Prof Tamás Paál, Hungary (Signal Reviewer for the WHO-UMC Programme for International Drug Monitoring)

Drotrecogin alfa (activated) is a recombinant form of human activated protein C that has anti-thrombotic, anti-inflammatory and profibrinolytic activities. It is used mainly in intensive care medicine as a treatment for severe sepsis (sepsis associated with acute organ dysfunction). It is to be administered in multiple slow infusions, as a rule, in the dose of 24 µg/kg/hour for four days.(1)

Sepsis is a complex illness involving both infection and inflammation when the body’s response, instead of being localised to the site of infection, is systemic, occurring throughout the body. This “overreaction” to the infection may result in organ damage and is more dangerous than the initial infection itself.(2)

Patients who die during episodes of sepsis are more likely to have coagulation defects, including lower levels of circulating antithrombin III and protein C. The latter is a vitamin K-dependent anticoagulant protease. In sepsis, protein C deficiency appears before the onset of observable indicators of septic shock. The administration of an exogenous analogue might be able to modulate the patient’s response during sepsis.(1,3)

Among the known adverse reactions of drotrecogin alfa, the only serious one observed in clinical trials was bleeding events.(3,4)

Description of the new ADR reports Thirteen non-duplicate reports of thrombotic events in septic patients treated with drotrecogin alfa were reported to VigiBase, the database of the WHO Collaborating Centre for International Drug Monitoring, in the period 2002 to 2007. There were 12 reports from the USA and one from the UK. The reports are summarised below:

1. A General Practitioner (GP) described a 66-year-old male who developed thrombosis after administration of drotrecogin alfa. No details were reported.

2. A 72-year-old male was treated with drotrecogin alfa for three days. On the second day of the treatment, pulmonary haemorrhage and thrombosis were observed. The type of the reporter was not disclosed.

3. A 34-year-old male was treated with drotrecogin alfa for six days in 2002. The concomitant medication comprised antibiotics as well as paracetamol and hydrocodone bitartrate. The report, sent by a GP, specified thrombosis, multiple organ failure and gangrene as adverse effects, the onset appeared eight days after the termination of treatment.

4. A 66-year-old male was treated with drotrecogin alfa for three days. The concomitant medication comprised paracetamol, codeine, atenolol, lorazepam, triamcinolone, propofol, dopamine, levofloxacin, morphine, famotidine, salbutamol, metoclopramide, diazepam, midazolam, thiamine, piperacillin-tazobactam combination and heparin. Their dosage and other treatment date were missing. The adverse reactions observed on the last day of the drotrecogin treatment were deep venous thrombophlebitis and thrombosis.

5. A pharmacist described a 45-year-old female who was administered drotrecogin alfa for four days. The concomitant medication comprised  dopamine and norepinephrine. The adverse effects described were intestinal ischaemia, decreased prothrombin level and thrombosis.

6. A pharmacist described a 72-year-old male treated with drotrecogin alfa for four days. The concomitant medication comprised sodium bicarbonate, pantoprazole, norepinephrine, vasopressin, paracetamol, dopamine, amiodarone, vancomycin and piperacillin-tazobactam combination. The adverse reactions described were anaemia, discoloured faeces and thrombosis.

7. A 68-year-old male was administered drotrecogin alfa for five days. The concomitant medication comprised cefotaxime, clarithromycin, amiodarone  for two days, hydrocortisone for eight days and lorazepam for two days. One day after the termination of the drotrecogin treatment the patient developed thrombosis.

8. A pharmacist described an 86-year-old male who was treated with drotrecogin alfa for two days. No concomitant medication was reported. The life threatening adverse reactions comprised hypotension, gastro-intestinal haemorrhage and thrombosis. Positive dechallenge was also observed.

9. A physician reported the case of a female treated with drotrecogin alfa who developed thrombosis. No details were disclosed.

10. A pharmacist described a 63-year-old female treated with drotrecogin alfa for three days. The concomitant medication comprised ranitidine, azithromycin, ceftriaxone, dopamine and norepinephrine. The adverse reactions reported were  increased blood chloride and urea, hypernatraemia, hypokalaemia, hyperglycaemia, peripheral oedema, thrombocythaemia and thrombosis. The dechallenge seemed to be negative. No further information was provided.

11. A physician described a 70-year-old female treated with drotrecogin alfa for two days. The reported adverse effects were rash, jaundice, rectal disorders, bacterial infection, peritonitis and thrombosis.

12. An “other health professional” reported the case of a 29-year-old female treated with drotrecogin alfa for two days. The concomitant medication comprised norepinephrine and dobutamine. The adverse reactions were haemorrhage and thrombosis.

