Omadacycline

Omadacycline belongs to the pharmacological class of Tetracycline antibiotics.

Omadacycline has been approved to relieve symptoms and also for the treatment and maintenance of Community-Acquired Bacterial Pneumonia (CABP),Acute Bacterial Skin and the Skin Structure Infections (ABSSSIs).

Omadacycline is a once-daily administered antibiotic that exhibits linear pharmacokinetics over a wide range of doses. After oral administration, its bioavailability is about 33%, with a median Tmax of 4 hours. The mean terminal half-life is approximately 22-24 hours, and steady-state plasma concentrations are typically achieved within 3 days of once-daily dosing. The volume of distribution is around 150-200 L, and protein binding is approximately 21%. Omadacycline is primarily eliminated through the feces, with only about 20% eliminated via urine. The major elimination pathway is through nonrenal clearance. The clearance is approximately 10 L/h, and the renal clearance is about 1 L/h.

The common side effects involved in using Omadacycline are Diarrhea, Nausea, Vomiting, Abdominal pain, Headache, Dizziness, Rash, discoloration of teeth , nails and gums and Itching.

Omadacycline is available in the form of Tablets, Intravenous , Injectable, lyophilized powder for reconstitution.

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

Omadacycline belongs to the pharmacological class of Tetracycline antibiotics.

With a high degree of specificity, Omadacycline binds to the primary tetracycline binding site on the bacterial 30s ribosomal subunit, disrupting various aspects of cellular function and impeding protein synthesis. This results in stasis or cell death.

Omadacycline has been approved to relieve symptoms and also for the treatment and maintenance of Community-Acquired Bacterial Pneumonia (CABP),Acute Bacterial Skin and the Skin Structure Infections (ABSSSIs).

Cmax (maximum concentration) of omadacycline in the blood is achieved around 1-3 hours after oral administration and around 0.5-2 hours after intravenous administration. The C max value after a single oral dose of 300 mg is approximately 1.8 mcg/mL. T max (time to reach maximum concentration) of omadacycline in the blood is approximately 2 hours after oral administration and approximately 1 hour after intravenous administration.

The onset of action for omadacycline varies depending on the indication and severity of the infection being treated. For Community-Acquired Bacterial Pneumonia (CABP), the median time to clinical response was 85.2 hours, while for Acute Bacterial Skin and the Skin Structure Infections (ABSSSI), the median time to clinical response was 60.3 hours.

The duration of action of omadacycline is approximately 12-24 hours, depending on the dose and the patient's individual factors such as age, weight, and kidney function. The recommended treatment duration for CABP and ABSSSI is 7-14 days.

Omadacycline is found to be available in the form of Tablets, Intravenous , Injectable, lyophilized powder for reconstitution.

Omadacycline can be used in the following treatment:

• Community-Acquired Bacterial Pneumonia (CABP)
• Acute Bacterial Skin and the Skin Structure Infections (ABSSSIs)

Omadacycline can help to relieve symptoms and also for the treatment and maintenance of Community-Acquired Bacterial Pneumonia (CABP),Acute Bacterial Skin and the Skin Structure Infections (ABSSSIs).

Omadacycline is approved for use in the following clinical indications:

• Community-Acquired Bacterial Pneumonia (CABP)
• Acute Bacterial Skin and Skin Structure Infections (ABSSSIs).

• For the treatment of Community-Acquired Bacterial Pneumonia (CABP) caused by susceptible microorganisms, this medication is recommended. The dosing regimen consists of a loading dose on the first day, followed by maintenance dosing beginning on the second day, and the treatment duration is typically 7-14 days. The loading dose can be administered as a 200 mg IV once, 100 mg IV twice, or 300 mg PO twice. Maintenance dosing can be given as 100 mg IV once daily or 300 mg PO once daily.
• This medication is also used for the treatment of Acute Bacterial Skin and the Skin Structure Infections (ABSSSIs) caused by susceptible microorganisms, and the treatment duration is again typically 7-14 days. The loading dose can be administered as 200 mg IV once or 100 mg IV twice on the first day, or 450 mg PO once daily for two days. The maintenance dose can be given as 100 mg IV once daily or 300 mg PO once daily.

Tablets: 150mg

Injectable: 100mg vial

Intravenous , Injectable, lyophilized powder for reconstitution.

• Dosage Adjustments in Pediatric Patients:

Safety and efficacy has not been established for individuals under the age of 18.

