Drug Criteria & Outcomes: Fondaparinux Sodium (Arixtra) Drug Evaluation

By Molly Campbell, PharmD candidate
Harrison School of Pharmacy
Auburn (AL) University
Melanie Hyte, PharmD
Pharmacy Practice Resident
Huntsville (AL) Hospital

Background

Fondaparinux sodium (Arixtra) is the first of a new class of synthetic antithrombotic agents, known as the selective Factor-Xa inhibitors.

Mechanism of action

Fondaparinux binds to antithrombin III (ATIII) with a selectivity of 94%. This produces a conformational change of ATIII, which increases the affinity between ATIII and Factor Xa. After the ATIII-fondaparinux complex has bound Factor Xa, the fondaparinux component is released unchanged and is free to bind more ATIII.

Enoxaparin (Lovenox) and dalteparin (Fragmin) affect both Factor Xa and Factor IIa and are classified as low molecular weight heparins (LMWHs). Their mechanism is to bind preferentially to ATIII, produce a conformational change, and increase the affinity to Factor Xa, very similar to fondaparinux. The difference between the LMWHs and fondaparinux lies within the affinity to Factor Xa. Fondaparinux was designed to have an advantage of higher specificity to ATIII over LMWHs and thus decrease clot formation compared with LMWHs.

Indications

Table 1, lists FDA-approved indications for fondaparinux, enoxaparin, and dalteparin.1-6

Pharmacokinetics

A pharmacokinetic comparison of fondaparinux, enoxaparin, and dalteparin can be found in Table 2.4-8

Since fondaparinux has a half-life of 17-21 hours, its dosing is every 24 hours. This can be a disadvantage, however, if the patient is over-anticoagulated. Currently, there is no known antidote to reverse the effects of fondaparinux and therefore no pharmacological mechanism for its reversal.

Special populations

Elderly: Due to natural decreases in renal function in the elderly population, the elimination of enoxaparin and fondaparinux may be prolonged. Dalteparin has not shown a difference in elimination profile based on age.

Body weight: Fondaparinux is contraindicated in patients weighing less than 50 kg.3 In this population, the total clearance of fondaparinux is decreased approximately 30%, increasing the patient’s risk of bleeding.2,3

Body weight is mentioned as a precaution with enoxaparin (in patients weighing less than 45 kg) and with dalteparin (in patients weighing less than 50 kg); a dosage adjustment for weight is recommended for both agents.4,5

Renal/hepatic impairment:

— Fondaparinux: Fondaparinux is contraindicated in patients with severe renal dysfunction (CrCl < 30 mL/min). Patients with any renal insufficiency (CrCl < 80 mL/min) may have decreased clearance of fondaparinux, so these patients should be monitored closely for any adverse reaction.

Hepatic impairment dosage adjustments have not been studied.2,3

— Enoxaparin: Dosage adjustment is advised for severe renal impairment (CrCl < 30 mL/min); specific recommendations are not given.

— Dalteparin: Precautions should be taken in patients with liver or renal impairment.

Specific recommendations are not given.

Pregnancy: Fondaparinux, enoxaparin, and dalteparin are Pregnancy Category B agents.

Drug interactions

Fondaparinux and the LMWHs do not significantly affect the CYP450 isoenzymes or have a high degree of protein binding (less than 10%), which most often is responsible for drug interactions. However, there is a possible increase in the risk of bleeding when using LMWHs concurrently with other medications that affect hemostasis, such as oral anticoagulants, sulfinpyrazone, salicylates, nonsteroidsal anti-inflammatory drugs (NSAIDS, particularly ketorolac), and dipyridamole. Fondaparinux product information does not mention these interactions, although they potentially do exist.2,3

Adverse drug reactions

The most common adverse event with fondaparinux is bleeding. Listed below are adverse effects derived from all clinical trials according to the clinical compendium distributed by the manufacturer of fondaparinux.2

Fondaparinux Enoxaparin

Anemia 19.6% 16.9%

Fever 13.6% 15.4%

Nausea 11.3% 12.2%

Edema 8.7% 8.8%

Constipation 8.5% 10.5%

Rash 7.5% 8.3%

Vomiting 5.9% 6.0%

Insomnia 5.0% 5.4%

Contraindications

Contraindications to therapy with fondaparinux, enoxaparin, and dalteparin are listed in Table 3.

