Introduction

Antibacterial; aminomethylcycline; tetracycline.

Uses for Omadacycline

Community-acquired Pneumonia

Treatment of community-acquired bacterial pneumonia (CABP) caused by Streptococcus pneumoniae, Staphylococcus aureus (methicillin-susceptible strains), Haemophilus influenzae, H. parainfluenzae, Klebsiella pneumoniae, Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydophila pneumoniae (formerly Chlamydia pneumoniae).

Skin and Skin-structure Infections

Treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by S. aureus (including methicillin-resistant S. aureus [MRSA; also known as oxacillin-resistant S. aureus or ORSA] and methicillin-susceptible S. aureus), S. lugdunensis, S. pyogenes, S. anginosus group (S. anginosus, S. intermedius, S. constellatus), Enterococcus faecalis, Enterobacter cloacae, and K. pneumoniae.

Omadacycline Dosage and Administration

Administration

Administer orally or by IV infusion.

Oral Administration

Administer orally with water under fasting conditions.

Fast for ≥4 hours prior to taking omadacycline tablets and do not consume food or drink (except water) for 2 hours after taking the drug.

Do not consume dairy products, antacids, iron-containing preparations, or multivitamins for 4 hours after taking omadacycline tablets. (See Interactions.)

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Must be reconstituted and further diluted prior to IV infusion.

Infuse through dedicated IV line or Y-site. Do not infuse omadacycline solutions simultaneously through the same IV line with any solution containing multivalent cations (e.g., calcium, magnesium).

Infusion using same IV line as other drugs not studied.

If same IV line used for sequential infusion of several different drugs, flush IV line with 0.9% sodium chloride injection or 5% dextrose injection before and after infusion of omadacycline.

Reconstitution

Reconstitute appropriate number of single-dose vials containing 100 mg of omadacycline by adding 5 mL of sterile water for injection, 0.9% sodium chloride injection, or 5% dextrose injection to each vial. Gently swirl vial and let stand until cake completely dissolves and any foam disperses; do not shake. If necessary, invert vial to dissolve any remaining powder; to avoid foaming, gently swirl vial.

Reconstituted solutions should be yellow to dark orange; discard if not correct color.

Dilution

To prepare a 100- or 200-mg dose, immediately (within 1 hour of reconstitution) withdraw 5 or 10 mL, respectively, of reconstituted solution and add to 100 mL of 0.9% sodium chloride injection or 5% dextrose injection. Final concentration of diluted solution will be 1 or 2 mg/mL for a 100- or 200-mg dose, respectively.

Discard unused portions of reconstituted solution.

If diluted solution stored under refrigeration (see Storage under Stability), allow it to reach room temperature prior to administration.

Rate of Administration

Administer 100- or 200-mg doses by IV infusion over 30 or 60 minutes, respectively.

Dosage

Available as omadacycline tosylate; dosage expressed in terms of omadacycline.

Adults

Community-acquired Pneumonia

IV

Initial loading dosage of 200 mg on day 1 (single 200-mg dose given IV over 60 minutes or two 100-mg doses given IV over 30 minutes 12 hours apart) followed by maintenance dosage of 100 mg once daily given IV over 30 minutes.

Total treatment duration is 7–14 days.

IV, then Oral

Initial loading dosage of 200 mg on day 1 (single 200-mg dose given IV over 60 minutes or two 100-mg doses given IV over 30 minutes 12 hours apart) followed by maintenance dosage of 100 mg once daily given IV over 30 minutes.

May switch maintenance therapy to omadacycline tablets given in a dosage of 300 mg orally once daily.

Total treatment duration (IV and oral) is 7–14 days.

Acute Skin and Skin Structure Infections

Oral

450 mg once daily on days 1 and 2 followed by 300 mg once daily.

Total treatment duration is 7–14 days.

IV

Initial loading dosage of 200 mg on day 1 (single 200-mg dose given IV over 60 minutes or two 100-mg doses given IV over 30 minutes 12 hours apart) followed by maintenance dosage of 100 mg once daily given IV over 30 minutes.

Total treatment duration is 7–14 days.

