Lepirudin
A yeast-made copy of the leech anticoagulant, used for clotting caused by heparin until 2012
Lepirudin is a recombinant version of hirudin, the anticoagulant made by the medicinal leech. It blocks thrombin directly and was approved as Refludan for people with heparin-induced thrombocytopenia (HIT), a dangerous immune reaction to heparin that causes clots. Its US marketing ended in 2012 and its EU authorisation was withdrawn the same year.
Last FDA label of a product discontinued in the US (not a current US recommendation): 0.4 mg/kg bolus, then 0.15 mg/kg/h (weight capped at 110 kg), Continuous infusion, Intravenous Details ↓
Recommended Dosing
Last FDA label of a product discontinued in the US (not a current US recommendation)
From the last US prescribing information of a product discontinued in the US (see the regulatory status on this page). It records what that label said while the product was sold there; it is not a current US recommendation. Other doses studied, if any, are in the full dosing data below.
Used in human trials
No manufacturer dose exists for this use: these are amounts given in published trials, not recommendations.
What is it?
In a small share of patients, heparin sets off an immune reaction called heparin-induced thrombocytopenia (HIT). The platelet count falls and, against expectation, new clots form, which can cost limbs and lives. These patients need an anticoagulant that works without heparin. Lepirudin was approved in the US for exactly this on March 6, 1998.
Lepirudin is hirudin made in yeast. Hirudin is an anticoagulant made by the medicinal leech; it locks onto thrombin one molecule to one and stops it from building a clot, without needing antithrombin as heparin does. Lepirudin differs from the natural molecule only at its first amino acid and in lacking one sulfate group. It is cleared almost entirely by the kidneys, which is the source of most of its dosing problems.
Three prospective studies, HAT-1 to HAT-3, made the case. Compared with historical control patients, lepirudin roughly halved the combined rate of death, amputation and new clots, mostly by preventing new thromboses. The price was bleeding: across 403 patients, 17.6% had a major bleed, and the authors suggested starting lower. A single-centre series later showed that dropping the bolus and using about half the labelled infusion rate worked, scaled down further for poor kidney function.
Two immune problems followed it. About 44% of HIT patients in the trials formed antibodies against lepirudin, more often with longer courses, and in about half of them the antibodies made it work more strongly, not less, probably by slowing its clearance. Rarely, a second course caused anaphylaxis: a review of about 35,000 treated patients found nine severe reactions and four deaths, all fatal cases in people re-exposed within weeks to months of a first course.
Outside HIT, lepirudin was tested in heart attacks and unstable angina. In OASIS-2, with more than 10,000 patients, it was compared with heparin and narrowly reduced cardiovascular death, heart attack or refractory angina at seven days, with more bleeding needing transfusion. It was never approved for those uses.
Bayer stopped marketing Refludan in the US on May 31, 2012, saying its outside manufacturer had permanently ceased production and that the decision was not about safety; it expected remaining stock to run out by mid-2013. The EU authorisation was withdrawn in April 2012. Argatroban and bivalirudin, other direct thrombin inhibitors, gave similar clot and bleeding rates in a meta-analysis. Nothing about lepirudin relates to peptides sold for self-use.
Mechanism of Action
Lepirudin is a direct thrombin inhibitor. It does not need antithrombin, and it is not inhibited by platelet factor 4, so it works where heparin cannot.
Thrombin blockade
One lepirudin molecule binds one thrombin molecule and blocks its clotting activity, prolonging the aPTT in a dose-related way (2004 US label).
Kidney clearance
Systemic clearance tracks kidney function, so the label cut the bolus and infusion when creatinine clearance fell below 60 mL/min (2004 US label; PMID 19059879).
Antibodies
Anti-hirudin antibodies can slow its elimination and strengthen its effect during longer courses (PMID 11001886).
Published Research
The studies behind lepirudin, read from their PubMed abstracts. The HIT trials compared treated patients with historical controls, because a placebo arm was not thought ethical.
HAT-1
In 82 patients with confirmed HIT given one of four lepirudin regimens (for thrombosis, a 0.4 mg/kg bolus then 0.15 mg/kg/h), platelets recovered quickly in 88.7%, and the combined rate of death, amputation and new clots was lower than in 120 historical controls, without more bleeding.
HAT-2
In 112 patients with confirmed HIT, the event rate per patient-day fell from 5.1% before treatment to 1.5% on lepirudin; bleeding was more frequent than in historical controls (44.6% against 27.2%), but bleeds needing transfusion were not significantly so and there was no intracranial bleeding.
