Fondaparinux Sodium

Class: Direct Factor Xa Inhibitors
Chemical Name: MethylO - 2 - deoxy - 6 - O - sulfo - 2 - (sulfoamino) - α - d - glucopyranosyl - (1→4) - O - β - d - glucopyranuronosyl - (1→4) - O - 2 - deoxy - 3,6 - di - O - sulfo - 2 - (sulfoamino) - α - d - glucopyranosyl - (1→4) - O - 2 - O - sulfo - α - l - idopyranuronosyl - (1→4) - 2 - deoxy - 6 - O - sulfo - 2 - (sulfoamino) - α - d - glucopyranoside decasodium salt
Molecular Formula: C₃₁H₄₃N₃Na₁₀O₄₉S₈
CAS Number: 114870-03-0
Brands: Arixtra

• Spinal/Epidural Hematoma Risk


• 
  

  Epidural or spinal hematomas and neurologic injury, including long-term or permanent paralysis, associated with concurrent use of fondaparinux, low molecular weight heparins, or heparinoids and neuraxial (spinal/epidural) anesthesia or spinal puncture.^{1 7 16 19}

  
  


• 
  

  Risk increased by use of indwelling epidural catheters or by concomitant use of drugs affecting hemostasis (e.g., NSAIAs, platelet inhibitors, other anticoagulants).^{1 7 19}

  
  


• 
  

  Risk also increased by history of traumatic or repeated epidural or spinal puncture or history of spinal deformity or spinal surgery.^{1 3 4 7 19}

  
  


• 
  

  Monitor frequently for signs and symptoms of neurologic impairment and treat urgently if neurologic compromise noted.^{1 7 19}

  
  


• 
  

  Consider potential benefits versus risks of spinal or epidural anesthesia or spinal puncture in patients receiving or being considered for thromboprophylaxis with anticoagulants.^{1 7 19} (See Neurologic Effects under Cautions and also see Interactions.)

  
  

Introduction

Anticoagulant; a synthetic activated factor X_a inhibitor.

Uses for Fondaparinux Sodium

Thromboprophylaxis in Hip-Fracture, Hip-Replacement, or Knee-Replacement Surgery

Prevention of postoperative DVT and PE in patients undergoing hip-fracture, hip-replacement, or knee-replacement surgery.^{1 2 3 4 5 6 10 19} The American College of Chest Physicians (ACCP) recommends fondaparinux, a low molecular weight heparin, or warfarin as first-line prophylaxis in such patients.¹⁹

Used for extended prophylaxis (i.e., approximately 3 weeks beyond the perioperative period) in patients undergoing hip-fracture surgery.^{1 18} ACCP recommends extended prophylaxis (e.g., up to 35 days) in patients undergoing total hip-replacement, total knee-replacement, or hip-fracture surgery who have ongoing risk factors for venous thromboembolism (e.g., history of venous thromboembolism, obesity, delayed mobilization, advanced age, cancer).¹⁹

Thromboprophylaxis in General Surgery

Prophylaxis of postoperative DVT and PE in patients undergoing general (e.g., abdominal) surgery who are at risk for thromboembolic complications, including those undergoing major surgical procedures or those undergoing general surgery with multiple risk factors for thromboembolism (e.g., history of previous venous thromboembolism, cancer, obesity, hypercoagulable state).^{1 19 26}

ACCP recommends a low molecular weight or unfractionated heparin or fondaparinux and/or intermittent pneumatic compression or graduated compression stockings for prevention of postoperative venous thromboembolism in patients at moderate or higher risk undergoing major general surgery, including abdominal, gynecologic†, and urologic surgery†, depending on the type of surgery and the risk for thromboembolism and bleeding.¹⁹

ACCP also recommends fondaparinux as an alternative to low molecular weight heparin or low-dose unfractionated heparin for thromboprophylaxis in patients undergoing extensive gynecologic surgery for malignancy, major open urologic procedures, inpatient bariatric surgery, or major thoracic surgery.¹⁹ Fondaparinux also recommended as an option for thromboprophylaxis in patients undergoing major vascular surgery, laparoscopic surgery, or gynecologic surgery who have additional risk factors for thromboembolism.¹⁹

Thromboprophylaxis in Selected Medical Conditions

ACCP recommends fondaparinux, low-dose unfractionated heparin, or low molecular weight heparin in acutely ill medical patients with heart failure, severe lung disease, or those confined to bedrest who have one or more additional risk factors (e.g., previous venous thromboembolism, sepsis, acute neurologic disease, inflammatory bowel disease).¹⁹

