Frequently Asked Questions
Lasix ONYU is a new diuretic option for furosemide — a drug which has been in widespread use for over 50 years. When people hear about this, they often have questions. We will try to answer the questions we are frequently asked here.
If you have any questions, you would like us to answer, please send them to us.
Please note that until a product is approved by the regulatory agency and considered safe and effective for use, some details may change.
Our Novel Formulation
Our formulation research started in the second half of 2018. Numerous novel strategies were tested to achieve the target concentration of 30mg/mL or higher. This research yielded three different promising formulations involving loop diuretics including furosemide. These are all based on ingredients that are commonly used in pharmaceutical products and are generally considered safe.
In 2022 a patent was issued for the composition of the novel formulation we use with the Infusor. A patent means it is distinctly different from other formulations before it. The standard formulation for furosemide is known as Furosemide Injection, USP. This has been the standard furosemide injection product for human use since 1968. It is almost exclusively used for intravenous administration. Our novel formulation was specifically formulated for subcutaneous infusion by reducing the pH from alkaline to neutral and to increase the concentration. The benefit of a higher concentration is that a small volume can be administered in a cost-effective manner. We also wanted a product that can be stored outside the refrigerator (room temperature) for 24 months.
Furosemide Injection was first introduced in the 1968. Furosemide is insoluble at the pH of the body and the standard product was made alkaline to prevent precipitation and breakdown. The pH of the standard furosemide formulation is typically around 9.0, which is fine for intravenous administration (blood flows and is a great buffer). However, when administered subcutaneously, alkaline product may cause a stinging or burning sensation and may cause skin irritation.
In 2012, research began trying to develop a product with neutral pH that could be used for subcutaneous infusion. Numerous buffers were tested, and it was discovered that when tromethamine is used in a particular molar ration to furosemide, the product would be stable at neutral pH. The molar ratio basically means a particular overage of tromethamine in relation to furosemide. Tromethamine at that time was well known and widely used in parenteral products. For example, tromethamine was first introduced with another loop diuretic (torsemide) in 1993 where it acted as a buffer to support the stability of the product. The discovery that tromethamine in higher concentrations can be used to enhance the solubility at neutral pH was unexpected and formed the basis for a patent.
Although the tromethamine discovery enabled subcutaneous infusion for treatment of edema, the concentration is still relatively low. A low concentration means that a relatively large volume needs to be administered for treatment. The typical clinical dose of parenteral furosemide is 80mg and it would require 8mL of the standard furosemide formulation (10mg/mL) to give 80mg. Although subcutaneous infusion of 8 or more mL is not a problem when done slowly (e.g., over 15 minutes or longer), needing 8mL or more limits the choice of delivery systems.
Diabetes and insulin use has driven the development of patch pumps. Insulin is potent and only a small volume is required. To date all patch pumps and cartridges which are in commercial use for diabetes and with other biological drugs have a volume of up to 3mL-3.5mL.
To develop a convenient, cost-effective platform one either needed to pursue the development of a new large-volume device or pursue the development of a higher concentration product so one can leverage the mature and lower-cost drug delivery platforms that are in use for diabetes. Examples of these are the OmniPod by Insulet (Acton, MA), or the V-Go (Valeritas, NJ).
In the summer of 2018, SQ Innovation initiated research aimed at the discovery of a novel next generation formulation that allowed furosemide concentration of at least 26mg/mL so that an 80mg clinical dose could be delivered with standard 3mL cartridges and drug delivery devices. This required a very different formulation that relied on solubilizers never before used with furosemide.
Betadex Sulfobutyl Ether Sodium is carbohydrate that is member of a family of compounds known as cyclodextrins. Cyclodextrins sugars that are made up of glucose subunits that form a ring. Cyclodextrins are commonly produced from starch through enzymatic conversion. They are used in food, detergents, pharmaceuticals, drug delivery, and chemical industries, as well as agriculture and environmental engineering. One common reason for using cyclodextrins is because they can “trap” other molecules. They trap them by forming a kind of envelope around them. For example cyclodextrins are used in leading odor-fighting products. They “trap” odor causing chemicals. Cyclodextrins are also used in food to help with flavor, stability, color, and protect sensitive nutrients such as vitamins. In pharmaceutical formulations special cyclodextrins “betadex” are used to improve the solubility of compounds. The sugary envelope around the drug envelope can help keep it in solution and help with stability. Betadex in its various forms is used a wide range of pharmaceutical products, including injectables, tablets, and topical gels.
Company / Product
Lasix ONYU was approved by the US FDA in October 2024 for the treatment of congestion due to fluid overload in adult patients with chronic heart failure. It is a combination product which means it consists of a drug product and a special device to deliver the drug to a patient. The FDA approval marks the end of a five-year development effort.