HAT-1 and HAT-2 together
Pooling 113 patients with HIT and clots, the risk of death, amputation or new clots fell from 6.1% per day before lepirudin to 1.3% during it; aPTT ratios of 1.5 to 2.5 worked best, while ratios above 2.5 carried a high bleeding risk.
HAT-3 and all three trials
Across 403 patients in the three HAT studies, the combined end point after starting lepirudin was 29.7% against 52.1% in historical controls, mainly through fewer new clots, but major bleeding was more frequent (29.4% against 9.1%); the authors suggested starting at 0.1 mg/kg/h.
A lower dose that still worked
In 68 patients with HIT, omitting the bolus and infusing 0.08 mg/kg/h with normal kidney function, 0.04 with moderate impairment and 0.01 to 0.02 with severe impairment reached target anticoagulation, with rare thrombosis (1 of 46) and major bleeding (4 of 46).
Antibodies against lepirudin
In 196 evaluable HIT patients, 44.4% developed IgG anti-hirudin antibodies, more often with longer treatment; in about 45% of those the antibodies strengthened lepirudin's effect, and they were not linked to more clots, amputations or bleeds.
Fatal anaphylaxis is rare but real
Reviewing the drug's safety databases from 1994 to 2002, nine patients had severe anaphylaxis within minutes of intravenous lepirudin and four died, each after an earlier course 1 to 12 weeks before; the estimated risk was 0.015% on first exposure and 0.16% on re-exposure.
Re-exposure at one clinic
Among 43 adults given at least two courses of lepirudin at the Cleveland Clinic, no anaphylaxis or allergic reaction was found; some had isolated drops in blood pressure that the authors did not attribute to anaphylaxis.
ALicia: lepirudin against argatroban
In a double-blind trial of 66 critically ill surgical patients with suspected HIT, dialysis filter life was similar, but relevant bleeding occurred in 11 on lepirudin against 4 on argatroban (odds ratio 3.9).
Comparing the thrombin inhibitors
A meta-analysis of nine studies found no significant difference between argatroban and lepirudin, or argatroban and bivalirudin, in new thromboembolic events or bleeding in HIT.
OASIS-2: unstable angina and non-ST-elevation heart attack
In 10,141 patients randomised to heparin or lepirudin (0.4 mg/kg bolus then 0.15 mg/kg/h for 72 hours), cardiovascular death, heart attack or refractory angina at 7 days was 5.6% against 6.7%; bleeding needing transfusion was more common with lepirudin (1.2% against 0.7%), life-threatening bleeds and strokes were not.
HIT-4: with clot-busting therapy
In 1,208 heart attack patients given streptokinase, lepirudin (0.2 mg/kg bolus then 0.5 mg/kg under the skin twice daily) did not significantly improve artery opening at 90 minutes or 30-day outcomes compared with heparin.
Its place in HIT, as of 2008
This review describes lepirudin's FDA-approved use for HIT with thromboembolic disease, calls it a valuable anticoagulant with the strongest trial support at the time, and argues that modest changes from the labelled dosing could make it simpler and safer.
Dosing Data
These are the last US Refludan label's doses that we could read (October 2004) and a lower regimen from a published series. Refludan has not been sold in the US since 2012; the figures explain the trials.
Educational information, not medical advice. Each dose above is tagged with its source: an approved label, a published human study, animal data, or amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.
What a Buyer Needs to Know
What is sold, how it is mixed, stored and taken, and what is known about its safety, quality and legal status. Each part names its source. Where we have none, it says unknown.
What is sold
Unknown: we hold no regulator's label that says in what form Lepirudin is supplied. It is prepared and given by clinical staff, not bought and mixed at home: the next part says where.
Mixing a vial: a worked example
Nothing to mix at home, and no syringe units to work out: Lepirudin is prepared and given by clinical staff, in hospital, often in intensive care.
In the carded trials it was infused into a vein in critically ill surgical patients and in people admitted with acute coronary syndromes.
Source: PMID 25344113 and PMID 9989712 (studies carded under Research below).
Storage before and after mixing
Unknown: no label on file says how Lepirudin is stored. It is kept and prepared by the hospital or clinic that gives it (see the part above); the home rules for a mixed vial in the mixing guide do not apply to it.
How it is taken
As the approved label gives it: Intravenous (Continuous infusion; Label: HIT with thromboembolic disease).
Source: Last FDA label of a product discontinued in the US (not a current US recommendation): the route and frequency of each row in Dosing Data below.