Treatment of DVT and PE

Used in conjunction with warfarin for treatment of DVT.^{1 20 22}

Used in conjunction with warfarin for treatment of PE, when initial therapy is given in the hospital.^{1 21 22} However, ACCP states that IV unfractionated heparin is preferred in patients experiencing massive PE; IV unfractionated heparin also preferred if there is concern about sub-Q absorption or in patients in whom thrombolytic therapy is being considered.²²

ST-Segment Elevation MI

Has been used as an adjunct to thrombolysis in a limited number of patients with acute ST-segment elevation MI†.^{25 29 32} The American College of Cardiology and American Heart Association (ACC/AHA) and ACCP recommend use of fondaparinux (given as an initial IV injection followed by daily sub-Q injections) in the management of such patients, except in those undergoing primary PCI.^{29 32 33}

Unstable Angina and Non-ST-Segment Elevation MI

Has been used as an alternative to unfractionated heparin or a low molecular weight heparin in the management of non-ST-segment elevation acute coronary syndromes† (unstable angina or non-ST-segment elevation MI)†.²⁸

ACCP recommends fondaparinux over enoxaparin in patients with non-ST-segment elevation acute coronary syndrome† undergoing early conservative or delayed invasive management.²⁸ ACC/AHA state that fondaparinux, unfractionated heparin, and enoxaparin are all acceptable options in patients with non-ST-segment elevation acute coronary syndrome being managed conservatively, but fondaparinux is preferred in patients with an increased risk of bleeding.³⁶

ACCP recommends unfractionated heparin and a GP IIb/IIIa-receptor inhibitor over fondaparinux in patients undergoing early invasive management.²⁸

Thrombosis Associated with Heparin-induced Thrombocytopenia

May be effective in the management of heparin-induced thrombocytopenia† (HIT).²⁷ However, ACCP states that other direct thrombin inhibitors such as lepirudin and argatroban are preferred as an alternative to unfractionated heparin in patients with confirmed or strongly suspected HIT†.²⁷

Fondaparinux Sodium Dosage and Administration

General

• 
  

  Evaluate the possibility of an underlying bleeding disorder before initiation of treatment.¹⁶ Since coagulation parameters are insensitive for monitoring fondaparinux activity, routine monitoring of such parameters is not required.^{1 16}

  
  

Administration

Administer by sub-Q injection; do not give IM.¹

Has been administered by direct IV injection† initially in the treatment of acute ST-segment elevation MI† or non-ST-segment elevation acute coronary syndromes†.^{28 29}

Patients should be sitting or supine during administration.¹⁶

Increased risk of major bleeding if administered <6 hours after surgery.¹

Sub-Q Administration

Administer by sub-Q injection into fatty tissue, alternating injection sites daily (e.g., between the left and right anterolateral or posterolateral abdominal wall).^{1 16}

Insert the entire length of the needle into a skin fold created by the thumb and forefinger; hold the skin fold, and push the plunger of the syringe the full length of the syringe barrel.^{1 16} Release the plunger, and the needle automatically withdraws from the skin and retracts into the security sleeve.^{1 16}

Dosage

Dosages for fondaparinux sodium and regular (unfractionated) heparin, heparinoids, or low molecular weight heparins cannot be used interchangeably on a unit-for-unit (or mg-for-mg) basis.¹ Differs from regular (unfractionated) heparin, heparinoids, or low molecular weight heparins in the manufacturing process, anti-factor Xa and antithrombin activity, and dosage.^{1 10}

The activity of fondaparinux sodium is measured based on plasma drug concentrations quantified by anti-Factor Xa activity using fondaparinux as the calibrator.¹

Dosage of fondaparinux sodium is expressed in terms of the salt.¹

Adults

Hip-Fracture, Hip-Replacement, or Knee-Replacement Surgery

Prophylaxis of DVT and PE

Sub-Q

Patients weighing ≥50 kg: 2.5 mg once daily.^{1 19} Manufacturer recommends that initial dose be given no earlier than 6–8 hours after surgery, provided hemostasis has been established.¹ ACCP states that initial dose may be given either 6–8 hours after surgery or the next day following major orthopedic procedures.¹⁹ Avoid use in patients weighing <50 kg.¹ (See Contraindications.)