There are no specific dietary restrictions related to the use of Omadacycline. However, like with most antibiotics, it is generally recommended to take Omadacycline with a full glass of water and to avoid taking it with milk or the other dairy products as they may decrease the absorption of the medication. Additionally, taking Omadacycline with food can help minimize the risk of gastrointestinal upset.

Omadacycline may be contraindicated under the following conditions:

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

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

• Mortality Imbalance in Patients with a Community-Acquired Bacterial Pneumonia

Observations of a mortality imbalance were made in the clinical trial of Omadacycline for CABP, with a higher incidence of deaths (2%) occurring in Omadacycline-treated patients compared to moxifloxacin-treated patients (1%). The cause of this mortality imbalance has not yet been established, but all deaths occurred in patients over the age of 65 with multiple comorbidities. Close monitoring of clinical response to therapy is recommended, particularly in those at higher risk for mortality.

• Tooth Discoloration and Enamel Hypoplasia

Omadacycline use during tooth development in pregnancy, infancy, and childhood up to the age of eight years may lead to permanent discoloration of the teeth (yellow-gray-brown). Long-term use of tetracycline-class drugs increases the likelihood of this adverse reaction, but it has also been observed following repeated short-term courses. Enamel hypoplasia has also been reported with tetracycline-class drugs, and patients should be advised of the potential risk to the fetus if Omadacycline is used during the second or third trimester of pregnancy.

• Inhibition of Bone Growth

Omadacycline use during the second and third trimester of pregnancy, infancy, and childhood up to the age of eight years may cause reversible inhibition of bone growth. All tetracyclines form a stable calcium complex in bone-forming tissue, leading to decreased fibula growth rate observed in premature infants given oral tetracycline. This reaction is reversible upon discontinuation of the drug, and patients should be advised of the potential risk to the fetus if Omadacycline is used during the second or third trimester of pregnancy.

• Hypersensitivity Reactions

Hypersensitivity reactions have been reported with Omadacycline, including life-threatening hypersensitivity (anaphylactic) reactions reported with other tetracycline-class antibacterial drugs. Omadacycline is structurally similar to tetracycline-class drugs and is contraindicated in patients with known hypersensitivity. If an allergic reaction occurs, Omadacycline should be discontinued.

• Clostridium difficile-Associated Diarrhea

Nearly all antibacterial agents have been associated with Clostridium difficile-associated diarrhea (CDAD), ranging in severity from mild diarrhea to fatal colitis. Clostridium difficile-associated diarrhea must be considered in all patients who present with diarrhea following antibacterial drug use, with appropriate management instituted as clinically indicated.

• Tetracycline Class Effects

Omadacycline is structurally similar to tetracycline-class drugs and found to have similar adverse reactions, including photosensitivity, pseudotumor cerebri, and anti-anabolic action which can lead to increased BUN, azotemia, acidosis, hyperphosphatemia, pancreatitis, as well as abnormal liver function tests. Omadacycline should be discontinued if any of these adverse reactions are suspected.

• Development of Drug-Resistant Bacteria

Omadacycline should only be prescribed in the presence of a proven or strongly suspected bacterial infection, as prescribing in the absence of infection increases the risk of drug-resistant bacteria development.

There is no specific alcohol warning associated with the use of Omadacycline. 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.

There is no data available on the presence of omadacycline in breast milk or its effects on breastfed infants, as well as its impact on milk production. Although tetracyclines are known to be excreted in human milk, the extent of absorption by the nursing infant remains uncertain for omadacycline and other tetracyclines. Given the availability of alternative antibiotics for treating CABP and ABSSSI in lactating women and the potential for severe side effects, such as tooth discoloration and bone growth inhibition, patients should be advised against breastfeeding during Omadacycline treatment and for four days (based on half-life) after the last dose.

