Subcutaneous versions of IV biologics like Keytruda, Opdivo and Rybrevant now take minutes to give. Here is how hyaluronidase co formulation works.
Last updated: November 8, 2026
Subcutaneous biologics deliver the same antibody as an IV infusion through an injection under the skin, usually in minutes. Most large volume versions pair the antibody with a hyaluronidase enzyme, which temporarily breaks down hyaluronan in tissue so a bigger dose can be absorbed.
This guide explains how subcutaneous and intravenous biologics differ, how hyaluronidase co formulation works, which major products have made the switch, and what it means for oncology practices, payers and drug developers.
What is the difference between subcutaneous and IV biologics?
An intravenous (IV) biologic is infused directly into a vein, usually over 30 minutes to several hours in an infusion chair. A subcutaneous (SC) biologic is injected into the fatty tissue under the skin and absorbed into the bloodstream over time. Same antibody, different route, very different workflow.
Monoclonal antibodies were built for IV use for a simple reason: the doses are large. Oncology antibodies are often given in hundreds of milligrams to grams, and the tissue under the skin normally only accepts a few milliliters before pressure and pain become a problem. That volume ceiling is what kept checkpoint inhibitors and other big antibodies in the infusion suite for a decade.
The difference that matters for operators is not pharmacology. It is time. IV dosing needs venous access, a pump, monitoring and a chair. SC dosing needs a clinician, a syringe and a few minutes. When the SC version gets the same label, the decision becomes one of capacity, cost and patient preference.
| Factor | IV infusion | SC injection with hyaluronidase |
|---|---|---|
| Route | Into a vein | Into tissue under the skin, such as the thigh |
| Typical administration time | 30 minutes to several hours | About 1 to 7 minutes where stated for the products below |
| Venous access | Required | Not required |
| Infusion chair | Required | Not required |
| Who gives it | Healthcare professional | Healthcare professional for the oncology products below |
| Dosing flexibility | Weight based or flat | Varies by product; Rybrevant Faspro is weight based |
| Combination with other IV drugs | Straightforward in one visit | Depends on the label; some combinations are excluded |
How does hyaluronidase make large subcutaneous doses possible?
Hyaluronidase is an enzyme that breaks down hyaluronan, a gel like molecule that fills the space between cells under the skin and limits how much fluid that space can take. Temporarily degrading it lets a larger volume disperse and absorb, and the tissue rebuilds it naturally.
The best known version is Halozyme’s ENHANZE technology, which the company describes as its recombinant human hyaluronidase PH20, or rHuPH20, for rapid, high volume subcutaneous delivery. Per Halozyme, the enzyme depolymerizes hyaluronan in the subcutaneous space, which helps co administered drugs disperse and absorb and reduces back pressure. Halozyme says hyaluronan is naturally restored in one to two days, which is why the effect is local and temporary rather than a lasting change to the tissue.
The drug company does not change the antibody. It co formulates the antibody with the enzyme into a single injection, and the FDA approves the combination as its own product. That is why the nonproprietary names carry two parts and an FDA suffix on the enzyme: amivantamab and hyaluronidase-lpuj, nivolumab and hyaluronidase-nvhy, atezolizumab and hyaluronidase-tqjs. Each enzyme gets its own suffix even when the underlying technology is the same.
Halozyme is no longer the only supplier. Merck’s Keytruda Qlex uses berahyaluronidase alfa, which Merck says was developed and manufactured by Alteogen. That second source is now at the center of a patent fight, covered below.
Which major biologics have FDA approved subcutaneous versions?
Keytruda, Opdivo and Tecentriq, three of the most used checkpoint inhibitors, have all crossed over since 2024, and J&J’s amivantamab followed. The table below lists the oncology products verified against FDA notices or company releases; Halozyme lists further ENHANZE partnered products including Darzalex Faspro, Phesgo, Herceptin Hylecta, Rituxan Hycela, Ocrevus Zunovo and Vyvgart Hytrulo.