Usual duration of therapy is 5–9 days,^{1 3 4 5 6 7} although up to 11 days has been studied in clinical trials of orthopedic surgery.^{1 16}

Extended prophylaxis: Recommended for up to 24 additional days (i.e., after perioperative prophylaxis) in patients who have undergone hip-fracture or hip-replacement surgery; prophylaxis for up to a total of 32 days (including perioperative and extended prophylaxis) has been administered in clinical trials.^{1 18} ACCP states that extended prophylaxis (e.g., up to 35 days) should be considered in patients undergoing total hip-replacement, total knee-replacement, or hip-fracture surgery who have ongoing risk factors for venous thromboembolism (e.g., history of venous thromboembolism, obesity, delayed mobilization, advanced age, cancer).¹⁹

General Surgery

Prophylaxis of DVT and PE in Abdominal Surgery

Sub-Q

Patients weighing ≥50 kg: 2.5 mg once daily, with the initial dose given 6–8 hours after surgery, provided hemostasis has been established.^{1 19 26} Avoid use in patients weighing <50 kg.¹ (See Contraindications.)

Usual duration of therapy is 5–9 days, although up to 10 days has been studied.¹

DVT and PE

Treatment

Sub-Q

Patients weighing <50 kg: 5 mg once daily.¹

Patients weighing 50–100 kg: 7.5 mg once daily.¹

Patients weighing >100 kg: 10 mg once daily.¹

Usual duration of therapy is 5–9 days, although up to 26 days of treatment has been used.¹

Initiate concurrent warfarin as soon as possible,¹ usually within 72 hours of fondaparinux injection;^{1 20} however, ACCP recommends initiating warfarin simultaneously on the first day of fondaparinux treatment.²²

Continue fondaparinux and warfarin for ≥5 days and until an adequate response to warfarin is achieved (i.e., a stable INR of 2–3);¹ ACCP recommends continuing concomitant therapy for ≥5 days and until INR of 2–3 has been maintained for ≥24 hours.^{1 22}

ST-Segment Elevation MI†

IV, then Sub-Q

Initially, 2.5 mg as a single dose by direct IV injection, followed by 2.5 mg sub-Q once daily for the duration of hospitalization or up to 8 days.^{29 32}

Special Populations

Hepatic Impairment

No dosage adjustment required in patients with mild to moderate hepatic impairment.¹ Pharmacokinetics not evaluated in patients with severe hepatic impairment.¹ (See Hepatic Impairment under Cautions.)

Renal Impairment

Contraindicated in patients with severe renal impairment (Cl_cr <30 mL/minute or S_cr ≥3); increased risk for major bleeding episodes.^{1 32} Exercise caution in patients with other degrees of renal impairment.¹

Low Body Weight

Use with caution and decrease dosage to 5 mg once daily for the treatment of DVT or PE in patients weighing <50 kg.¹ Contraindicated for prophylaxis of DVT or PE in patients with body weight <50 kg undergoing hip-fracture, hip-replacement, knee-replacement, or abdominal surgery; increased incidence of major bleeding.¹

Geriatric Patients

No specific dosage recommendations; however, careful attention to dosage directions recommended.¹ (See Specific Populations under Cautions.)

Cautions for Fondaparinux Sodium

Contraindications

• 
  

  Patients with severe renal impairment (Cl_cr <30 mL/minute or S_cr ≥3).^{1 32}

  
  


• 
  

  Prophylactic use in patients undergoing hip-fracture, hip-replacement, knee-replacement, or abdominal surgery who weigh <50 kg.¹

  
  


• 
  

  Active major bleeding, bacterial endocarditis, or thrombocytopenia associated with a positive in vitro test for antiplatelet antibody (heparin-induced thrombocytopenia) in the presence of the drug.^{1 3 4 10 16}

  
  

Warnings/Precautions

Warnings

Neurologic Effects

Epidural or spinal hematomas and neurologic injury, including long-term or permanent paralysis, associated with concurrent use of fondaparinux and neuraxial (spinal/epidural) anesthesia or spinal puncture procedures.^{1 7 16} (See Boxed Warning.) Frequent monitoring for signs of neurologic impairment recommended.^{1 7} Some experts suggest that anticoagulant prophylaxis with fondaparinux be avoided in patients receiving epidural analgesia.^{3 4 7 19}

Hematologic Effects

Use with extreme caution in patients with an increased risk of hemorrhage (e.g., congenital or acquired bleeding disorders; active ulceration and angiodysplastic GI disease; hemorrhagic stroke; uncontrolled arterial hypertension; diabetic retinopathy; recent brain, spinal, or ophthalmic surgery).^{1 3 4} Use with caution in the treatment of DVT or PE in patients who weigh <50 kg.¹ Use with caution in patients with moderate renal insufficiency (Cl_cr 30–50 mL/minute).¹