IV, then Oral

Initial loading dosage of 200 mg IV on day 1 (single 200-mg dose given IV over 60 minutes or two 100-mg doses given IV over 30 minutes 12 hours apart) followed by 100 mg once daily given IV over 30 minutes.

May switch maintenance therapy to omadacycline tablets given in a dosage of 300 mg orally once daily.

Total treatment duration (IV and oral) is 7–14 days.

Special Populations

Hepatic Impairment

Dosage adjustments not needed in patients with hepatic impairment (Child-Pugh class A, B, or C).

Renal Impairment

Dosage adjustments not needed in patients with renal impairment, including those with end-stage renal disease receiving dialysis.

Geriatric Patients

Dosage adjustment based on age not needed.

Contraindications

• Known hypersensitivity to omadacycline, other tetracyclines, or any excipients in the preparation.

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions reported. Life-threatening hypersensitivity (anaphylactic) reactions reported with other tetracyclines. Because omadacycline is structurally similar to other tetracyclines, contraindicated in patients with known hypersensitivity to any tetracycline.

Discontinue omadacycline if allergic reaction occurs.

Increased Mortality

Mortality imbalance observed in clinical trial evaluating omadacycline in patients with community-acquired pneumonia. Deaths reported in more patients receiving omadacycline (2%) than in those receiving the comparator drug (1%). Cause of the difference in mortality rates not established. All deaths in both treatment groups occurred in patients >65 years of age and most patients had multiple comorbid conditions. Causes of death included complications of and/or worsening of the infection and underlying conditions.

When omadacycline used for treatment of community-acquired pneumonia, closely monitor clinical response, particularly in those at higher risk of mortality.

Tooth Discoloration and Enamel Hypoplasia

Use of tetracyclines, including omadacycline, during tooth development (i.e., last half of pregnancy, infancy, childhood up to 8 years of age) may cause permanent discoloration of the teeth (yellow-gray-brown). Tooth discoloration more common during long-term use of tetracyclines, but also observed following repeated short-term use. Enamel hypoplasia also reported with tetracyclines.

Inhibition of Bone Growth

Use of tetracyclines, including omadacycline, during second or third trimester of pregnancy, infancy, or childhood up to 8 years of age may cause reversible inhibition of bone growth. Tetracyclines form a stable calcium complex in any bone-forming tissue. Decreased fibula growth rate observed in premature infants receiving oral tetracycline; this effect was reversible when the drug was discontinued.

Tetracycline-class Effects

Because omadacycline is structurally similar to conventional tetracyclines, adverse effects reported with tetracyclines (e.g., photosensitivity, pseudotumor cerebri, anti-anabolic action leading to increased BUN, azotemia, acidosis, hyperphosphatemia, pancreatitis, abnormal liver function tests) may occur. Discontinue omadacycline if any of these adverse effects are suspected.

C. difficile-associated Diarrhea and Colitis

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridioides difficile (formerly Clostridium difficile). C. difficile infection (CDI) and C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) reported with nearly all anti-infectives, including omadacycline, and may range in severity from mild diarrhea to fatal colitis. C. difficile produces toxins A and B which contribute to development of CDAD; hypertoxin-producing strains of C. difficile are associated with increased morbidity and mortality since they may be refractory to anti-infectives and colectomy may be required.

Consider CDAD if diarrhea develops during or after therapy and manage accordingly. Obtain careful medical history since CDAD may occur as late as ≥2 months after anti-infective therapy is discontinued.

If CDAD suspected or confirmed, discontinue anti-infectives not directed against C. difficile as soon as possible. Initiate appropriate anti-infective therapy directed against C. difficile (e.g., vancomycin, fidaxomicin, metronidazole), supportive therapy (e.g., fluid and electrolyte management, protein supplementation), and surgical evaluation as clinically indicated.

Selection and Use of Anti-infectives

To reduce development of drug-resistant bacteria and maintain effectiveness of omadacycline and other antibacterials, use only for treatment of infections proven or strongly suspected to be caused by susceptible bacteria. Prescribing omadacycline in absence of proven or strongly suspected bacterial infection unlikely to provide benefit to the patient and increases risk of development of drug-resistant bacteria.

When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing. In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.