| Product (company) | Nonproprietary name | FDA approval | SC administration | Label scope |
|---|---|---|---|---|
| Tecentriq Hybreza (Genentech) | atezolizumab and hyaluronidase-tqjs | September 12, 2024 | About 7 minutes every 3 weeks, in the thigh | All adult indications of IV atezolizumab |
| Opdivo Qvantig (Bristol Myers Squibb) | nivolumab and hyaluronidase-nvhy | December 27, 2024 | Not stated on the FDA notice | Adult solid tumor nivolumab indications; not with IV ipilimumab |
| Keytruda Qlex (Merck) | pembrolizumab and berahyaluronidase alfa-pmph | September 19, 2025 | About 1 minute every 3 weeks or 2 minutes every 6 weeks, per Merck, vs a 30 minute IV infusion | Adult and pediatric (12 and older) solid tumor indications of IV pembrolizumab |
| Rybrevant Faspro (Johnson & Johnson) | amivantamab and hyaluronidase-lpuj | December 2025 (EGFR mutated lung cancer, per J&J); November 5, 2026 (head and neck cancer) | As little as 5 minutes vs several hours IV, per J&J | EGFR mutated NSCLC; recurrent or metastatic head and neck squamous cell carcinoma (accelerated approval) |
Sources: FDA approval notices for atezolizumab, nivolumab, pembrolizumab and amivantamab co formulations; Merck release (September 2025); J&J release as reported by Pharmacy Times (December 2025).
The newest entry is a good example of how SC is now the launch format, not an afterthought. On November 5, 2026, the FDA granted accelerated approval to Rybrevant Faspro for adults with recurrent or metastatic head and neck squamous cell carcinoma that progressed on or after platinum chemotherapy and an anti PD-(L)1 antibody, given subcutaneously every three weeks on a weight based dose. The new indication was approved directly in the SC form.
Why are drugmakers moving blockbusters to subcutaneous dosing?
Three reasons, in order of how much money they protect: franchise life cycle, capacity in the clinic, and patient preference.
Life cycle. A co formulated SC product is a new product with its own patents on the formulation and delivery. When IV exclusivity on the antibody ends and biosimilars arrive, a physician base already converted to the SC version is harder to switch. As we noted in October, Merck is counting on the SC format to defend the Keytruda franchise as IV exclusivity erodes later this decade, which is why the patent dispute over its enzyme matters so much.
Capacity. Infusion chairs are a bottleneck in many oncology practices. Moving a 30 minute infusion to a one minute injection frees chair time for therapies that can only be given IV, like many antibody drug conjugates and bispecifics with step up dosing.
Patient experience. Shorter visits and no IV line matter to patients on therapy for months or years. That is the argument companies lead with in launch materials.
What is the Halozyme and Merck patent dispute over Keytruda Qlex?
Halozyme alleges that Merck’s subcutaneous pembrolizumab infringes its MDASE patents, which cover modified hyaluronidase enzymes. Per Reuters, a court in The Hague found in October 2026 that Merck infringed a Halozyme MDASE patent and ordered it to stop producing and selling subcutaneous Keytruda in eight European countries.
The Dutch ruling followed a German preliminary injunction against Keytruda SC in 2025, and Halozyme is pursuing a US case alleging infringement of 15 patents, per Reuters. Merck did not immediately comment on the Dutch ruling. The order covers only the SC formulation; IV Keytruda is unaffected. For the industry, the takeaway is that the enzyme is not a commodity input. Whoever controls the delivery technology has leverage over the franchise extension strategy built on it.
What does the shift mean for oncology practices and payers?
It changes the economics of the visit. Practices that earn on infusion administration lose some of that revenue per patient when a drug moves to a short injection, but gain chair capacity. Payers and health systems trade infusion fees for drug cost, which depends on how the SC version is priced against IV.
Operators should watch three practical points. First, billing: SC co formulations are separate products, so coding, contracting and formulary status need to be set up for each one. Second, pharmacy workflow: SC doses typically come ready to use, which can cut compounding time compared with preparing IV bags. Third, site of care: shorter administration makes it easier for payers to push therapy into lower cost settings, so expect site of care policies to follow.
Our framework: how to evaluate a switch from IV to subcutaneous
- Label match. Confirm the SC label covers the indications and combinations you use. Opdivo Qvantig, for example, is not approved for use with IV ipilimumab.
- Dosing. Check whether dosing is flat or weight based and how dose rounding and waste change.
- Visit time. Map total visit time, not just injection time; observation, labs and other drugs still take time.
- Chair capacity. Estimate the chair hours freed and what IV only therapies can fill them.
