Christine Blank

Madrid, Spain-based Salvat has submitted a new drug application (NDA) for a new treatment for fungal otitis externa, clotrimazole, to the FDA. The pharmaceutical manufacturer expects the drug, if approved, to be available in the United States by the summer of 2023. Company officials 

 would be the first topical drug indicated to treat otomycosis, an ear infection caused by a fungus. It usually affects the outer ear canal.

“While there are other medications or formulations on the market that can help manage the symptoms of this condition, Salvat’s….is the only one focused on effectively treating otomycosis,” the company said.

Salvta enters a potentially lucrative market as the value of fungal otitis external medications was estimated at $169 million in 2021, according to 

. The group of medications is expected to produce a compounded annual growth rate of 2.9% from 2021 through 2028.

“This project is a reflection of the firm commitment we have made to R&D in the area of otology, and reinforces our leadership position in this therapeutic area, without losing focus on other areas of strategic growth for Salvat,” said Alberto Bueno, CEO of Salvat.

Salvat formulated clotrimazole for otic use in the form of single-dose vials, making it easier for patients to use, according to the company. “This format also ensures the sterility of the product and, by containing the necessary amount of active ingredient, also warrants the correct use of the drug,” Salvat said.

The NDA is based on two clinical trials conducted over three years in more than 400 adult patients affected by otomycosis. “Both studies have concluded with very positive results that confirm the efficacy and safety of the new drug for the eradication of the fungus that causes otomycosis and the associated clinical symptoms (pain, itching, feeling of fullness and hearing loss),” Salvat said.

Since 2019, Salvat has invested more than 22 million euros ($23 million) to develop this formulation of clotrimazole. Salvat also manufactures Otovel (ciprofloxacin and fluocinolone acetonide), a combination antibiotic and steroid medication for ear infections, and Cetraxal (ciprofloxacin) to treat acute otitis externa caused by ciprofloxacin susceptible microorganisms.

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If approved, clotrimazole would be the first topical drug indicated to treat otomycosis, an ear infection caused by a fungus.

Salvat Submits NDA for Ear Infection Drug

The latest trial results show Biogen and Eisai’s investigational Alzheimer’s disease drug lecanemab slowed cognitive in early disease, but safety questions remain. While two deaths have been reported during clinical trials, the manufacturers do not believe the deaths were caused by the medication.

Deaths occurred in 0.7% of patients in the lecanemab and 0.8% of patients in the placebo group, and no deaths were related to lecanemab in the 18-month double-blind study period, Michael Irizarry, M.D., senior vice president of clinical research and deputy chief clinical officer of Alzheimer’s Disease and Brain Health at Eisai, told 

 that a 65-year-old woman with early Alzheimer’s disease in the clinical trial died from a massive brain hemorrhage that some researchers link to the drug. The clinical trial death, which described in an unpublished case report 

 obtained, is the second thought to be associated with lecanemab, according to the publication.

“The two cases on lecanemab occurred in the open-label extension study. Both cases had significant comorbidities and risk factors including anticoagulation contributing to macrohemorrhage or death. Therefore, it is Eisai’s assessment that the deaths cannot be attributed to lecanemab,” the pharma maker said in a statement to 

Lecanemab is an investigational anti-amyloid beta antibody being developed jointly by Eisai and Biogen for the treatment of mild cognitive impairment due to Alzheimer’s disease. It is currently under review by the FDA and a decision is expected by Jan. 6.

Biogen and Eisai released new clinical trial results at the 2022 

Clinical Trials on Alzheimer’s Disease (CTAD) conference

 held in San Francisco and virtually November 29-December 2. In the core study and subsequent open-label extension study, rates of deaths with concurrent cerebral macrohemorrhage were 0.1% in both the placebo group (1/897) and the lecanemab group (2/1,608), Eisai said.

In the phase 2 Clarity AD study, the rate of macrohemorrhage in the subjects on both anticoagulants and lecanemab was 2.4% and 3.6% across the core phase and the open-label extension phases, Irizarry said. “Background rate of macrohemorrhage in AD patients on anticoagulation is not known,but is expected to be higher than in non-AD patients due to cerebral amyloid angiopathy (CAA); therefore, comparative risk is difficult to assess.”

Irizarry also noted that “the well-being of the patients enrolled in our clinical studies is always Eisai’s top priority. Eisai has established a rigorous safety monitoring process to ensure patient safety. This includes an independent data safety monitoring committee of external experts.”