Information on test methods and quality control standards for in vitro susceptibility testing of antibacterial agents and specific interpretive criteria for such testing recognized by FDA is available at [Web].

Specific Populations

Pregnancy

The manufacturer recommends that women of childbearing potential use an effective form of contraception while receiving omadacycline.

Omadacycline, like other tetracyclines, may cause permanent discoloration of deciduous teeth and reversible inhibition of bone growth if administered during second or third trimester of pregnancy. (See Tooth Discoloration and Enamel Hypoplasia and see Inhibition of Bone Growth under Cautions.)

Insufficient data on use of omadacycline in pregnant women to inform a drug-associated risk of major birth defects and miscarriages.

In animals, tetracyclines cross the placenta, are found in fetal tissues, and may have toxic effects on the developing fetus (e.g., retardation of skeletal development). Evidence of embryotoxicity also noted in animals that received tetracyclines early in pregnancy.

In rats and rabbits, use of omadacycline during organogenesis resulted in fetal loss and/or congenital malformations. Tooth discoloration observed in rats.

Advise patients of potential risks to the fetus if omadacycline is used during second or third trimester of pregnancy. (See Advice to Patients.)

Lactation

Not known if omadacycline distributes into human milk, affects breast-fed infant, or affects milk production.

Tetracyclines distribute into human milk; however, extent of absorption of tetracyclines, including omadacycline, by breast-fed infants not known.

Because other antibacterial options are available to treat community-acquired pneumonia and skin and skin structure infections in lactating women and because of the potential for serious adverse effects in the breast-fed infant (see Tooth Discoloration and Enamel Hypoplasia and see Inhibition of Bone Growth under Cautions), breast-feeding not recommended during omadacycline treatment and for 4 days after last dose of the drug.

Fertility

Although human data not available, animal studies indicate omadacycline can affect fertility.

In fertility studies in male rats, omadacycline caused injury to the testis and reduced sperm counts and sperm motility, but had no effect on fertility parameters. In general toxicity studies in rats, inhibition of spermatogenesis occurred when omadacycline given for ≥37 days at doses resulting in exposures 6–8 times higher than human exposures; such effects did not occur with lower doses or shorter treatment periods (≤4 weeks).

In fertility studies in female rats, reduced ovulation and increased embryonic loss reported at exposures similar to human exposures.

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.

Use in pediatric patients <8 years of age not recommended because of adverse effects of tetracyclines on tooth development and bone growth. (See Tooth Discoloration and Enamel Hypoplasia and see Inhibition of Bone Growth under Cautions.)

Geriatric Use

In one study in adults with community-acquired pneumonia, clinical success rate was lower in patients ≥65 years of age than in those <65 years of age; all deaths in this study occurred in patients >65 years of age. (See Increased Mortality under Cautions.)

Hepatic Impairment

Pharmacokinetics in individuals with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C) similar to those in healthy individuals.

Dosage adjustments not needed in patients with mild, moderate, or severe hepatic impairment.

Renal Impairment

Pharmacokinetics in adults with end-stage renal disease receiving hemodialysis similar to those observed in healthy individuals.

Dosage adjustments not needed in patients with mild, moderate, or severe renal impairment, including those with end-stage renal disease receiving hemodialysis.

Common Adverse Effects

Infusion site reactions, increased AST and ALT, increased γ-glutamyltransferase (GGT, γ-glutamyltranspeptidase, GGTP), hypertension, insomnia, GI effects (diarrhea, vomiting, constipation, nausea ), headache.

Administration

Administer orally or by IV infusion.

Oral Administration

Administer orally with water under fasting conditions.

Fast for ≥4 hours prior to taking omadacycline tablets and do not consume food or drink (except water) for 2 hours after taking the drug.

Do not consume dairy products, antacids, iron-containing preparations, or multivitamins for 4 hours after taking omadacycline tablets. (See Interactions.)

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Must be reconstituted and further diluted prior to IV infusion.

Infuse through dedicated IV line or Y-site. Do not infuse omadacycline solutions simultaneously through the same IV line with any solution containing multivalent cations (e.g., calcium, magnesium).

Infusion using same IV line as other drugs not studied.

