Eravacycline

Eravacycline belongs to the pharmacological class of Tetracycline antibiotics.

Eravacycline has been approved to relieve symptoms and also for the treatment and maintenance of Intra-abdominal infections, complicated, Plague treatment, bubonic or pharyngeal (alternative agent, off-label use).

Eravacycline is administered intravenously and has a rapid distribution phase with a volume of distribution of approximately 16 L, indicating good tissue penetration. The elimination half-life of eravacycline is approximately 14 hours, allowing for once-daily dosing. Eravacycline is primarily eliminated via hepatic metabolism, with less than 10% of the dose excreted unchanged in the urine. Eravacycline is not a substrate or inhibitor of major cytochrome P450 enzymes, and it does not affect the QT interval or interact with other commonly used medications.

The common side effects involved in using Eravacycline are Diarrhea, Nausea, Vomiting, Abdominal pain, Headache, Dizziness, Rash, yellowness of teeth and Itching.

Eravacycline is available in the form of Injection, lyophilized powder for reconstitution.

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

Eravacycline belongs to the pharmacological class of Tetracycline antibiotics.

Eravacycline is an antibacterial drug that belongs to the tetracycline class and is classified as a fluorocycline. Its mechanism of action involves binding to the 30S ribosomal subunit of bacteria, which disrupts their protein synthesis, and prevents the incorporation of amino acid residues into growing peptide chains. Gram-positive bacteria such as Staphylococcus aureus and Enterococcus faecalis are typically inhibited by eravacycline, and it is mainly bacteriostatic in action. However, certain strains of Escherichia coli and Klebsiella pneumoniae have shown in vitro bactericidal activity when exposed to eravacycline. These details are available on the label of eravacycline.

Eravacycline has been approved to relieve symptoms and also for the treatment and maintenance of Intra-abdominal infections, complicated, Plague treatment, bubonic or pharyngeal (alternative agent, off-label use).

Eravacycline has a maximum plasma concentration (Cmax) of approximately 1.3 µg/mL when administered as a single 1 mg/kg intravenous (IV) infusion over an hour.

Eravacycline has a time to maximum plasma concentration (Tmax) of approximately 1.5 to 2 hours after the end of the infusion.

Eravacycline's onset of action is not well defined and may vary depending on the type and severity of the infection being treated.The duration of action of eravacycline is approximately 12 hours, with steady-state concentrations achieved by the second day of dosing when administered every 12 hours. The drug is typically administered for a duration of 4 to 14 days depending on the severity of the infection being treated.

Eravacycline is found to be available in the form of Injection, lyophilized powder for reconstitution.

Eravacycline can be used in the following treatment:

• Intra-abdominal infections, complicated
• Plague treatment, bubonic or pharyngeal (alternative agent, off-label use).

Eravacycline can help to relieve symptoms and also for the treatment and maintenance of Susceptible infections caused by the following Intra-abdominal infections, complicated, Plague treatment, bubonic or pharyngeal (alternative agent, off-label use).

Eravacycline is approved for use in the following clinical indications:

• Intra-abdominal infections, complicated:

For intravenous use, administer 1 mg/kg every 12 hours for 4 to 14 days.

• Plague treatment, bubonic or pharyngeal (alternative agent, off-label use):

Please note that specific recommendations for events should be consulted with public health officials. For intravenous use, administer 1 mg/kg every 12 hours for 10 to 14 days and continue for several days after clinical resolution.

• For susceptible infections, the recommended dosage of the medication is 1 mg/kg every 12 hours for 14 days.

• Injection, lyophilized powder for reconstitution: 50mg/single-dose vial

Injection, lyophilized powder for reconstitution.

There are no specific dietary restrictions related to the use of Eravacycline. However, like with most antibiotics, it is generally recommended to take Eravacycline with a full glass of water and to avoid taking it i decrease the absorption of the medication. Additionally, taking Eravacycline with food can help minimize the risk of gastrointestinal upset.

