Author: EMDEX Editor

The U.S. Food and Drug Administration (FDA) has approved XERAVA (Eravacycline), a fluorocycline antibacterial within the tetracycline class of antibacterial drugs, for the treatment of complicated intra-abdominal infections (cIAI) caused by susceptible microorganisms in patients 18 years of age and older.

XERAVA is not indicated for the treatment of complicated urinary tract infections (cUTI). To reduce the development of drug-resistant bacteria and maintain the effectiveness of XERAVA and other antibacterial drugs, XERAVA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.

Susceptible microorganisms include: Escherichia coli, Klebsiella pneumoniae, Citrobacter freundii, Enterobacter cloacae, Klebsiella oxytoca, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Streptococcus anginosus group, Clostridium perfringens, Bacteroides species, and Parabacteroides distasonis.

The approved recommended dosage of XERAVA is 1 mg/kg by intravenous infusion over approximately 60 minutes every 12 hours for a total duration of 4 to 14 days. The duration of therapy should be guided by the severity and location of infection and the patient’s clinical response. Additional information regarding dosage and administration can be found in the full prescribing information linked below.

Life-threatening hypersensitivity (anaphylactic) reactions have been reported with XERAVA.

is contraindicated for use in patients with known hypersensitivity to eravacycline, tetracycline-class antibacterial drugs, or to any of the excipients. Discontinue XERAVA if an allergic reaction occurs. The use of XERAVA may cause tooth discoloration and enamel hypoplasia, inhibition of bone growth, andclostridium difficile-associated diarrhea. Additional information regarding these important warnings can be found in the full prescribing information linked below.

Mechanism of Action (MOA) and Pharmacokinetics (PK)

• MOA: Eravacycline disrupts bacterial protein synthesis by binding to the 30S ribosomal subunit thus preventing the incorporation of amino acid residues into elongating peptide chains.
• General PK: Eravacycline AUC and C_max increase proportionally over doses from 1 mg/kg to 3 mg/kg (3 times the approved recommended dosage). Accumulation is approximately 45% following the approved recommended dosage.
• Distribution: Protein binding of eravacycline increases with increasing plasma concentrations, with 79% to 90% (bound) at plasma concentrations ranging from 100 to 10,000 ng/mL. The volume of distribution at steady-state is approximately 321 L.
• Elimination: The mean elimination half-life is 20 hours.
• Metabolism: Eravacycline is metabolized primarily by CYP3A4- and FMO-mediated oxidation.
• Excretion: Following a single intravenous dose of radiolabeled eravacycline 60 mg, approximately 34% of the dose is excreted in urine and 47% in feces as unchanged eravacycline (20% in urine and 17% in feces) and metabolites.

Drug Interactions

CYP3A Inducers 

Concomitant use of strong CYP3A inducers decreases the exposure of eravacycline, which may reduce the efficacy of XERAVA. Administer XERAVA 1.5 mg/kg every 12 hours for a total duration of 4 to 14days when used concomitantly with a strong CYP3A inducer. No dosage adjustment is warranted in patients with concomitant use of a weak or moderate CYP3A inducer.

Anticoagulant Drugs 

Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage.

Use in Specific Populations

No clinically significant differences in the pharmacokinetics of eravacycline were observed based on age (18-86 years), sex, race, or renal impairment.

Patients with Hepatic Impairment 

In patients with severe hepatic impairment (Child-Pugh C), administer XERAVA 1 mg/kg every 12 hours on Day 1, followed by XERAVA 1 mg/kg every 24 hours starting on Day 2 for a total duration of 4 to 14 days. No dosage adjustment is warranted in patients with mild to moderate hepatic impairment (Child-Pugh A and Child-Pugh B).

Efficacy and Safety

Efficacy of XERAVA was demonstrated in two Phase 3, randomized, double-blind, active-controlled, multinational, multicenter trials in adult patients hospitalized with cIAI. Additional information regarding efficacy trials can be found in the full prescribing information linked below.

The most common adverse reactions (incidence ≥ 3%) are infusion site reactions, nausea, and vomiting.

Full prescribing information available at www.accessdata.fda.gov

The U.S. Food and Drug Administration has approved Annovera^® (segesterone acetate and ethinyl estradiol vaginal system), which is a combined hormonal contraceptive for women of reproductive age used to prevent pregnancy and is the first vaginal ring contraceptive that can be used for an entire year.

Description

Annovera combines a new progestin (segesterone acetate) with a widely used estrogen (ethinyl estradiol) into a single reusable ring. It is a soft, reusable flexible silicone ring (2¼ inches diameter) that can be inserted and removed by a woman herself. Left in place for 21 days and removed for 7 days, at which time the woman may experience a period (a withdrawal bleed). This schedule is repeated every four weeks for one year (thirteen 28-day menstrual cycles).