If same IV line used for sequential infusion of several different drugs, flush IV line with 0.9% sodium chloride injection or 5% dextrose injection before and after infusion of omadacycline.

Reconstitution

Reconstitute appropriate number of single-dose vials containing 100 mg of omadacycline by adding 5 mL of sterile water for injection, 0.9% sodium chloride injection, or 5% dextrose injection to each vial. Gently swirl vial and let stand until cake completely dissolves and any foam disperses; do not shake. If necessary, invert vial to dissolve any remaining powder; to avoid foaming, gently swirl vial.

Reconstituted solutions should be yellow to dark orange; discard if not correct color.

Dilution

To prepare a 100- or 200-mg dose, immediately (within 1 hour of reconstitution) withdraw 5 or 10 mL, respectively, of reconstituted solution and add to 100 mL of 0.9% sodium chloride injection or 5% dextrose injection. Final concentration of diluted solution will be 1 or 2 mg/mL for a 100- or 200-mg dose, respectively.

Discard unused portions of reconstituted solution.

If diluted solution stored under refrigeration (see Storage under Stability), allow it to reach room temperature prior to administration.

Rate of Administration

Administer 100- or 200-mg doses by IV infusion over 30 or 60 minutes, respectively.

Dosage

Available as omadacycline tosylate; dosage expressed in terms of omadacycline.

Adults

Community-acquired Pneumonia

IV

Initial loading dosage of 200 mg on day 1 (single 200-mg dose given IV over 60 minutes or two 100-mg doses given IV over 30 minutes 12 hours apart) followed by maintenance dosage of 100 mg once daily given IV over 30 minutes.

Total treatment duration is 7–14 days.

IV, then Oral

Initial loading dosage of 200 mg on day 1 (single 200-mg dose given IV over 60 minutes or two 100-mg doses given IV over 30 minutes 12 hours apart) followed by maintenance dosage of 100 mg once daily given IV over 30 minutes.

May switch maintenance therapy to omadacycline tablets given in a dosage of 300 mg orally once daily.

Total treatment duration (IV and oral) is 7–14 days.

Acute Skin and Skin Structure Infections

Oral

450 mg once daily on days 1 and 2 followed by 300 mg once daily.

Total treatment duration is 7–14 days.

IV

Initial loading dosage of 200 mg on day 1 (single 200-mg dose given IV over 60 minutes or two 100-mg doses given IV over 30 minutes 12 hours apart) followed by maintenance dosage of 100 mg once daily given IV over 30 minutes.

Total treatment duration is 7–14 days.

IV, then Oral

Initial loading dosage of 200 mg IV on day 1 (single 200-mg dose given IV over 60 minutes or two 100-mg doses given IV over 30 minutes 12 hours apart) followed by 100 mg once daily given IV over 30 minutes.

May switch maintenance therapy to omadacycline tablets given in a dosage of 300 mg orally once daily.

Total treatment duration (IV and oral) is 7–14 days.

Special Populations

Hepatic Impairment

Dosage adjustments not needed in patients with hepatic impairment (Child-Pugh class A, B, or C).

Renal Impairment

Dosage adjustments not needed in patients with renal impairment, including those with end-stage renal disease receiving dialysis.

Geriatric Patients

Dosage adjustment based on age not needed.

Drugs Metabolized by Hepatic Microsomal Enzymes

Does not inhibit or induce CYP isoenzymes 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5.

Not expected to affect pharmacokinetics of drugs metabolized by CYP isoenzymes.

Drugs Metabolized by Uridine Diphosphate-glucuronosyltransferase 1A1

Does not inhibit or induce UGT1A1.

Not expected to affect pharmacokinetics of drugs metabolized by UGT1A1.

Drugs Affecting or Affected by Membrane Transporters

Low-affinity substrate of P-glycoprotein (P-gp) transport system.

Not a substrate of breast cancer resistance protein (BCRP), organic anion transporter (OAT) 1, OAT3, or multidrug resistance-associated protein (MRP) 2. At supratherapeutic concentrations, not a substrate of organic anion transporting polypeptide (OATP) 1B1 or 1B3.

Does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, or MRP2. Not likely to induce P-gp or MRP2 expression.

Specific Drugs