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Pharmaceutical Approval Update February 2019

Michele B. Kaufman PharmD, BCGP, RPh

Xofluza (baloxavir marboxil) tablets for oral use

Manufacturer: Genentech, South San Francisco, California

Date of Approval: October 24, 2018

Indication: Baloxavir marboxil is indicated for treating acute uncomplicated influenza in patients 12 years of age and older who have been symptomatic for no more than 48 hours.

Drug Class: An oral polymerase acidic (PA) endonuclease inhibitor antiviral agent

Uniqueness of Drug: Baloxavir marboxil is the first new influenza antiviral treatment with a novel mechanism of action approved in close to 20 years. Baloxavir marboxil was granted a priority review. designation from the FDA.

Contraindications: Baloxavir marboxil is contraindicated in patients who have a history of hypersensitivity to the drug or any of its ingredients.

Warnings and Precautions

Risk of bacterial infection. Serious bacterial infections may begin with influenza-like symptoms, or they may coexist with or occur as a complication of influenza. Baloxavir marboxil has not been shown to prevent these complications. Prescribers should be alert to the potential for secondary bacterial infections and treat them appropriately.

Drug Interactions: The co-administration of baloxavir marboxil should be avoided with polyvalent cation-containing agents: laxatives, antacids, oral supplements (e.g., calcium, iron, magnesium, selenium, zinc, etc.). The use of live attenuated influenza vaccines has not been studied with baloxavir marboxil; the drug may affect the anti-viral efficacy of vaccines.

Special Populations: There are no data on pregnant or breastfeeding women.

In addition, the safety and efficacy of baloxavir marboxil in patients younger than 12 years or in those who weigh less than 40 kilograms (kg)have not been established.

Availability, Dosage, and Administration: Baloxavir marboxil is available in 20-mg and 40-mg tablets. Patients who weigh 40–80 kg should receive a single 40-mg dose of baloxavir marboxil. Patients who weigh at least 80 kg should receive a single 80-mg dose.

Administration: A single dose of baloxavir marboxil should be administered orally within 48 hours of symptom onset with or without food. Avoid the co-administration of baloxavir marboxil with dairy products, calcium-fortified beverages, or polyvalent cation-containing laxatives, antacids, or oral supplements (e.g., calcium, iron, magnesium, selenium, zinc, etc.).

Commentary: The efficacy and safety of once-daily baloxavir marboxil were determined in two randomized, controlled clinical trials. Patients (n = 400) were randomized to receive either baloxavir marboxil or placebo; and in the second trial, baloxavir marboxil once daily or oseltamivir twice-daily were compared to placebo. In both trials, the agents were administered in patients who were within 48 hours of developing flu symptoms. Patients in both trials who were treated with baloxavir marboxil had a shorter time to symptom mitigation compared with placebo-treated patients. In the second trial (n = 1,436), there was no difference in the time to alleviation of symptoms between patients who received baloxavir marboxil and those who received oseltamivir. The most common adverse reactions in clinical trials were bronchitis and diarrhea.

Sources: Genentech, Xofluza prescribing information;

Nuzyra (omadacycline) injection and tablets

Manufacturer: Paratek Pharmaceuticals, Boston, Massa-chusetts

Date of Approval: October 2, 2018

Indication: For the treatment of adults with community-acquired bacterial pneumonia (CABP) and/or acute bacterial skin and skin structure infections (ABSSSIs) caused by susceptible microorganisms.

Drug Class: A tetracycline antibacterial

Uniqueness of Drug: Omadacycline is the first and only once-daily intravenous (IV) and oral antibiotic that is FDA-approved to treat patients with CABP and/or ABSSSIs in almost 20 years. Omadacycline is a modernized tetracycline that exhibits activity across a spectrum of bacteria, including Gram-positive, Gram-negative, atypical infections, and drug-resistant strains. The drug was granted approval using the qualified infectious disease product and fast track designations, and will be available in the first quarter of 2019. A condition of the FDA approval is that the manufacturer must perform postmarketing studies in CABP and pediatric patients.

Contraindications: This agent is contraindicated in patients with known hypersensitivity to omadacycline, tetracycline-class antibacterial agents, or any of the excipients in omadacycline.

Warnings and Precautions

Hypersensitivity reactions. Life-threatening anaphylactic reactions have occurred with other tetracyclines, and hypersensitivity reactions have been reported with omadacycline.

This drug is structurally similar to other tetracycline-class antibacterial agents and is contraindicated in patients with known hypersensitivity to tetracycline-class antibacterial agents. If an allergic reaction occurs, omadacycline should be discontinued.

Mortality imbalance in patients with CABP. In the CABP trial, omadacycline-treated patients had a mortality rate of 2% versus 1% of moxifloxacin-treated patients. The cause of this difference has not been established. In both treatment arms, all deaths occurred in patients over 65 years of age, and most patients had multiple comorbidities. The clinical response to therapy should be closely monitored in CABP patients, particularly in those who are at a higher mortality risk.