Dosage

FDA-approved dosages for fondaparinux, enoxaparin, and dalteparin are listed by indication in Table 4.

Clinical trials

EPHESUS 2000

Lassen et al. Postoperative fondaparinux vs. preoperative and postoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: A randomized double-blind comparison.10

  • N = 2,309.
  • Methods: Patients received fondaparinux 2.5 mg SQ, given a mean of six hours post-operation and continuing once daily for 5-9 days or enoxaparin 40 mg 12 hours before operation and continuing once daily for 5-9 days.
  • Primary efficacy outcome: Venous thromboembolism (VTE) up to day 11.
  • Primary safety outcomes: Bleeding and death.
  • Primary efficacy results: VTE: fondaparinux 4%, enoxaparin 9%. Fondaparinux had a relative risk reduction of 55.9% over enoxaparin (P < 0.001).
  • Primacy safety results: No fatal bleeding or severe thrombocytopenia was reported in either group.
  • Limitations: Twenty-two percent of enoxaparin patients did not receive a preoperative dose as per study protocol.

PENTATHLON 2000

Turpie et al. Postoperative fondaparinux vs. postoperative enoxaparin for prevention of venous thromboembolism after elective hip-replacement surgery: A randomized double-blind comparison.11

  • N = 1,584.
  • Methods: Patients received either fondaparinux 2.5 mg SQ 4-8 hours postoperatively and continuing once daily for 5-9 days or enoxaparin 30 mg SQ 12-24 hours preoperatively and continuing every 12 hours for 5-9 days.
  • Primary efficacy outcome: VTE to day 1.
  • Primary safety outcome: Bleeding and death.
  • Primary efficacy result: VTE: fondaparinux 6%, enoxaparin 8%. Fondaparinux had a statistically insignificant 26.3% relative risk reduction over enoxaparin (P = 0.099).
  • Primacy safety result: No fatal bleeding or severe thrombocytopenia was reported in either group. The bleeding index ³ 2 was higher in the fondaparinux group (2% fondaparinux vs. 0.7% enoxaparin), but no statistical information was provided.

PENTAMAKS 1999

Bauer et al. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery.12

  • N = 1,049.
  • Methods: Patients received either fondaparinux 2.5 mg SQ 6 ± 2 hours postoperatively and continuing once daily for 5-9 days or enoxaparin 30 mg SQ 12-24 hours postoperatively and continuing every 12 hours for 5-9 days.
  • Primary efficacy outcome: VTE to day 11.
  • Primary safety outcome: Bleeding.
  • Primary efficacy result: VTE: fondaparinux 12.5%, enoxaparin 27.8%. Fondaparinux had a 55.2% relative risk reduction over enoxaparin (P < 0.001).
  • Primacy safety result: The total for the primary safety outcome was 11 major bleedings in the fondaparinux group and one in the enoxaparin group (P = 0.006).
  • Limitations: Enoxaparin had a higher percentage of patients who received discouraged therapy (NSAIDS or ASA; fondaparinux 12.2% vs. 16.5 % enoxaparin).

PENTHIFRA 1999

Eriksson et al. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip fracture surgery.13

  • N = 1,673.
  • Methods: Patients received either fondaparinux 2.5 mg SQ given 6 ± 2 hours postoperatively and continuing for 5-9 days or enoxaparin 40 mg SQ given 12 ± 2 hours preoperatively and continuing once daily for 5-9 days.
  • Primary efficacy outcome: VTE to day 11.
  • Primary safety outcomes: Major bleeding and mortality from all causes.
  • Primary efficacy result: VTE: fondaparinux 8.3%, enoxaparin 19.1%. Fondaparinux had a 56.4% relative risk reduction over enoxaparin (P < 0.001).
  • Primary safety result: No statistically significant differences were reported between the two groups in the incidence of death or clinically relevant bleeding.
  • Limitations:

— 10.9% of fondaparinux patients received a dose preoperatively.

— 74.4% of enoxaparin patients did not receive the medication preoperatively.