The independent Data Safety Monitoring Board (DSMB) review of all ARIA-related safety data from the clinical study found that “all the available safety information indicates that lecanemab therapy is not associated with an increased risk of death overall or from any specific cause,” Irizarry noted.

Serious adverse events were experienced by 14% of participants in the lecanemab group and 11.3% of participants in the placebo group. Treatment-emergent adverse events occurred in 88.9% and 81.9% of participants in the lecanemab and placebo groups, respectively, Eisai and Biogen said in a 

. Treatment-emergent adverse events leading to drug withdrawal occurred in 6.9% and 2.9% of participants in the lecanemab and placebo groups, respectively.

The most common adverse events in the lecanemab group were infusion reactions, ARIA-H (combined cerebral microhemorrhages, cerebral macrohemorrhages, and superficial siderosis), ARIA-E (edema/effusion), headache, and fall. Infusion reactions were largely mild-to-moderate and occurred on the first dose.

Despite adverse events, the Clarity AD study showed that lecanemab treatment resulted in “highly statistically significant results,” reducing clinical decline on the global cognitive and functional scale, compared with placebo at 18 months — a 27% slowing of decline, Eisai and Biogen said.

All key secondary endpoints also showed highly statistically significant results compared with placebo. In the amyloid PET sub-study, treatment with lecanemab showed statistically significant reduction in amyloid plaque burden at all timepoints starting at 3 months.

“We believe that the results of Clarity AD are an important step forward in the field of Alzheimer's disease…The insights from the Clarity AD data will deepen our understanding of the disease to pursue further advancement of the treatment of the disease,” Irizarry said.

Lecanemab is an investigational anti-amyloid beta antibody to treat mild cognitive impairment due to Alzheimer’s disease. It is currently under review by the FDA and a decision is expected by Jan. 6. 

Safety Questions Follow Positive Results for Lecanemab in Alzheimer’s

The Drug Enforcement Administration said there is a sharp nationwide increase in the lethality of fentanyl-laced fake prescription pills even as authorities crack down on counterfeit drug rings. Popular counterfeit medications include Adderall (mixed amphetamine salts) and oxycodone.

The DEA Laboratory has found that, of the fentanyl-laced fake prescription pills analyzed in 2022, six out of 10 now contain a potentially lethal dose of fentanyl, the agency said in a 

 in 2021 that four out of 10 fentanyl-laced fake prescription pills were found to contain a potentially lethal dose.

“We’ve seen an enormous rise in new types of counterfeits, such as fake Adderall made with methamphetamine, and the use of a new substance, xylazine, in pills that used to contain fentanyl,” Shabbir J. Imber Safdar, executive director of the Partnership for Safe Medicines, told 

. “We’re also seeing fake blood thinners with no active ingredient at all this year. It's a dangerous time.”

 on the widespread drug trafficking of fentanyl-laced fake prescription pills in the United States. In 2021, the DEA seized more than 20.4 million fake prescription pills and earlier this year, the agency conducted a nationwide operational surge to target the trafficking of fentanyl-laced fake prescription pills. Earlier this year, the DEA conducted a nationwide operational surge to target the trafficking of fentanyl-laced fake prescription pills and in about three months seized 10.2 million fake pills in all 50 states.

“These pills are largely made by two Mexican drug cartels, the Sinaloa Cartel and the Jalisco (CJNG) Cartel, to look identical to real prescription medications, including OxyContin, Percocet, and Xanax, and they are often deadly,” the DEA said.

Recently, the U.S. Attorney in Massachusetts 

 23 people with running drug trafficking organization that manufactured and sold genuine and counterfeit prescription medications. Law enforcement officials seized 74,000 counterfeit Adderall pills containing methamphetamine and more than 1,000 counterfeit oxycodone pills containing fentanyl.

The drug trafficking organization manufactured and distributed both pharmaceutical-grade Adderall and counterfeit pills containing methamphetamine, along with methamphetamine, Xanax (alprazolam), oxycodone (both pharmaceutical-grade and counterfeit pills containing fentanyl), cocaine and marijuana.

In another recent case, two North Store, Massachusetts, men w

 of prescription pills made with fentanyl and methamphetamine. In August, law enforcement opened an investigation into Charles Brennick Bates after he ordered 50 kilograms of an orange binding agent commonly used to make counterfeit Adderall pills. Investigators seized an industrial pill press, 14 firearms, and counterfeit Adderall suspected to contain methamphetamine and oxycodone pills suspected to contain fentanyl, from a co-conspirator’s home.

In addition, police in Red Hook, New York charged a man they believe is responsible for 

distributing counterfeit oxycodone pills made of fentanyl

, The Partnership for Safe Medicines reported.