- Net cost. Compare drug cost plus administration fees for each route under your main payer contracts.
- Supply risk. Note any patent litigation or supply constraints on the SC product in your markets.
- Patient preference. Ask patients; for long courses, shorter visits often decide it.
What to watch next
- The US outcome of Halozyme’s patent case against Merck over Keytruda Qlex.
- More new indications launched directly in SC form, as Rybrevant Faspro did in head and neck cancer.
- Biosimilar entry for IV checkpoint inhibitors and how much SC conversion protects share.
- Payer site of care policies that steer SC dosing out of hospital outpatient departments.
- Additional enzyme suppliers beyond Halozyme and Alteogen.
Frequently asked questions
Is subcutaneous Keytruda the same drug as IV Keytruda?
It contains the same antibody, pembrolizumab, co formulated with the enzyme berahyaluronidase alfa. The FDA approved Keytruda Qlex on September 19, 2025 for solid tumor indications of IV pembrolizumab in adults and in children 12 and older.
How long does subcutaneous Keytruda take to give?
Merck says about one minute every three weeks or two minutes every six weeks, compared with a 30 minute IV infusion.
What does hyaluronidase do in a subcutaneous injection?
It temporarily breaks down hyaluronan, a gel like substance under the skin, so a larger volume of drug can spread and be absorbed. Halozyme says hyaluronan is naturally restored in one to two days.
What is Halozyme ENHANZE?
ENHANZE is Halozyme’s recombinant human hyaluronidase PH20 (rHuPH20) technology, licensed to drugmakers to turn IV biologics into rapid, high volume subcutaneous injections.
Which company makes the enzyme in Keytruda Qlex?
Merck says the berahyaluronidase alfa in Keytruda Qlex was developed and manufactured by Alteogen.
Can patients give these subcutaneous cancer drugs at home?
The oncology products discussed here are given by a healthcare professional. The time saving is in the clinic, not a move to self injection.
Is subcutaneous Opdivo approved with Yervoy?
No. The FDA notice for Opdivo Qvantig excludes use in combination with IV ipilimumab.
How long does subcutaneous Tecentriq take?
The FDA notice describes about 7 minutes every three weeks, injected into the thigh.
What is Rybrevant Faspro approved for?
EGFR mutated non small cell lung cancer, per J&J’s December 2025 release, and since November 5, 2026, recurrent or metastatic head and neck squamous cell carcinoma after platinum chemotherapy and an anti PD-(L)1 antibody, under accelerated approval.
Why does the nonproprietary name include a four letter suffix?
Under FDA naming practice for biologics, the hyaluronidase in each co formulation carries a distinct suffix, such as hyaluronidase-lpuj or hyaluronidase-nvhy, even when the technology is the same.
Does a subcutaneous version extend a drug’s exclusivity?
Not for the antibody itself, but the co formulation can carry its own patents, and a market already converted to SC dosing is harder for IV biosimilars to win.
Will IV versions disappear?
Not soon. IV remains needed for some combinations, weight ranges and settings, and biosimilars of IV antibodies will keep that route commercially active.
Sources
Primary: FDA, “FDA grants accelerated approval to amivantamab and hyaluronidase-lpuj for recurrent or metastatic head and neck squamous cell carcinoma” (November 2026); FDA, “FDA approves pembrolizumab and berahyaluronidase alfa-pmph subcutaneous injection” (September 2025); FDA, “FDA approves nivolumab and hyaluronidase-nvhy subcutaneous injection” (December 2024); FDA, “FDA approves atezolizumab and hyaluronidase-tqjs subcutaneous injection” (September 2024); Merck press release on Keytruda Qlex (September 19, 2025); Halozyme, ENHANZE technology page (halozyme.com).
Attributed: J&J release on the first Rybrevant Faspro approval, as reported by Pharmacy Times (December 18, 2025); Reuters on the Halozyme and Merck patent rulings (October 2026), as covered in our October 8 report.
Related coverage
- Rybrevant Faspro approved in head and neck cancer on 42% ORR
- The Dutch court order against Keytruda SC, in our October 8 report
- FDA accelerated approval: confirmatory trial rules explained
- Medicare cuts 340B drug pay in the outpatient rule
- Gene therapy long term follow up: what FDA requires
- BioMed Nexus company directory
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