Eravacycline may be contraindicated under the following conditions:

• Patients who have a known hypersensitivity to any component of Eravacycline or to other drugs in the same class.

The physician should closely monitor the patients and keep pharmacovigilance as follows:

• Hypersensitivity Reactions:

Eravacycline, a tetracycline-class antibacterial drug, has been associated with life-threatening hypersensitivity (anaphylactic) reactions. Patients with known hypersensitivity to the tetracycline-class antibacterial drugs should avoid using Eravacycline. If an allergic reaction occurs, the drug should be discontinued immediately.

• Tooth Discoloration and Enamel Hypoplasia:

The use of Eravacycline during the tooth development (last half of pregnancy, infancy, and childhood to the age of eight years) can lead to permanent discoloration of the teeth (yellow-grey-brown) and enamel hypoplasia. While this adverse reaction is more commonly associated with long-term use of tetracycline-class drugs, it has also been observed following repeated short-term courses. Patients should be informed of the potential risk to the fetus if Eravacycline is used during the second or third trimester of pregnancy.

• Inhibition of Bone Growth:

Eravacycline use during the second and third trimester of pregnancy, infancy, as well as childhood up to the age of eight years may cause reversible inhibition of bone growth. Tetracyclines forms a stable calcium complex in any bone-forming tissue, leading to decreased bone growth. Premature infants given oral tetracycline in doses of 25 mg/kg every six hours have shown a decrease in fibula growth rate, which was reversible when the drug was discontinued. Patients should be informed of the potential risk to the fetus if Eravacycline is used during the second or third trimester of pregnancy.

• Clostridium difficile-Associated Diarrhea:

Eravacycline has been associated with Clostridium difficile associated diarrhea (CDAD), a condition that can range from mild diarrhea to fatal colitis. Antibacterial agents alter the normal flora of the colon, leading to overgrowth of C. difficile. Careful medical history is necessary as CDAD had been reported to occur over two months after the administration of antibacterial agents.

• Tetracycline Class Adverse Reactions:

Eravacycline, being structurally similar to tetracycline-class antibacterial drugs, may lead to similar adverse reactions. Photosensitivity, pseudotumor cerebri, and anti-anabolic action leading to increased BUN, azotemia, acidosis, hyperphosphatemia, pancreatitis, as well as abnormal liver function tests have been reported with other tetracycline-class antibacterial drugs and may also occur with Eravacycline. If any of these adverse reactions are suspected, discontinue Eravacycline immediately.

• Potential for Microbial Overgrowth:

Eravacycline use may result in overgrowth of non-susceptible organisms, including fungi. If such infections occur, discontinue Eravacycline and institute appropriate therapy.

• Development of Drug-Resistant Bacteria:

Eravacycline should not be prescribed in the absence of a proven or a strongly suspected bacterial infection, as it is unlikely to provide any benefit to the patient and may increase the risk of developing drug-resistant bacteria.

There is no specific alcohol warning associated with the use of Eravacycline. However, it is generally recommended to avoid excessive alcohol consumption while taking antibiotics as it can interfere with the effectiveness of the medication and may also increase the risk of certain side effects such as nausea, vomiting, and dizziness.

The presence of Eravacycline in human breast milk is currently unknown. Eravacycline and its metabolites have been detected in the milk of lactating rats, as stated in the available data. Although tetracyclines, including eravacycline, are excreted in human milk, the extent of absorption by the breastfed infant is unclear. There is no information regarding the potential effects of Eravacycline on milk production or the breastfed infant. Considering the potential for severe adverse reactions, such as tooth discoloration and inhibition of bone growth, and the availability of other antibacterial drugs to treat cIAI in lactating women, patients should be informed that breastfeeding is not recommended during Eravacycline treatment and for four days after the last dose based on the drug's half-life.