Periodic routine blood counts, including platelet counts, and tests for occult blood in stool recommended.¹

Avoid concomitant use of drugs that increase risk of bleeding unless essential for management of underlying condition (e.g., concomitant use of vitamin K antagonists for treatment of venous thromboembolism).¹ Closely monitor for signs and symptoms of bleeding.¹

Do not administer earlier than 6–8 hours after surgery because of increased risk of major bleeding.¹

Moderate thrombocytopenia (platelet counts of 50,000–100,000/mm³) and severe thrombocytopenia (platelet counts <50,000/mm³) reported.¹ Fondaparinux unlikely to cause HIT;^{2 11 12 13} however, isolated cases of thrombocytopenia with thrombosis resembling HIT reported during postmarketing experience.¹ Manufacturer recommends monitoring thrombocytopenia of any degree closely and discontinuing fondaparinux if platelet counts fall below 100,000/mm³.¹ However, ACCP states that routine platelet count monitoring is not necessary due to the low frequency of HIT.²⁷

Patients with Prosthetic Heart Valves

Cases of valve thrombosis resulting in death and/or requiring surgical intervention reported with low molecular weight heparin (e.g., enoxaparin) therapy in patients with prosthetic heart valves; some cases included pregnant women, and maternal and/or fetal deaths have been reported.¹⁵ Manufacturer states that fondaparinux has not been studied in patients with prosthetic heart valves and that no information is available on safety of the drug in such patients.¹⁶

Sensitivity Reactions

Latex Sensitivity

Some packaging components (e.g., needle covers) contain natural latex proteins in the form of dry natural rubber (latex), which may cause allergic-type reactions (including life-threatening hypersensitivity reactions) in susceptible individuals.^{1 24 30 31} The needle cover of the diluent syringe should not be handled by individuals sensitive to latex.^{1 24 30 31}

Specific Populations

Pregnancy

Category B.¹

Lactation

Distributed into milk in rats; not known whether distributed into human milk.¹ Use caution.¹

Pediatric Use

Safety and efficacy not established in children <17 years of age.^{1 16}

Geriatric Use

Use with caution.¹ No substantial differences in efficacy relative to younger adults.^{1 16} Possible increased major bleeding or other serious adverse effects in patients ≥75 years of age compared with younger adults.^{1 16} Substantially eliminated by kidneys; assess renal function periodically since geriatric patients are more likely to have decreased renal function.¹ Careful attention to dosage directions and concomitant therapy (particularly platelet-aggregation inhibitors) is advised.¹

Hepatic Impairment

Following a single 7.5 mg dose in patients with moderate hepatic impairment, response (i.e., aPTT, PT/INR, and antithrombin III) similar to that in patients with normal hepatic function.¹ Pharmacokinetics not studied in patients with severe hepatic impairment.¹

Increased risk of hemorrhage; closely monitor for signs and symptoms of bleeding.¹ (See Hematologic Effects under Cautions.)

Renal Impairment

Use with caution in those with moderate renal impairment (Cl_cr 30–50 mL/minute); increased risk of hemorrhage.^{1 16} Contraindicated in patients with severe renal impairment (Cl_cr <30 mL/minute or S_cr ≥3).^{1 16 32} Assess renal function periodically (e.g., serum creatinine determinations).¹ Discontinue immediately in patients who develop severe renal impairment during therapy.¹

Common Adverse Effects

Patients undergoing hip-fracture, hip- or knee-replacement surgery: Anemia, fever, nausea, edema, constipation, rash, vomiting, insomnia, increased wound drainage, hypokalemia, urinary tract infection, dizziness, purpura, hypotension, confusion, bullous eruption, urinary retention, hematoma, major bleeding, diarrhea, dyspepsia, postoperative hemorrhage, headache.^{1 16}

Patients undergoing abdominal surgery: Postoperative wound infection, postoperative hemorrhage, fever, surgical site reaction, anemia, hypertension, pneumonia, vomiting.¹

Venous thromboembolism: Constipation, headache, insomnia, fever, nausea, urinary tract infection, coughing.¹

