specific dietary restrictions or precautions associated with the use of Telithromycin have been found.

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

Common

• Nausea
• Diarrhea
• Vomiting
• Abdominal pain
• Headache
• Dizziness
• Taste disturbances

Less Common

• Rash
• Pruritus (itching)
• Dyspepsia (indigestion)
• Fatigue
• Insomnia
• Increased liver enzymes (transaminases)
• Dry mouth
• Constipation
• Flatulence
• Gastritis

Rare

• Allergic reactions (e.g., angioedema, anaphylaxis)
• Severe skin reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis)
• Prolongation of the QT interval (affects the electrical activity of the heart)
• Hepatotoxicity (liver damage)
• Pancreatitis (inflammation of the pancreas)
• Myasthenic syndrome (a condition that causes muscle weakness)
• Psychiatric reactions (e.g., hallucinations, confusion)

• Effects of CYP 3A4 Inhibitors on Telithromycin:

Telothromycin Cmax increased by 22%

Telithromycin AUC increased by 54%

• Ketoconazole:

Telithromycin Cmax increased by 51%

Telithromycin AUC increased by 95%

• Grapefruit Juice:

No significant effect on telithromycin pharmacokinetics

• Effects of Telithromycin on CYP 3A4 and CYP 2D6 Substrates:
• Cisapride:

Telithromycin increased peak plasma concentrations of cisapride by 95%, resulting in QTc prolongation

• Simvastatin:

Telithromycin increased simvastatin Cmax by 5.3-fold and AUC by 8.9-fold

Telithromycin increased the active metabolite Cmax by 15-fold and AUC by 12-fold

• Midazolam:

Telithromycin increased the AUC of midazolam by 2-fold (intravenous) and 6-fold (oral)

• Paroxetine:

No significant effect on paroxetine pharmacokinetics

• Metoprolol:

Telithromycin increased metoprolol Cmax and AUC by approximately 38%

Other Drug Interactions:

• Digoxin:

Telithromycin increased plasma levels of digoxin by 73% (peak) and 21% (trough)

• Theophylline:

Telithromycin increased steady-state Cmax and AUC of theophylline by approximately 16% and 17%

• Sotalol:

Telithromycin decreased sotalol Cmax and AUC by 34% and 20%, respectively

• Warfarin:

No significant effects on warfarin pharmacodynamics or pharmacokinetics

• Oral Contraceptives:

Telithromycin did not affect the AUC of ethinyl estradiol

Telithromycin increased the AUC of levonorgestrel by 50%

• Ranitidine and Antacid:

No clinically relevant interaction with telithromycin

• Rifampin:

Telithromycin Cmax and AUC decreased by 79% and 86%, respectively, when co-administered with rifampin.

The following are the side effects involving Telithromycin:

• Nausea
• Vomiting
• Diarrhea
• Rashes
• Hives
• Itching
• Difficulty in breathing and swallowing
• Hoarseness

Pregnancy:

Pregnancy C

There is a lack of sufficient and well-controlled studies involving pregnant women. However, animal studies have indicated embryofetal toxicity only at doses that caused toxicity in the mothers. In rats, these effects were observed at doses of 300 mg/kg/day, which is approximately 18.8 times the recommended human clinical dose. In rabbits, similar effects were seen at doses of 60 mg/kg/day, approximately 3.75 times the recommended human clinical dose. The potential risk to humans is currently unknown. Therefore, Telithromycin should generally be avoided during pregnancy unless the anticipated benefits to the mother clearly outweigh any potential risks to the fetus.

Lactation:

The excretion of telithromycin in human milk is currently unknown. However, studies in lactating animals have shown that telithromycin is excreted in milk at concentrations approximately five times higher than those found in maternal plasma. In experiments involving preweaned rats, who were indirectly exposed to telithromycin through consumption of milk from dams treated with 200 mg/kg/day for 3 weeks, no adverse effects were observed despite the higher levels of the drug in milk compared to plasma. However, it is important to note that animal data may not always accurately predict the response in humans.

Considering the uncertainty surrounding the excretion of telithromycin in human milk and the potential risks involved, Telithromycin should generally be avoided during lactation unless the expected benefits for the mother clearly outweigh any possible risks to the baby.

Pediatric:

For pediatric populations from birth to 18 years old, the safety of Telithromycin has not been established in those under 13 years of age. In 16 Phase III trials, a group of 124 individuals aged 13 to 18 years were treated with Telithromycin. The efficacy and safety observed in this group were comparable to those seen in older patients

Geriatric Use:

In the 16 Phase III clinical trials, which included a total of 4,780 patients analyzed for safety, Telithromycin was given to 694 individuals aged 65 years and older, with 231 of them being 75 years and older.