Pregnancy Category D:

Omadacycline, which belongs to the tetracycline-class of antibacterial drugs, has the potential to cause tooth discoloration and reversible inhibition of bone growth when used during the second and third trimester of pregnancy. The available data on the use of Omadacycline in pregnant women is limited, and insufficient to provide information on the risk of major birth defects and miscarriages associated with the drug [see Warnings and Precautions (5.2, 5.3), Use in Specific Populations (8.4)]. Animal studies have shown that omadacycline administration during organogenesis in pregnant rats and rabbits resulted in fetal loss and/or congenital malformations at levels 7 times and 3 times higher, respectively, than the mean AUC exposure of the clinical intravenous dose of 100 mg and oral dose of 300 mg. Additionally, reductions in fetal weight occurred in rats at all administered doses . In a fertility study, embryo loss occurred in rats at 20 mg/kg/day, which was equivalent to clinical exposure. Studies in rats have also shown tooth discoloration with omadacycline use. The estimated background risk of the major birth defects as well as miscarriage in the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes, and the estimated background risk of the major birth defects and miscarriage in clinically recognized pregnancies in the general U.S. population is 2-4% and 15-20%, respectively.

There are no specific food warnings related to the use of omadacycline. However, like other tetracycline-class antibiotics, omadacycline may reduce the effectiveness of oral contraceptives, so patients taking both drugs should use additional methods of contraception to prevent pregnancy. Additionally, absorption of oral tetracyclines, including omadacycline, may be impaired by antacids containing aluminum, calcium, or magnesium, bismuth subsalicylate, and iron-containing preparations. Therefore, these antacids and iron preparations should be avoided or administered at least 2 hours before or after taking omadacycline.

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

Common

• Nausea
• Vomiting
• Dizziness
• Diarrhea
• Headache
• Skin rash
• Pruritus (itching)
• Abdominal pain
• Hypertension (high blood pressure)
• Phlebitis (inflammation of a vein)

Less Common

• Anorexia (loss of appetite)
• Photosensitivity (increased sensitivity to sunlight)
• Asthenia (weakness or lack of energy)
• Dyspnea (shortness of breath)
• Chest pain
• Tachycardia (rapid heart rate)
• Arthralgia (joint pain)
• Myalgia (muscle pain)
• Hyperpigmentation (excess pigmentation of the skin)
• Urinary tract infection

Rare

• Hypersensitivity reactions (e.g. anaphylaxis, angioedema)
• Hepatotoxicity (liver damage)
• Renal failure
• Blood dyscrasias (abnormalities in blood cell counts)
• Intracranial hypertension (increased pressure inside the skull)

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

Anticoagulant medications

As tetracyclines have demonstrated a decrease in plasma prothrombin activity, patients receiving anticoagulant therapy may need to lower their anticoagulant dosage while taking Omadacycline.

Antacids and Iron Supplements

The absorption of oral tetracyclines, such as Omadacycline, is negatively impacted by antacids containing aluminum, calcium, or magnesium, bismuth subsalicylate, and iron supplements.

The following are the side effects involving Omadacycline:

• Nausea and vomiting
• Dizziness
• Headache
• Rash
• Diarrhea
• Discoloration of skin, teeth, nails, or gums
• Yeast infections

Pregnancy:

Pregnancy Category D:

Omadacycline, which belongs to the tetracycline-class of antibacterial drugs, has the potential to cause tooth discoloration and reversible inhibition of bone growth when used during the second and third trimester of pregnancy. The available data on the use of Omadacycline in pregnant women is limited, and insufficient to provide information on the risk of major birth defects and miscarriages associated with the drug . Animal studies have shown that omadacycline administration during organogenesis in pregnant rats and rabbits resulted in fetal loss and/or congenital malformations at levels 7 times and 3 times higher, respectively, than the mean AUC exposure of the clinical intravenous dose of 100 mg and oral dose of 300 mg. Additionally, reductions in fetal weight occurred in the rats at all administered doses . In a fertility study, embryo loss occurred in rats at 20 mg/kg/day, which was equivalent to clinical exposure. Studies in rats have also shown tooth discoloration with omadacycline use. The estimated background risk of major birth defects and miscarriage in the indicated population is unknown. All pregnancies has a background risk of birth defects, loss, or other adverse outcomes, and the estimated background risk of major birth defects and miscarriage in a clinically recognized pregnancies in the general U.S. population is 2-4% and 15-20%, respectively.

Nursing Mothers

There is no data available on the presence of omadacycline in breast milk or its effects on breastfed infants, as well as its impact on milk production. Although tetracyclines are known to be excreted in human milk, the extent of absorption by the nursing infant remains uncertain for omadacycline and other tetracyclines. Given the availability of alternative antibiotics for treating CABP and ABSSSI in lactating women and the potential for severe side effects, such as tooth discoloration and bone growth inhibition, patients should be advised against breastfeeding during Omadacycline treatment and for four days (based on half-life) after the last dose.