Interactions for Fondaparinux Sodium

Weak inhibitor of CYP2A6, 1A2, 2C9, 2C19, 2D6, 3A4, and 3E1 in vitro.¹

Drugs Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interaction unlikely.¹

Protein-bound Drugs

Pharmacokinetic interaction unlikely.¹

Specific Drugs

Drug	Interaction	Comments
Anticoagulants, oral	Increased risk of bleeding1	Discontinue oral anticoagulants prior to initiation of fondaparinux1 If coadministration is essential, monitor patients closely1
Digoxin	Pharmacokinetic/pharmacodynamic interaction unlikely1 16
NSAIAs	Pharmacodynamic interaction unlikely1	Discontinue NSAIAs prior to initiation of fondaparinux1 If coadministration is essential, monitor patients closely
Platelet-aggregation inhibitors	Increased risk of bleeding1	Discontinue platelet-aggregation inhibitors prior to initiation of fondaparinux1 If coadministration is essential, monitor patients closely1

Fondaparinux Sodium Pharmacokinetics

Absorption

Bioavailability

Sub-Q: Absolute bioavailability 100%.^{1 10 b}

Duration

Anticoagulant effects may persist for 2–4 days following discontinuance of therapy in patients with normal renal function (i.e., ≥3–5 half-lives).¹

Special Populations

In patients with renal impairment, anticoagulant effects may persist for >2–4 days following discontinuance of therapy.¹

Distribution

Extent

In healthy adults, distributes mainly in blood and only to a minor extent in extravascular fluid.¹ Distributed into milk in rats; not known whether distributed into human milk.¹

Plasma Protein Binding

In vitro, 94% bound to antithrombin III.¹

Elimination

Metabolism

Most of dose not metabolized.¹

Elimination Route

Eliminated unchanged in urine in individuals with normal renal function.^{1 b}

Half-life

17–21 hours.¹

Special Populations

In patients with renal impairment, the total clearance is reduced by 25, 40, and 55% in patients with mild, moderate, and severe renal impairment, respectively, compared with those with normal renal function.¹

In geriatric patients >75 years of age, total clearance is approximately 25% lower compared with patients <65 years of age.¹

In dialysis-dependent patients, approximately 20% of the drug is removed by hemodialysis.¹

In patients weighing <50 kg, total clearance is reduced by approximately 30%.¹

Stability

Storage

Parenteral

Solution for Injection

25°C (may be exposed to 15–30°C).¹

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Do not mix with other injections or infusions.¹

Actions

• 
  

  Anticoagulation results from rapid inhibition of factor Xa by antithrombin III bound to fondaparinux (about 300-fold greater than innate activity).^{1 2 4 9 10} Neutralization of coagulation factor Xa inhibits the conversion of prothrombin to thrombin and subsequent thrombus formation.^{1 2 4 9 10} Unable to lyse established thrombi.¹⁶

  
  


• 
  

  Binds selectively to antithrombin III; unable to inactivate thrombin.^{1 2 4 8 9 16} At the recommended dosage, fibrinolytic activity not affected.¹

  
  


• 
  

  Platelet function or global clotting function tests (e.g., PT, bleeding time, aPTT) generally not affected when administered at the recommended dosage.^{1 10 16}

  
  

Advice to Patients

• 
  

  Importance of initiating self-administration only if a clinician determines that the such administration is appropriate and that medical follow-up is available as necessary.¹ Importance of appropriate training in injection technique.¹

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.¹

  
  


• 
  

  Importance of informing patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Fondaparinux Sodium

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection, for subcutaneous use	2.5 mg/0.5 mL	Arixtra (available as a 0.5-mL, disposable prefilled syringe)	GlaxoSmithKline
		5 mg/0.4 mL	Arixtra (available as a 0.4-mL, disposable prefilled syringe)	GlaxoSmithKline
		7.5 mg/0.6 mL	Arixtra (available as a 0.6-mL, disposable prefilled syringe)	GlaxoSmithKline
		10 mg/0.8 mL	Arixtra (available as a 0.8-mL, disposable prefilled syringe)	GlaxoSmithKline

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions November 11, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. GlaxoSmithKline. Arixtra (fondaparinux sodium) injection prescribing information. Research Triangle Park, NC: 2010 Mar.

2. Turpie AGG, Gallus AS, Hoek JA, for the Pentasaccharide Investigators. A synthetic pentasaccharide for the prevention of deep-vein thrombosis after total hip replacement. N Engl J Med. 2001; 344:619-25. [IDIS 459860] [PubMed 11228275]

3. 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; 345:1298-304. [IDIS 471305] [PubMed 11794148]

4. 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; 345:1305-10. [IDIS 471306] [PubMed 11794149]

5. Lassen MR, Bauer KA, Eriksson BI et al. Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: A randomized double-blind comparison.Lancet 2002; 359:715-20.