Efficacy, safety, and cost

Comparative efficacy, safety, and cost information is listed in Table 5, Table 6 and Table 7.

Conclusions

Fondaparinux sodium appears to be an effective medication for the prophylaxis of DVT in hip fracture, hip replacement, and knee replacement surgeries. However, there are several weaknesses in the trials that may limit their reliability. According to the PENTAMAKS study, the VTE occurrence with enoxaparin is greater than 25%. Historically, this occurrence has been reported as 10%-15%. There was no statistically significant different in VTE occurrence between fondaparinux and enoxaparin in the PENTATHLON study. Another fondaparinux limitation is its inability to be reversed by protamine, compromising its safety. In the clinical trials, there was a tendency toward more bleeding with fondaparinux, but limited statistical information was provided. This medication also has stringent renal dosing restrictions, as well as a contraindication in those patients with severe renal impairment.

In addition to those limitations mentioned, the manufacturer funded all of the clinical trials. In two of the studies, the authors served as consultants to the company that manufactures fondaparinux. Due to the weaknesses in clinical studies, high cost, its indications being limited to orthopedics only, and the lack of published data to support other indications, fondaparinux should not replace dalteparin as the workhorse for these indications. According to current prices, approximately $150,000-$200,000 will be saved annually if dalteparin is used in 100% of the patients prescribed low molecular weight heparin or fondaparinux. Every time either enoxaparin or fondaparinux is used, it will decrease cost savings. For these reasons, fondaparinux will not be added as a formulary agent at our institution at this time. Fondaparinux may have a place in therapy in the future, but currently, there is not enough reliable information to correlate the relative safety and efficacy of these products.

References

1. Arixtra Clinical Compendium Product Information-Executive Summary. Sponsored by Organon Sanofi-Synthelabo LLC. West Orange, NJ: Organon Sanofi- Synthelabo LLC, December 2001.

2. Arixtra Clinical Compendium Product Information-Product Monograph. Sponsored by Organon Sanofi-Synthelabo LLC. West Orange, NJ: Organon Sanofi- Synthelabo LLC, December 2001.

3. Arixtra Clinical Compendium Product Information-Prescribing Information. Sponsored by Organon Sanofi-Synthelabo LLC. West Orange, NJ: Organon Sanofi- Synthelabo LLC, December 2001.

4. Enoxaparin (monograph in electronic version). MICROMEDEX Healthcare Series. Englewood, CO: MICROMEDEX; 2002.

5. Dalteparin (monograph in electronic version). MICROMEDEX Healthcare Series. Englewood, CO: MICROMEDEX; 2002.

6. "Low Molecular Weight Heparins." In: Hebel SK. Drug Facts and Comparisons. St Louis: Facts and Comparisons; 2002:163-155a.

7. Fondaparinux (monograph in electronic version). MICROMEDEX Healthcare Series. Englewood, CO: MICROMEDEX; 2002.

8. Enoxaparin (Lovenox). Physicians’ Desk Reference. 55th ed. Montvale, NJ: Medical Economics Co.; 2001:713-716.

9. Dalteparin (Fragmin). Physicians’ Desk Reference. 55th ed. Montvale, NJ: Medical Economics Co.; 2001:713-716.

10. Lassen MR, Bauer KA, Ericksson BI, et al. Posteroperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: A randomized double-blind comparison. Lancet 2002;359:1715-1720.

11. Turpie AGG, Bauer KA, Ericksson BI, et al. Posteroperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism after elective hip-replacement surgery: A randomized double-blind comparison. Lancet 2002;359:1721-1726.

12. Bauer KA, Eriksson BI, Lassen MR, et al. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med 2001;345:1305-1310.

13. Eriksson BI, Bauer KA, Lassen MR, et al. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip fracture surgery. N Engl J Med 2001;345:1298-1304.

14. Knowles G, Baty S. LMWH formulary review: Dalteparin (Fragmin) and Enoxaparin (Lovenox). Huntsville Hospital Pharmacy & Therapeutics Committee. Huntsville, AL; June 2002.

15. Hall, Cindy. Personal Communication. Huntsville (AL) Hospital. July 2002.