SQ Innovation is pursuing regulatory approvals in Europe and the UK. The efforts started recently and leverage the extensive development and testing that was performed in support of the US FDA filing and approval.
Products for subcutaneous infusion of drugs require a drug formulation that is suitable for this and a device to deliver it. Although the FDA has several options to regulate these, for new combinations the FDA often decides they want them regulated as a single, combined entity. In this case they are usually regulated as a drug and fall under the New Drug Application process. This is also the case for Lasix ONYU. For those familiar with the device regulations this means there is not a separate 510(k) application for the device. Everything is part of the drug filing and registration.
This is different from insulin pump devices. These are usually developed and commercialized independent of a specific insulin product. In this case the device is regulated under the 510(k) device regulations and the insulin products follow the biopharmaceutical regulations.
Even if there is no separate regulatory filing for the device, the FDA requires that the device component be developed, tested and manufactured in accordance with the strict device regulations. The device regulations are different than the ones that apply to the drug component and companies must setup procedures and systems to support both.
Infusor
We designed the Infusor to reuse the electronic components for many successful treatments and the only thing that is thrown away is the Disposable Unit. The Disposable Unit consists of plastic components and a stainless-steel needle/cannula. The Disposable Unit houses all components that are in contact with the drug during delivery and are in direct contact with the body. Therefore the Disposable Unit needs to be sterilized in a similar way as medical syringes and many other medical products are. Sterilization by radiation is the standard for these products.
Medical devices are sterilized in a variety of ways including using moist heat (steam), dry heat, radiation, Ethylene oxide gas, vaporized hydrogen peroxide, and other sterilization methods (e.g., chlorine dioxide gas, vaporized peracetic acid, and nitrogen dioxide).
One of the methods that is widely used in medical devices is called Ethylene oxide. Unfortunately, Ethylene oxide possesses several physical and health hazards that merit special attention. The FDA has started a program to promote the use of radiation as an alternative to Ethylene oxide. However this does not mean that products sterilized with Ethylene oxide carries a risk because of that. The FDA assures that residual levels in approved products are safe so they do not pose a risk to the user.
In the design of the Infusor, environmental considerations and worker safety were important to us. Avoiding Ethylene oxide is promoted by the FDA, US Department of Labor and the US Environmental Protection Agency. We wanted to design our product so we did not have to use it and could use gamma radiation instead. We are proud to say we exceeded.
For those interested, the following US government websites provide more information:
US Department of Labor (OSHA): https://www.osha.gov/ethylene-oxide
US Environmental Protection Agency (EPA): https://www.epa.gov/hazardous-air-pollutants-ethylene-oxide
The Infusor attaches to the abdominal skin with medical tape. This is the same kind of tape that is used in hospitals and with the old-style adhesive bandages. Getting something to stick to the body sounds easy. However there is much more to it than one might think. Medical adhesive tapes use a form of glue known as acrylate adhesives. These have been the standard for decades and are still considered the best for most applications. Acrylate adhesives bond to the top layer of the skin. As with other glues, after a short period of drying, the bond is irreversible to the top layer of the skin.
Some adhesives have an additive to make the acrylate glue flow deeper into the openings, lines and creases of the skin. These are called tackified adhesives. Tackified are typically used for longer term wear — 14 days or longer. Tackified adhesive are also used when the adhesive needs to hold during swimming or bathing.
Our Infusor is small and light and not to be used during swimming or bathing. This allowed us to try a gentle adhesive. We worked closely with 3M to select a gentle adhesive for our Infusor. 3M is a leading manufacturer of medical adhesives and offers a broad range of medical tapes. We tested the most gentle version of the series 3M offered. It is the same adhesive used for other applications where easy removal without skin irritation is important. The non-tackified medical tape we selected is used for temporary tattoos, under eye patches and medical use such as for around the stomach. All of these applications require minimal risk of irritation, skin damage, and removal with the least amount of discomfort. We know how much most people hate painful removal of medical tape and bandages. We are very pleased the gentle 3M acrylate adhesive was able to hold the device in place during treatment. This avoids or minimizes any discomfort during removal. This is another benefit of using a small volume and light Infusor.
Unfortunately skin irritation, bruising and damage may still occur. See the Prescribing Information for more detail. Also note that under some circumstances the device may fall of during use. This risk is higher when the skin is wet or sweaty. Patients should be instructed to limit activity during treatment. If the Infusor falls off during treatment not all the drug will be delivered. See Instructions for Use for additional information and instructions in the event the Infusor may fall off before treatment is complete.