Pediatric Use

The efficacy and safety of Omadacycline has not been established in children under the age of 18 years . Omadacycline belongs to the tetracycline class of drugs, which can have negative effects on tooth development and bone growth, thus the use of Omadacycline is not recommended for pediatric patients under 8 years of age.

Geriatric Use

Out of the total number of patients (n=1073) who received Omadacycline in the Phase 3 clinical trials, 200 patients were 65 years of age or older, with 92 patients being 75 years of age or older. In Trial 1, there were numerically lower clinical success rates at the early clinical response (ECR) time point for patients ≥65 years of age with CABP who were treated with Omadacycline and moxifloxacin (75.5% and 78.7%, respectively) compared to patients less than 65 years of age (85.2% and 86.3%, respectively). Furthermore, all deaths in the CABP trial occurred in patients older than 65 years . However, no significant difference in Omadacycline exposure was observed between healthy elderly subjects and the younger subjects following a single 100-mg IV dose of Omadacycline.

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

There is no specific information on the management of overdosing with Omadacycline. However, it is worth noting that after administering a single intravenous dose of 100 mg of omadacycline, 8.9% of the dose was recovered in the dialysate.

Absorption:

● Dose Proportionality: Omadacycline Cmax and AUC increases proportionally with dose following single oral doses of Omadacycline from 300 to 450 mg.

● Accumulation: After a single 300 mg dose of Omadacycline, the accumulation ratio was 1.5 with a 34.5% increase. The accumulation ratio at steady state was 0.50 (0, 1) with a 20% increase, which was not concentration dependent. The accumulation ratio at steady state following multiple doses was 2.50 (0, 8).

● The type of food consumed can affect the absorption of Omadacycline, an oral medication. When a high-fat meal containing dairy was consumed two hours before taking a 300-mg dose of Omadacycline, the medication's absorption rate and extent were reduced by 40% and 42%, and 59% and 63%, respectively, compared to taking the medication on an empty stomach. However, a high-fat meal without dairy consumed four hours before taking the medication or a light non-fat meal, a standard low-fat meal, or a standard high-fat meal consumed two hours after taking the medication did not significantly impact its absorption rate or extent.

Distribution:

Omadacycline has a plasma protein binding of around 20%, which does not depend on concentration. At steady-state, the mean volume of distribution of omadacycline following intravenous (IV) administration in healthy individuals was 190 (27.7) L.

Elimination:

In healthy individuals, renal clearance of omadacycline following IV administration ranged from 2.4 to 3.3 L/h. After a 100-mg IV dose, 27% of the drug was recovered unchanged in the urine. In healthy male volunteers who received a 300-mg oral [14C] omadacycline dose, approximately 14.4% (range 10.8% to 17.4%) was recovered in the urine, and 77.5% to 84.0% was recovered in the feces. The elimination half-life of omadacycline is approximately 16.2 hours.

Metabolism:

In vitro studies conducted using human liver microsomes and hepatocytes have shown that omadacycline is not metabolized.

• O’Riordan, W., Green, S., Overcash, J. S., Puljiz, I., Metallidis, S., Gardovskis, J., … Das, A. F. (2019). Omadacycline for Acute Bacterial Skin and Skin-Structure Infections. The New England Journal of Medicine, 380(6), 528–538. https://doi.org/10.1056/NEJMoa1806802
• Stets, R., Popescu, M., Gonong, J. R., Mitha, I., Nseir, W., Madej, A., … Steenbergen, J. N. (2019). Omadacycline for Community-Acquired Bacterial Pneumonia. The New England Journal of Medicine, 380(6), 517–527. https://doi.org/10.1056/NEJMoa1800201
• Pullman, J., Gardovskis, J., Farley, B., Sun, E., Quintas, M., Lawrence, L., & Das, A. (2019). Omadacycline Versus Linezolid for Treatment of Acute Bacterial Skin and Skin-Structure Infections: The OASIS-2 Randomized Trial. Antimicrobial Agents and Chemotherapy, 63(11), e01348-19. https://doi.org/10.1128/AAC.01348-19.

• https://go.drugbank.com/drugs/DB12455
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209816_209817lbl.pdf
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• https://medlineplus.gov/druginfo/meds/a618066.html
• https://www.sciencedirect.com/topics/medicine-and-dentistry/omadacycline