Tooth discoloration and enamel hypoplasia. Using omadacycline during tooth development (during the last half of pregnancy, in infancy, and in children up to eight years of age) may cause permanent tooth discoloration (yellow, gray, brown) and enamel hypoplasia.

Bone growth inhibition. Using omadacycline during the second and third trimesters of pregnancy, during infancy, and during childhood up to 8 years of age may cause reversible inhibition of bone growth. All tetracyclines form a stable calcium complex in any bone-forming tissue.

Clostridium difficile-associated diarrhea (CDAD). If diarrhea occurs, evaluate for CDAD.

Availability, Dosage, and Administration

Tablets. 50 mg, in bottles of 30; Injection vials. 100 mg lyophilized powder for injection, which must be reconstituted and further diluted prior to infusion. The diluted solution is stable for 24 hours at room temperature and for 48 hours in the refrigerator. The product labeling should be reviewed for IV solution and compatibility with other drugs.

The tablets must be administered in a fasted state (of at least 4 hours) and then taken with water. After oral dosing, no food or drink (except water) is to be consumed for 2 hours and no dairy products, antacids, or multivitamins are to be consumed for 4 hours.

Commentary: The safety and efficacy of omadacycline were evaluated in two, double-blind, placebo-controlled clinical trials in adults 18–90 years of age (n = 1,380) with ABSSSI. In both trials, patients were assigned to receive omadacycline every 12 hours for two doses on day 1, followed by daily IV doses, or linezolid twice daily IV for 7 to 14 days. Patients could switch to oral medication (of either antimicrobial) after three treatment days. The benefit of treatment was assessed based on the response to treatment at 48 to 72 hours after the first dose for both groups. A positive response was a 20% or greater decrease in skin lesion size. There was one CABP trial (n = 774) where 386 patients were randomized to receive omadacycline and 388 patients were randomized to receive moxifloxacin. Patients were administered an IV-to-oral switch dosage regimen for omadacycline, with a total treatment duration of 7 to 14 days. The mean duration of IV treatment was 5.7 days and the mean total duration of treatment was 9.6 days in both treatment arms. Omadacycline achieved clinical success in these three trials. The most common adverse reactions (incidence > 2%) in clinical trials were: diarrhea; increases in any of the following: alanine aminotransferase, aspartate aminotransferase, and/or gamma-glutamyl transferase; constipation; infusion-site reactions; insomnia; headache; hypertension; nausea; and vomiting.

Sources: Paratek Pharmaceuticals, Inc., Nuzyra prescribing information;

Arikayce (amikacin liposome inhalation suspension) for oral inhalation use

Manufacturer: Insmed, Bridgewater, New Jersey

Date of Approval: September 28, 2018

Indication: Amikacin liposome inhalation suspension is an aminoglycoside antibacterial indicated in adults for treating Mycobacterium avium complex (MAC) lung disease as part of a combination antibacterial drug regimen in patients who do not achieve negative sputum cultures after a minimum of six consecutive months of a multidrug background regimen. Amikacin liposome inhalation suspension should be reserved for treating adults with limited or no alternative options. This drug is indicated for use in a limited and specific population of patients.

Drug Class: Inhaled aminoglycoside antimicrobial

Uniqueness of Drug: Amikacin liposome inhalation suspension, a novel, inhaled, once-daily formulation of amikacin, is the first and only therapy approved by the Food and Drug Administration (FDA) indicated for MAC lung disease as part of a combination antibacterial drug regimen for adults with limited or no alternative treatment options. It is delivered to the lungs using proprietary Pulmovance™ liposomal technology through the Lamira™ Nebulizer System, where it is taken up by lung macrophages. This delivery prolongs the drug’s release while limiting systemic exposure. It is also the first product approved via the Limited Population Pathway for Antibacterial and Antifungal Drugs (LPAD). LPAD was enacted as part of the 21st Century Cures Act, and serves to advance new antibacterial drug development for serious or life-threatening infections in limited populations of patients with unmet needs. This indication received an accelerated approval based on achieving sputum culture conversion (defined as three consecutive, negative monthly sputum cultures) by month 6. The clinical benefit of amikacin liposome inhalation suspension has not yet been established.

Warnings and Precautions

Boxed warning – respiratory adverse reactions. Increased respiratory adverse reactions have occurred with this drug, including: hypersensitivity pneumonitis, hemoptysis, bronchospasm, and the exacerbation of underlying pulmonary disease. Some of these reactions led to hospitalization.

Hypersensitivity pneumonitis. Hypersensitivity pneumonitis presenting as allergic alveolitis, pneumonitis, interstitial lung disease, and allergic reaction was reported at a higher frequency in patients treated with amikacin liposome inhalation suspension plus a background regimen (3%) versus patients treated only with a background regimen (0%). Most hypersensitivity pneumonitis patients discontinued amikacin liposome inhalation suspension treatment and received corticosteroids. If hypersensitivity pneumonitis occurs, the drug should be discontinued and the patient managed appropriately.