Annovera is indicated to prevent pregnancy for up to a year and does not require refrigeration, which is particularly important for distribution and use in low-resource settings. It is washed and stored in a compact case for the seven days not in use; does not require refrigeration prior to dispensing and can withstand storage temperatures up to 30°C (86°F).

Efficacy & safety considerations

The efficacy and safety of Annovera were studied in three, open label clinical trials with healthy women ranging from 18 to 40 years of age. Based on the results, about two to four women out of 100 women may get pregnant during the first year they use Annovera. Annovera has not been adequately evaluated in women with a body mass index (BMI) greater than 29 kg/m²

All hormonal contraception carries serious risks. Similar to other combined hormonal contraceptives, Annovera has a boxed warning regarding cigarette smoking and serious cardiovascular events. Women over 35 who smoke should not use Annovera. Cigarette smoking increases the risk of serious cardiovascular events from combination hormonal contraceptive use.

Annovera is contraindicated and should not be used in women with:

• A high risk of arterial or venous thrombotic diseases;
• Current or history of breast cancer or other estrogen- or progestin-sensitive cancer;
• Liver tumors, acute hepatitis, or severe (decompensated) cirrhosis;
• Undiagnosed abnormal uterine bleeding;
• Hypersensitivity to any of the components of Annovera; and
• Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir.

The most common side effects in women using Annovera are similar to those of other combined hormonal contraceptive products and include headache/migraine, nausea/vomiting, yeast infections, abdominal pain, dysmenorrhea (painful menstruation), breast tenderness, irregular bleeding, diarrhea and genital itching.

Full prescribing information available at www.annovera.com/pi.pdf

FDA is strengthening the current warnings in the prescribing information that fluoroquinolone antibiotics may cause significant decreases in blood sugar and certain mental health side effects.

BACKGROUND: Fluoroquinolone antibiotics are approved to treat certain serious bacterial infections, and have been used for more than 30 years. They work by killing or stopping the growth of bacteria that can cause illness. Without treatment, some infections can spread and lead to serious health problems.

Most fluoroquinolone antibiotic drug labels include a warning that blood sugar disturbances, including high blood sugar and low blood sugar and depending on the fluoroquinolone antibiotic class, a range of mental health side effects are already described under Central Nervous System Effects in the Warnings and Precautions section of the drug label, which differed by individual drug.

RECOMMENDATION: The new label changes will add that low blood sugar levels, also called hypoglycemia, can lead to coma and the new label will also make the mental health side effects more prominent and more consistent across the systemic fluoroquinolone drug class. The mental health side effects to be added to or updated across all the fluoroquinolones are:

• disturbances in attention
• disorientation
• agitation
• nervousness
• memory impairment
• serious disturbances in mental abilities called delirium

FDA continues to monitor and evaluate the safety and effectiveness of medicines after we approve them and they go on the market. In the case of fluoroquinolones, we reviewed reports of cases submitted to FDA and the published medical literature of apparently healthy patients who experienced serious changes in mood, behavior, and blood sugar levels while being treated with systemic fluoroquinolones.

Patients should tell your healthcare professionals if you are taking a diabetes medicine when your health care professional is considering prescribing an antibiotic, and also if you have low blood sugar or symptoms of it while taking a fluoroquinolone. For patients with diabetes, your healthcare professional may ask you to check your blood sugar more often while taking a fluoroquinolone. Early signs and symptoms of low blood sugar include:

• confusion
• pounding heart or very fast pulse
• dizziness
• pale skin
• feeling shaky
• sweating
• unusual hunger
• trembling
• headaches
• weakness
• irritability
• unusual anxiety

Health care professionals should be aware of the potential risk of hypoglycemia sometimes resulting in coma, occurring more frequently in the elderly and those with diabetes taking an oral hypoglycemic medicine or insulin.

• Alert patients of the symptoms of hypoglycemia and carefully monitor blood glucose levels in these patients, and discuss with them how to treat themselves if they have symptoms of hypoglycemia.
• Inform patients about the risk of psychiatric adverse reactions that can occur after just one dose.
• Stop fluoroquinolone treatment immediately if a patient reports any central nervous system side effects, including psychiatric adverse reactions, or blood glucose disturbances and switch to a non-fluoroquinolone antibiotic if possible.
• Stop fluoroquinolone treatment immediately if a patient reports serious side effects involving the tendons, muscles, joints, or nerves, and switch to a non-fluoroquinolone antibiotic to complete the patient’s treatment course.

Healthcare professionals should not prescribe fluoroquinolones to patients who have other treatment options for acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated urinary tract infections because the risks outweigh the benefits in these patients