Pregnancy Category D:

Eravacycline, similar to other antibacterial drugs in the tetracycline class, may result in tooth discoloration and temporary inhibition of bone growth when administered during the second and third trimester of pregnancy. The available data on the use of Eravacycline during pregnancy is insufficient to determine the drug's association with a higher risk of major birth defects and miscarriages. Animal studies suggest that eravacycline can cross the placenta and can be found in fetal plasma. Administration of doses greater than approximately 3 times and 2.8 times the clinical exposure based on AUC in the rats and rabbits, respectively, during organogenesis was associated with decreased ossification, decreased fetal body weight, and/or increased post-implantation loss .

The background risk of the major birth defects and miscarriage in the indicated population is not known. All pregnancies carry a risk of birth defects, loss, or other adverse outcomes. In the general population of the United States, the estimated background risk of the major birth defects and miscarriage in clinically recognized pregnancies is approximately 2 to 4% and 15 to 20%, respectively.

There are no specific food warnings related to the use of Eravacycline. However, taking Eravacycline with dairy products or antacids that contain aluminum, calcium, or magnesium can decrease its absorption and effectiveness. It is generally recommended to take Eravacycline on an empty stomach, at least one hour before or two hours after meals.

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

Common

• Nausea
• Vomiting
• Diarrhea
• Loss of appetite
• Stomach upset
• Photosensitivity (increased sensitivity to sunlight)
• Headache

Less Common

• Rash or hives
• Itching
• Swelling
• Difficulty swallowing
• Sore throat
• Vaginal itching or discharge
• Dizziness
• Blurred vision
• Confusion
• Muscle pain
• Joint pain

Rare

• Severe allergic reactions (anaphylaxis)
• Liver damage or inflammation
• Kidney damage or inflammation
• Blood disorders, such as anemia or thrombocytopenia
• Intracranial hypertension (increased pressure inside the skull)
• Esophageal ulceration (ulceration of the esophagus)
• Pancreatitis (inflammation of the pancreas)
• Cardiac arrhythmias (abnormal heart rhythms)
• Stevens-Johnson syndrome (a rare, serious skin reaction)

The clinically relevant drug interactions of Eravacycline are briefly summarized here:

Impact of Strong CYP3A Inducers on Eravacycline

Eravacycline is an antibiotic drug that may be affected by strong CYP3A inducers, which can decrease the exposure of eravacycline, and potentially lower the efficacy of Eravacycline. This is supported by clinical pharmacology data.

Dosage and Administration for Patients on Strong CYP3A Inducers

To address the potential impact of strong CYP3A inducers, healthcare providers may need to adjust the dosage of Eravacycline in patients taking these inducers. The recommended dosage adjustment is stated in the Eravacycline prescribing information.

Interaction of Eravacycline with Anticoagulant Drugs

Tetracycline-class antibiotics, including Eravacycline, have been shown to reduce plasma prothrombin activity, which may affect the efficacy of anticoagulant therapy. Therefore, patients who are on anticoagulant treatment and also require treatment with Eravacycline may require a downward adjustment of their anticoagulant dosage.

The following are the side effects involving Eravacycline:

• Nausea
• Vomiting
• Diarrhea
• Upset stomach
• Photosensitivity reactions
• Skin rash
• Tooth discoloration
• Esophageal ulceration
• Hepatotoxicity
• Renal toxicity
• Blood dyscrasias such as thrombocytopenia, neutropenia, and anemia
• Intracranial hypertension (pseudotumor cerebri)
• Hypersensitivity reactions such as anaphylaxis and angioedema.

Pregnancy:

Pregnancy Category D:

Eravacycline, similar to other antibacterial drugs in the tetracycline class, may result in tooth discoloration and temporary inhibition of bone growth when administered during the second and third trimester of pregnancy. The available data on the use of Eravacycline during pregnancy is insufficient to determine the drug's association with a higher risk of major birth defects and miscarriages. Animal studies suggest that eravacycline can cross the placenta and can be found in fetal plasma. Administration of doses greater than approximately 3 times and 2.8 times the clinical exposure based on AUC in rats and rabbits, respectively, during organogenesis was associated with decreased ossification, decreased fetal body weight, and/or increased post-implantation loss .