Hemoptysis. Hemoptysis occurred at a higher frequency in patients treated with this drug who were on a background regimen (18%) versus patients treated with a background regimen (13.5%) alone. If this occurs, patients should be managed appropriately.

Bronchospasm. Bronchospasm presenting as asthma, bronchial hyper-reactivity, dyspnea, dyspnea exertional, prolonged expiration, throat tightness, and wheezing occurred at a higher frequency in patients treated with Amikacin liposome inhalation suspension with a background regimen (29%) compared with patients treated with only a background regimen (11%). If this occurs, discontinue treatment and manage appropriately.

Exacerbations of underlying pulmonary disease were reported as chronic obstructive pulmonary disease (COPD), infective exacerbation of COPD, and infective exacerbation of bronchiectasis. These have been reported at a higher frequency in patients treated with amikacin liposome inhalation suspension who were on a background regimen (15%) versus patients treated with a background regimen alone (10%). If this occurs, discontinue the drug and manage patients appropriately.

Ototoxicity. A higher frequency of ototoxicity has been reported in patients receiving amikacin liposome inhalation suspension treatment (17%) compared to patients treated with a background regimen only (7%). Closely monitor patients with known or suspected auditory or vestibular dysfunction. If patients develop tinnitus, it may be an early symptom of ototoxicity.

Nephrotoxicity. Aminoglycosides can cause nephrotoxicity. Nephrotoxicity was observed during clinical trials in patients with MAC lung disease but not at a higher frequency than in those receiving the background regimen alone. Close monitoring of patients with known or suspected renal dysfunction may be needed when prescribing amikacin liposome inhalation suspension.

Neuromuscular blockade. Aminoglycosides may aggravate muscle weakness because of a potential curare-like effect on neuromuscular function. Patients with neuromuscular disorders were not enrolled in clinical trials for this agent. Patients with known or suspected neuromuscular disorders (e.g., myasthenia gravis) should be closely monitored as aminoglycosides may aggravate muscle weakness by blocking acetylcholine release at the neuromuscular junction. If neuromuscular blockade occurs, it may be reversed by administering calcium salts, but mechanical assistance may be necessary.

Embryo-fetal toxicity. Aminoglycosides can cause fetal harm when administered to pregnant women. They can cause total, irreversible, bilateral congenital deafness in pediatric patients who were exposed in utero. Patients who use amikacin liposome inhalation suspension during pregnancy, or who become pregnant while taking this drug, should be apprised of the potential fetal hazard.

Contraindications: This agent is contraindicated in patients with a known hypersensitivity to any aminoglycoside.

Use in renal and hepatic impairment. Amikacin liposome inhalation suspension has not been studied in patients with hepatic impairment, and no dose adjustments based on hepatic impairment are required as it is not hepatically metabolized. The drug also has not been studied in patients with renal impairment. But given the low systemic exposure to amikacin following pulmonary administration, clinically relevant accumulation is unlikely to occur in patients with renal impairment. However, renal function should be monitored in patients with known or suspected renal impairment, including elderly patients.

Availability, Dosage, and Administration: Amikacin liposome inhalation suspension is supplied as a sterile, aqueous, liposome suspension for oral inhalation in a unit-dose glass vial containing amikacin 590 mg/8.4 mL. The recommended (adult) dosage is once-daily oral inhalation of the contents of one 590-mg/8.4-mL vial. Inhaled bronchodilator pre-treatment should be considered in patients with a history of hyper-reactive airway disease.

Commentary: The safety and efficacy of amikacin liposome inhalation suspension were demonstrated in a randomized, controlled clinical trial where patients were assigned to one of two treatment groups. This was an open-label, randomized (2:1), multicenter trial in patients with refractory MAC lung disease as confirmed by at least two sputum culture results. Patients were randomized to either amikacin liposome inhalation suspension plus a background multidrug regimen (n = 224) or a background regimen alone (n = 122). At baseline, background regimens included a macrolide (92%), a rifamycin (86%), or ethambutol (80%). Overall, 55% of subjects were receiving a triple background regimen of a macrolide, a rifamycin, and ethambutol. The surrogate endpoint for assessing efficacy was based on achieving culture conversion (three consecutive, monthly, negative sputum cultures) by month 6. The conversion date was defined as the date of the first of the three negative monthly cultures, which had to be achieved by month 4 in order to meet the endpoint by month 6. By month 6, 29% of patients treated with amikacin liposome inhalation suspension had no mycobacterial growth in their sputum cultures for three consecutive months compared to 9% of patients who had received only a background multidrug regimen. The most common adverse reactions occurring in ≥ 10% of patients, and which were higher than in the control group, were: bronchospasm, cough, diarrhea, dysphonia, exacerbation of underlying pulmonary disease, fatigue/asthenia, hemoptysis, musculoskeletal pain, nausea, ototoxicity, and upper airway irritation.

Sources: Insmed Inc., Arikayce prescribing information;

Author bio: 
Dr. Kaufman is a freelance medical writer living in New York City and a pharmacist in the New York–Presbyterian Lower Manhattan Hospital Pharmacy Department.