What to expect, and when
How long it stays in the body: a half-life of about 1.3 hours (terminal); initial phase about 10 minutes. After about five half-lives almost none is left.
How long the doses were given: Label: HIT with thromboembolic disease: 2 to 10 days or longer; target aPTT ratio 1.5 to 2.5; Label: kidney impairment: Avoid or stop below 15 mL/min.
When effects appear: unknown; no source on this page gives a time to effect for Lepirudin. Results reported in the studies are under Published Research.
Source: half-life: Refludan [lepirudin (rDNA) for injection] US prescribing information as of October 2004 (Berlex; copy read at hemonc.org on October 28, 2026); not on DailyMed or Drugs@FDA: Bayer ended US marketing on May 31, 2012, Clinical Pharmacology; Last FDA label of a product discontinued in the US (not a current US recommendation), the duration of each row in Dosing Data below.
Side effects, and when to stop or get help
From the Side Effects section: Major bleeding, in 17.6% across the HAT trials; Anti-hirudin antibodies that can strengthen its effect; Rare severe or fatal anaphylaxis, mostly on re-exposure; More bleeding needing transfusion than heparin in OASIS-2. Full list and cautions ↓
When to stop or get help: unknown; no label or trial on file sets rules for stopping Lepirudin. Treat a severe or unexpected reaction as a reason to stop and see a doctor.
Source: the Side Effects section below (“From the studies above”).
Interactions
Unknown: a PubMed search for human interaction studies of Lepirudin (reviewed 2026-10-28) found none. Unknown is not the same as safe to combine.
Every peptide's record, with its source: the interaction matrix.
Checking what you bought
Unknown: no published independent test of Lepirudin products is in our lab-results database yet, so how products sold under this name measure up is not known.
To read a certificate of analysis, paste it into the COA decoder; it checks the measured mass against Lepirudin's expected mass, 6,979.0 Da, from this entry's molecular data. Trust & Verification explains what independent testing can and cannot show.
Legal status
US: Discontinued (US: approved March 6, 1998 as Refludan for Hoechst Marion Roussel (archived FDA drug information page)). Sport: Unsettled (S0 may apply).
Country by country ↓ · Regulatory tracker
Source: this entry's approval status and the WADA Prohibited List, as in Legal Status below.
Side Effects & Contraindications
Reported Side Effects
From the studies above.
Contraindications & Cautions
From the contraindications, warnings and precautions of the 2004 US Refludan label.
Legal Status
Lepirudin was an approved anticoagulant in the US and EU; both markets ended in 2012.
Frequently Asked Questions
?Why was lepirudin discontinued?
Bayer said its outside manufacturer permanently stopped making it and that the decision was not related to safety. US marketing ended on May 31, 2012.
?What replaced it?
Other non-heparin anticoagulants. Among direct thrombin inhibitors, a meta-analysis found argatroban and bivalirudin gave similar clot and bleeding rates, and one randomised trial found fewer bleeds with argatroban.
?Is it the same as leech hirudin?
Almost. It is made in yeast and differs from natural hirudin at its first amino acid and by lacking a sulfate group on residue 63 (2004 US label).
?Why did doses have to be cut in kidney disease?
The kidneys clear it, so it builds up when they fail. The label cut the bolus to 0.2 mg/kg and the infusion to as little as 15% of normal, and one centre used far lower doses throughout.
?Can a second course cause a reaction?
Rarely. Fatal anaphylaxis was reported in people re-exposed within weeks to months of a first course, though one clinic's 43 repeat courses caused no reactions.
References
- [clinical-trial] Greinacher A, et al. "Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia: a prospective study." Circulation, 1999;99(1):73-80. PMID: 9884382.
- [clinical-trial] Greinacher A, et al. "Lepirudin (recombinant hirudin) for parenteral anticoagulation in patients with heparin-induced thrombocytopenia. Heparin-Associated Thrombocytopenia Study (HAT) investigators." Circulation, 1999;100(6):587-93. PMID: 10441094.
- [review] Greinacher A, et al. "Heparin-induced thrombocytopenia with thromboembolic complications: meta-analysis of 2 prospective trials to assess the value of parenteral treatment with lepirudin and its therapeutic aPTT range." Blood, 2000;96(3):846-51. PMID: 10910895.
- [clinical-trial] Lubenow N, et al. "Lepirudin in patients with heparin-induced thrombocytopenia - results of the third prospective study (HAT-3) and a combined analysis of HAT-1, HAT-2, and HAT-3." J Thromb Haemost, 2005;3(11):2428-36. PMID: 16241940.