According to the CDC, 107,622 Americans died of drug poisoning in 2021, and 66% of the deaths involved synthetic opioids like fentanyl, the DEA said.

Patients can protect themselves by “not trying to guess at what’s a safe online pharmacy,” Safdar said. “Almost everything online is unlicensed by your state board of pharmacy. If you find one that is licensed, use it, but they are few and far between.”

Adderall pills containing methamphetamine and oxycodone pills containing fentanyl have been among the fake pills the DEA and investigators have confiscated.

Authorities Seize Fake Drugs with Lethal Doses of Meth and Fentanyl

 on November 18, stipulating minimum steps pharmacies that compound beta lactam oral antibiotic suspension products must take to mitigate the potential for cross-contamination with other products. The steps include only compounding for FDA-approved beta-lactam tablets and capsules instead of bulk drug substances; use of dedicated or disposable equipment, utensils, and personal protective equipment; trituration of the FDA-approved product after wetting it with a quantity of the suspension vehicle sufficient to eliminate formation of product dust; and six other essential steps.

“This guidance is a remarkably rapid and helpful response from the agency, and I know compounders will take seriously their commitment to mitigate risks to get these medications to the children who need them,” said Scott Brunner, chief executive officer of the Alliance for Pharmacy Compounding (APC).

 amoxicillin oral powder for suspension in 

 on its website in late October. The widely-used antibiotic — particularly for a multitude of pediatric infections — is in short supply from several companies due to increased demand, the agency noted.

In addition to amoxicillin, APC members are also reporting growing difficulty in sourcing cephalexin suspension, an alternative to amoxicillin, Brunner told 

“Whether the shortage ends next month or next year, that’s no comfort to parents of sick children who need the medication now. FDA issued the guidance to authorize a path — within some very tight guidelines — compounders can take to help alleviate the current shortage,” Brunner said.

APC first alerted the agency three weeks ago that “compounders’ ability to help mitigate the amoxicillin suspension shortage and get life-saving medicine to children in need was impeded by provisions in FDA’s Insanitary Conditions Guidance,” APC said.

The guidance requires compounders to “completely and comprehensively separate beta lactams from non-beta lactam products”— a provision with which many pharmacies, both hospital and retail, could not comply. The regulatory agency requires this separation because of the possibility that cross-contamination could expose penicillins to patients with allergic reactions.

The FDA recently requested the addition of a warning on the labels of amoxicillin products about several rare and serious skin reactions. These reactions were already reported in the adverse reactions section of the labels but given their severity, regulatory officials felt that they should be listed in the Warnings and Precautions section of the label.

Related: FDA Calls Attention to Serious Skin Reactions of Amoxicillin

“Both hospital and retail pharmacies knew they had the ability to compound amoxicillin suspension from commercially available tablets or capsules,” Brunner said. “But they were unable to meet that requirement of complete and comprehensive separation from other products—and so they were concerned, rightly, about the potential for regulatory action to be taken against them for serving the need of their patients.”

While the guidance is permanent and final, Brunner suspects it will be withdrawn by FDA after the shortage passes.

The FDA has issued a final guidance for beta-lactam oral antibiotic suspension products, including amoxicillin.

Compounding Pharmacies to Help Alleviate Amoxicillin Shortage

The FDA issued a Federal Register notice, 

Safety and Effectiveness of Certain Naloxone Hydrochloride Drug Products for Nonprescription Use

, that may help facilitate the development and approval of certain over-the-counter (OTC) naloxone drug products — including through the switch of certain naloxone drugs from prescription status to nonprescription status.

Naloxone is a medicine that can help reduce opioid overdose deaths and when administered timely — usually within minutes of the first signs of an opioid overdose — can counter the overdose effects, the agency said in a 

More than 80,000 people died of opioid-involved overdose deaths in the 12-month period ending in January 2022, up from 71,000 deaths in the preceding year, according to the FDA.

"Current evidence suggests that increasing access to naloxone has the potential to reduce opioid overdose deaths. Results from multiple observational studies show that naloxone distribution and overdose education targeted to populations likely to observe an overdose is an effective intervention strategy,” FDA said in the notice. “The public health benefits of FDA-approved prescription naloxone products in preventing overdose deaths clearly outweigh potential serious adverse reactions associated with naloxone administration,” the agency added.

The Federal Register notice includes a preliminary assessment that certain naloxone drug products — up to 4 mg nasal spray and up to 2 mg autoinjector for intramuscular or subcutaneous use — may be approvable as safe and effective for nonprescription use.