13. A physician reported a 30-year-old female who was administered drotrecogin alfa (no other information was available). The adverse reaction was thrombosis.

Evaluation of the reports
Six of the thirteen reports do not mention concomitant medication. Because of the clinical situation in which drotrecogin is used, it is almost certain that other medicines were coadministered. Thus, it is possible that some concomitantly used but undisclosed medicine might have contributed to the adverse effect.

Seven reports (3, 4, 5, 6, 7, 10 and 12) describe a range of concomitant medications. According to  European Summaries of Product Characteristics (SPCs) of these medicines as well as an international database,(5) only propofol (administered in a single case) has a recognised, although very rare adverse effect of thrombophlebitis.(6)

Signal assessment
On the basis of the pharmacologic properties of drotrecogin alfa its administration is unlikely to lead to thrombosis. On the contrary, drotrecogin use is frequently associated with bleeding, related to its antithrombotic and profibrinolytic properties.(1) In a Phase III placebo controlled clinical trial, the incidence of thrombotic events was similar in the drotrecogin and placebo arms.(4) This was confirmed by an analysis of results from combined clinical trials: when compared with placebo, patients in the active treatment arms experienced numerically fewer thrombotic events, although the difference was not statistically significant.(7)

Thrombosis frequently occurs in patients with severe sepsis.(7) Disseminated intravascular coagulation (DIC) may develop in 30-50% of patients with severe sepsis and septic shock, especially when caused by Gram-negative bacteria. The mortality of sepsis is correlated with the development and severity of DIC.(8) Protein C serves as an important anticoagulant compensatory mechanism. The cytokines produced in sepsis incapacitate the protein C pathway. One of the critical mediators of DIC is the release of a transmembrane glycoprotein, Tissue Factor. This is released in response to exposure to cytokines or endotoxin and plays a major role in the development of DIC in septic conditions. For this reason, drotrecogin alfa is recommended in the therapy of DIC.(8,9) Additionally, a retrospective subgroup analysis of a clinical trial demonstrated a lower mortality rate among patients treated with drotrecogin alfa who met the criteria for DIC.(10)
Hence the conclusion is that, in these spontaneous reports, a manifestation of the underlying disease was reported as a possible adverse drug reaction. This hypothesis is further supported by the following:
•  The clinical manifestations of DIC are extremely variable.(9) The pathological processes involved deplete the body of its platelets and coagulation factors, and so paradoxically may lead to both thrombus formation and haemorrhage;
•  Septic patients are generally treated in intensive care units but the adverse effect reporters (if disclosed) were mostly GPs, pharmacists and “other health professionals”, possibly not possessing first-hand information;
•  On consulting the WHO database, it can be seen that other reports to drotrecogin alfa between 2002 and 2007 specified various haemorrhages (the well-known adverse effects of drotrecogin alfa), as well as 43 reports of DIC itself.

In thirteen reports of thrombosis associated with the use of drotrecogin alfa, retrieved from VigiBase, it appears likely that the reported thrombotic events represent a manifestation of the underlying disease process (severe sepsis), rather than an adverse reaction to any administered medicine. This analysis underlines the importance of considered assessment of all reported adverse drug reactions data.

1. L Goshman: Drotrecogin Alfa, Activated. Journal of the Pharmacy Society of  Wisconsin, Mar/Apr 2002, 33-35.
2. – understanding sepsis and severe sepsis. understanding.jsp?reqNavId=5.2, downloaded 03. 01. 2008.
3. D J Cada, T Levien: Drotrecogin Alfa. Hospital Pharmacy, 2002, 37(5), 511-517.
4. G R Bernard, J-l Vincent, P-F Laterre: Efficacy and safety of recombinant human activated protein C for severe sepsis. New England Journal of Medicine, 2001, 344, 699-709.
5. 1974-2207 Thomson MICROMEDEX Database.
6. Propofol. Merck Manual.,htm, downloaded 08. 08. 2008.
7. G R Bernard et al.: Extended evaluation of Recombinant Human Activated Protein C United States Trial (ENHANCE US). Chest 2004, 125, 2206-2216.
8. J U Becker, C R Wira: Disseminated Intravascular Coagulation., downloaded 07. 08. 2008.
9. A Aysola, I Lopez-Plaza: Disseminated Intravascular Coagulation., downloaded 07. 08. 2008.
10. J F Dhainaut et al.: Treatment effects of drotrecogin alfa (activated) in patients with severe sepsis with or without disseminated intravascular coagulation. Journal of Thrombosis and Haemostasis 2004, 2(11), 1924-1933.

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