- [clinical-trial] Tschudi M, et al. "Dosing lepirudin in patients with heparin-induced thrombocytopenia and normal or impaired renal function: a single-center experience with 68 patients." Blood, 2009;113(11):2402-9. PMID: 19059879.
- [pubmed] Eichler P, et al. "Antihirudin antibodies in patients with heparin-induced thrombocytopenia treated with lepirudin: incidence, effects on aPTT, and clinical relevance." Blood, 2000;96(7):2373-8. PMID: 11001886.
- [pubmed] Greinacher A, et al. "Anaphylactic and anaphylactoid reactions associated with lepirudin in patients with heparin-induced thrombocytopenia." Circulation, 2003;108(17):2062-5. PMID: 14568897.
- [pubmed] Cardenas GA, et al. "Risk of anaphylaxis after reexposure to intravenous lepirudin in patients with current or past heparin-induced thrombocytopenia." Mayo Clin Proc, 2005;80(4):491-3. PMID: 15819285.
- [clinical-trial] Treschan TA, et al. "Argatroban versus Lepirudin in critically ill patients (ALicia): a randomized controlled trial." Crit Care, 2014;18(5):588. PMID: 25344113.
- [review] Sun Z, et al. "Comparisons of argatroban to lepirudin and bivalirudin in the treatment of heparin-induced thrombocytopenia: a systematic review and meta-analysis." Int J Hematol, 2017;106(4):476-483. PMID: 28600720.
- [clinical-trial] "Effects of recombinant hirudin (lepirudin) compared with heparin on death, myocardial infarction, refractory angina, and revascularisation procedures in patients with acute myocardial ischaemia without ST elevation: a randomised trial. Organisation to Assess Strategies for Ischemic Syndromes (OASIS-2) Investigators." Lancet, 1999;353(9151):429-38. PMID: 9989712.
- [clinical-trial] Neuhaus KL, et al. "Recombinant hirudin (lepirudin) for the improvement of thrombolysis with streptokinase in patients with acute myocardial infarction: results of the HIT-4 trial." J Am Coll Cardiol, 1999;34(4):966-73. PMID: 10520777.
- [review] Gajra A, et al. "Lepirudin in the management of heparin-induced thrombocytopenia." Expert Opin Drug Metab Toxicol, 2008;4(8):1131-41. PMID: 18680447.
- [other] PubChem CID 118856773, Lepirudin: formula C287H440N80O111S6, molecular weight 6979. Read October 28, 2026. https://pubchem.ncbi.nlm.nih.gov/compound/118856773
- [other] European Medicines Agency, medicines list (JSON report, downloaded October 28, 2026): Refludan (lepirudin): status withdrawn; marketing authorisation date March 13, 1997; withdrawal date April 24, 2012; indication anticoagulation in adult patients with heparin-induced thrombocytopenia type II and thromboembolic disease.
- [fda-pi] Refludan [lepirudin (rDNA) for injection] US prescribing information as of October 2004, Berlex. Copy read at https://hemonc.org/docs/packageinsert/lepirudin.pdf (not on DailyMed or Drugs@FDA: US marketing ended 2012). Read October 28, 2026.
- [fda] US FDA, archived drug information page for Refludan: date approved by FDA March 6, 1998; Hoechst Marion Roussel. https://webarchive.library.unt.edu/eot2008/20090511170131/http://www.fda.gov/cder/consumerinfo/druginfo/refludan.HTM. Read October 28, 2026. Drugs@FDA (openFDA) returns no application for lepirudin.
- [other] Bayer HealthCare, letter to US healthcare providers dated May 31, 2012: Refludan discontinued in the US after the third-party manufacturer permanently ceased production; not related to safety; supply expected to run out by mid-2013. Archived HRSA copy: https://webarchive.library.unt.edu/web/20120915144934/http://www.hrsa.gov/opa/Docs/Refludan_2012.pdf. Read October 28, 2026.
Sources & Citations
Studies were read from their PubMed abstracts; doses, half-life and warnings from the October 2004 US Refludan label (a copy, as no version is on DailyMed or Drugs@FDA); the US end of marketing from Bayer's May 31, 2012 letter and approval date from FDA's archived drug page, read October 28, 2026; the EU record from the EMA medicines list.
Medical Disclaimer: This content is for educational and informational purposes only. It is not medical advice, and nothing here is an instruction to obtain or use any compound. Talk to a licensed clinician about your own situation.