The efficacy and safety of Telithromycin in older patients were comparable to those observed in younger patients. However, it is important to note that older individuals may potentially have a higher sensitivity to Telithromycin or telithromycin, although this possibility cannot be completely ruled out.

Based on age alone, no dosage adjustment is necessary. However, in elderly patients with severe renal impairment (creatinine clearance less than 30 mL/min), a dosage adjustment is recommended.

Physicians should be knowledgeable as well as vigilant about the treatment and identification of over dosage of Telithromycin.

Administration of activated charcoal may be considered as a potential treatment option.

The patient should undergo careful observation, including monitoring of electrocardiogram (ECG) and electrolyte levels. Additionally, symptomatic and supportive treatment should be provided. It is important to maintain adequate hydration. The effectiveness of hemodialysis in cases of Telithromycin overdose is unknown.

Post-market reports indicate that an overdose of Telithromycin(telithromycin) may result in gastrointestinal symptoms such as nausea, vomiting, and diarrhea.

Based on animal studies, telithromycin demonstrates low acute toxicity. The LD50 value, which represents the lethal dose for 50% of the tested population, is within the range of 1500-2000 mg/kg in mice. In rats, the minimum lethal dose exceeds 2000 mg/kg. No clinical signs were observed in rats, while mice exhibited hypotonia at doses of 1500 mg/kg and higher, along with tremors before death.

Pharmacodynamics

Typically, the oral administration of Telithromycin results in an absolute bioavailability of approximately 30 to 40%. Following an oral dose of 1 g, the maximum concentration of the drug in the bloodstream ranged from 0.4 to 1.4 mg/L.

Pharmacokinetics

Absorption: After being taken orally, telithromycin reaches its highest concentration within approximately 1 hour (ranging from 0.5 to 4 hours). The absolute bioavailability, which is the extent to which the drug is absorbed and reaches the systemic circulation, is around 57% in both young and elderly individuals after a single 800 mg dose. Telithromycin undergoes first-pass metabolism.

The absorption rate and extent of the regular-size tablet are not affected by food intake. In adult healthy volunteers under fasting conditions, the "reduced-size" tablet was found to be equivalent to the "regular-sized" tablet, indicating that Telithromycin tablets can be administered with or without food.

In fasting healthy adult subjects, the peak concentration of telithromycin in the plasma reaches approximately 2 μg/mL within a median time of 1 hour after taking an 800 mg oral dose.

Steady-state plasma concentrations, which refer to the balance between drug intake and elimination, are achieved within 2 to 3 days of once-daily administration of telithromycin 800 mg. These concentrations are approximately 1.5 times higher than the concentration achieved after a single dose after 7 days of continued dosing.

Distribution:

● Protein Binding: Within a clinically relevant concentration range, telithromycin exhibits approximately 60% to 70% total protein binding in vitro, primarily attributed to human serum albumin. This protein binding remains unaltered in elderly individuals and patients with hepatic impairment.

● Tissue Distribution: Telithromycin is extensively distributed throughout the body, with similar distribution patterns observed in both young and elderly subjects. The rapid distribution of telithromycin into various tissues leads to considerably higher concentrations in target tissues compared to plasma levels. For more detailed information, please refer to the "Human Pharmacology" section in the "Detailed Pharmacology" subsection.

Metabolism:

● Primary Metabolism: The liver primarily metabolizes telithromycin.

● Oral Administration: Following oral administration, approximately two-thirds of the dose undergoes metabolism into metabolites, while one-third remains unchanged. Telithromycin is the predominant compound found in plasma. The main circulating metabolite represents approximately 12.6% of the area under the concentration-time curve (AUC) of telithromycin, but its antimicrobial activity is significantly lower than that of the parent drug. Three other plasma metabolites, each accounting for 3% or less of the AUC of telithromycin, are detected in plasma, urine, and feces. Approximately 50% of telithromycin metabolism is mediated by cytochrome P450 (3A4), while the remaining 50% is independent of cytochrome P450.

Excretion:

● First-Pass Effect: Prior to entering systemic circulation, 33% of the telithromycin dose undergoes metabolism through a first-pass effect, while 57% reaches systemic circulation.

● Routes of Elimination: The unchanged dose reaching systemic circulation is eliminated through multiple pathways: approximately 7% is excreted unchanged in feces via biliary and/or intestinal secretion, 13% is excreted unchanged in urine through renal excretion, and 37% is metabolized by the liver.

● Elimination Half-Lives: The main elimination half-life of telithromycin is approximately 2-3 hours, while the terminal elimination half-life is around 10 hours when administered at a once-daily dose of 800 mg.

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