Ahead of the FDA announcement, Harm Reduction Therapeutics, a nonprofit pharmaceutical company, 

 a rolling submission for a new drug application (NDA) for RiVive (naloxone), as 

a nonprescription emergency treatment for opioid overdose

. The first module has been submitted to the FDA, and the company expects the submission to be complete by the end of the year.

RiVive is an intranasal formulation of naloxone (3.0 mg) delivered as an atomized spray (0.1 ml) using a standard unit dose system for single administration. If approved, the company anticipates a launch of early 2024.

FDA’s notice does not cover all naloxone products, as more data are needed on the safety and efficacy for nonprescription use of higher dose naloxone products and naloxone supplied in other presentations (including vials, ampules or syringes without integrated needles) before a preliminary assessment with respect to those products can be reached, the agency said.

The FDA is requesting comments from the public on whether there is data to support safe and effective nonprescription use of higher dose naloxone products and on potential consequences of a switch from prescription to nonprescription status.

The risks associated with naloxone use also need to be considered, according to the FDA. “It is well-known that among patients with physical dependence to opioids, naloxone use may result in acute-onset, precipitated opioid withdrawal (precipitated withdrawal), referred to in the labeling for currently marketed naloxone products…” the agency said in the notice.

As noted in the labeling for currently approved naloxone products, naloxone-induced precipitated withdrawal may also be associated with other clinically serious adverse events such as pulmonary edema, cardiac arrythmias, and agitation, according to the agency.

“Despite these potential risks, the benefit of broader use of naloxone in reversing potentially fatal events is significant, even as surveillance for and mitigation of risks….resulting from administration of an opioid antagonist, should be considered mechanistically and clinically distinct from withdrawal resulting from cessation, or significant reduction in opioid use,” the FDA said.

The agency is encouraging sponsors to submit applications for low-dose, nonprescription naloxone products.

FDA Proposes Prescription-to-OTC Naloxone 

 the second-line maintenance indication for its ovarian cancer drug Zejula (niraparib) to only the patient population with deleterious germline BRCA mutations. The FDA reviewed a recent GSK phase 3 study, which showed a hazard ratio of 1.05 in the non-germline BRCA mutations cohort in overall survival (OS) with the PARP-inhibitor Zejula, GSK said in a press release.

 the upcoming meeting with the Oncologic Drugs Advisory Committee that was scheduled for Nov. 22, 2022, to discuss the phase 3 data of Zejula to treat patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer

However, the first-line indication of Zejula remains unchanged for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who have a complete or partial response to platinum-based chemotherapy, GSK said.

The primary endpoint of the phase 3 NOVA study was progression-free survival (PFS). Results demonstrated the clinically meaningful and statistically significant benefit of Zejula in both cohorts, as well as in subgroups of the non-germline BRCA mutations cohort, particularly patients with homologous recombination deficiency.

Secondary endpoints were safety and long-term exploratory endpoints, including overall survival. “GSK is in ongoing discussions about these and other emerging OS data with health authorities worldwide,” the pharmaceutical manufacturer said.

GSK continues to evaluate Zejula in trials across multiple tumors, including the FIRST phase 3 trial assessing niraparib in combination with dostarlimab, a PD-1-blocking antibody, as a potential treatment for first-line ovarian cancer maintenance and the phase 3 ZEAL trial assessing niraparib in combination with standard of care for the maintenance treatment of first-line advanced non-small cell lung cancer. GSK also is evaluating niraparib in HER2-negative BRCA-mutated or triple-negative breast cancer.

 for another PARP-inhibitor, Lynparza (olaparib), after consulting with the FDA on Lynparza’s phase 3 trial results. “A recent subgroup analysis indicated a potential detrimental effect on overall survival for Lynparza compared to the chemotherapy control arm in the subgroup of patients who had received three or more lines of chemotherapy,” AstraZeneca said in a 

 that the phase 3 LYNK-003 trial investigating Lynparza with or without Genentech’s Avastin (bevacizumab) to treat patients with metastatic colorectal cancer was 

Lynparza as a monotherapy and in combination with Avastin did not meet its objectives at a planned interim analysis. An independent data monitoring committee made the recommendation to discontinue both arms of the study. No new safety issues were seen, and the safety profile was similar to previous studies

Lynparza is approved for several indications, including advanced ovarian cancer, metastatic prostate cancer, metastatic pancreatic cancer, and early or metastatic breast cancer.


After review of phase 3 data, GSK will limit the use of Zejula in the second line to those with inherited BRCA mutations.