The background risk of major birth defects and miscarriage in the indicated population is not known. All pregnancies carry a risk of birth defects, loss, or other adverse outcomes. In the general population of the United States, the estimated background risk of the major birth defects also the miscarriage in clinically recognized pregnancies is approximately 2 to 4% and 15 to 20%, respectively.

Nursing Mothers

The presence of Eravacycline in human breast milk is currently unknown. Eravacycline and its metabolites have been detected in the milk of lactating rats, as stated in the available data. Although tetracyclines, including eravacycline, are excreted in human milk, the extent of absorption by the breastfed infant is unclear. There is no information regarding the potential effects of Eravacycline on milk production or the breastfed infant. Considering the potential for severe adverse reactions, such as tooth discoloration and inhibition of bone growth, and the availability of other antibacterial drugs to treat cIAI in lactating women, patients should be informed that breastfeeding is not recommended during Eravacycline treatment and for four days after the last dose of eravacycline based on the drug's half-life.

Pediatric Use

Eravacycline has not been proven to be safe and effective in pediatric patients. The use of Eravacycline in children under the age of eight is not recommended due to the potential adverse effects of the tetracycline-class of drugs, including Eravacycline, on tooth development and bone growth.

Geriatric Use

In Phase 3 clinical trials, 520 patients with cIAI were treated with Eravacycline, out of which 158 subjects were 65 years or older and 59 subjects were 75 years or older. The safety and efficacy of Eravacycline were comparable between the older subjects and younger ones, indicating no significant differences. Furthermore, in a population pharmacokinetic analysis of eravacycline, no clinically relevant age-related differences in the drug's pharmacokinetics were observed.

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

There were no instances of overdose reported during clinical trials of Eravacycline. If an overdose is suspected, treatment with Eravacycline should be discontinued, and the patient should be closely monitored for any adverse reactions. Hemodialysis is not expected to be effective in removing substantial amounts of Eravacycline.

Pharmacodynamics

Complicated intraabdominal infections can be treated with eravacycline, which is an antibiotic that interferes with bacterial protein synthesis.

Pharmacokinetics

● Absorption:

Eravacycline AUC (area under the curve) and Cmax (maximum concentration) increase in dose-proportionally for doses from 1 mg/kg - 3 mg/kg (three times the approved dose) following single-dose intravenous administration. Approximately 45% accumulation occurs after intravenous dosing of 1 mg/kg every 12 hours.

● Volume of distribution:

The volume of distribution at steady-state is approximately 321 Litres.

● Protein binding:

Eravacycline's binding to human plasma proteins increases with increasing plasma concentrations. At plasma concentrations ranging from 100 to 10,000 ng/mL, 79% to 90% of eravacycline is bound to plasma proteins.

● Metabolism:

Eravacycline is primarily metabolized through CYP3A4- and FMO-mediated oxidation.

● Route of elimination:

After a single intravenous dose of radiolabeled eravacycline 60 mg, approximately about 34% of the dose is eliminated in urine and 47% in feces. Unchanged eravacycline (about 20% in urine and 17% in feces) and metabolites are the main excretion products.

• https://go.drugbank.com/drugs/DB12329#
• https://www.Eravacycline.com/
• https://www.sciencedirect.com/topics/medicine-and-dentistry/eravacycline
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505493/
• https://reference.medscape.com/drug/Eravacycline-eravacycline-1000245
• https://www.ema.europa.eu/en/documents/product-information/Eravacycline-epar-product-information_en.pdf
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf
• https://www.drugs.com/mtm/eravacycline.html
• https://www.webmd.com/drugs/2/drug-175946/eravacycline-intravenous/details