6. Turpie GG, Bauer KA, Eriksson BI et al.. Postoperative enoxaparin for prevention of venous thromboembolism after elective hip-replacement surgery: A randomized double-blind trial. Lancet 2002; 359:1721-6. [IDIS 481278] [PubMed 12049860]

7. Geerts WH, Heit JA, Clagett GP et al. Prevention of venous thrombembolism. Chest. 2001; 119 (Suppl):133S-75S.

8. Hirsh J, Warkentin TE, Shaughnessy SG et al. Heparin and low- molecular-weigh heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest. 2001; 119:64S-94s. [IDIS 459443] [PubMed 11157643]

9. Weitz J, Hirsh J. New anticoagulant drugs. Chest. 2001; 119:95S- 107s. [IDIS 459444] [PubMed 11157644]

10. Bauer KA. Fondaparinux sodium: a selective inhibitor of factor Xa. Am J Health-Syst Pharm. 2001; 58 (Suppl.2):S14-7. [IDIS 472189] [PubMed 11715834]

11. Rosenberg RD. Redesigning heparin. N Engl J Med. 2001; 344:673-4. Editorial. [IDIS 459863] [PubMed 11228284]

12. Ahmad S, Jeske WP, Walenga JM et al. Synthetic pentasaccharides do not cause platelet activation by antiheparin-platelet factor 4 antibodies. Clin Appl Thromb Hemost. 1999; 5:259-66. [PubMed 10726024]

13. Amiral J, Lormeau JC, Marfaing-Koka A et al. Absence of cross- reactivity of SR90107A/ORG31540 pentasaccharide with antibodies to heparin-PF4 complexes developed in heparin-induced thrombocytopenia. Blood Coagul Fibrinolysis. 1997; 8:114-7. [PubMed 9518042]

14. Hull R, Pineo G. A synthetic pentasaccharide for the prevention of deep- vein thrombosis. N Engl J Med. 2001; 345:291. Letter. [IDIS 467250] [PubMed 11474672]

15. Aventis. Lovenox (enoxaparin sodium) injection prescribing information. Bridgewater, NJ; 2001 Jul.

16. Organon Sanofi-Synthelabo, West Orange, NJ: Personal communication.

17. Bounameaux, H, Perneger T. Fondaparinux: A new synthetic pentasaccharide for thrombosis prevention. Lancet.2002; 359:1710-1.

18. Eriksson BI, Lassen MR. Duration of prophylaxis against venous thromboembolism with fondaparinux after hip fracture surgery: a multicenter, randomized, placebo-controlled, double-blind study. Arch Intern Med. 2003; 163:1337-42. [IDIS 499798] [PubMed 12796070]

19. Geerts WH, Bergqvist D, Pineo GF et al. Prevention of venous thromboembolism: American College of Chest Physicians evidence-based clinical practice guidelines (8th ed). Chest. 2008; 133(Suppl.):381S-453S. [IDIS 523840] [PubMed 15383478]

20. Buller HR, Davidson BL, Decousus H et al. Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: a randomized trial. Ann Intern Med. 2004; 140:867-73. [IDIS 516440] [PubMed 15172900]

21. Buller HR, Davidson BL, Decousus H et al. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med. 2003; 349:1695-702. [IDIS 505897] [PubMed 14585937]

22. Kearon C, Kahn SR, Agnelli G et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians evidence-based clinical practice guidelines (8th ed). Chest. 2008:133 (Suppl.):454S-545S.

23. Organon Sanofi-Synthelabo. Arixtra (fondaparinux sodium) injection prescribing information. West Orange, NJ: 2001 Dec.

24. Food and Drug Administration. Natural rubber-containing medical devices; user labeling. 21 CFR Part 801. Final rule. (Docket No. 96N-0119) Fed Regist. 1997; 62:51021-30.

25. Antman EM, Anbe DT, Armstrong PW et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction-executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction). J Am Coll Cardiol. 2004; 44(3):671-719. [PubMed 15358045]

26. Agnelli G, Bergvist D, Cohen AT et al. Randomized clinical trial of postoperative fondaparinux versus perioperative dalteparin for prevention of venous thromboembolism in high-risk abdominal surgery. Br J Surg. 2005; 92:1212-20. [PubMed 16175516]

27. Warkentin TE, Greinacher A, Koster A et al. Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians evidence-based clinical practice guidelines (8th ed). Chest. 2008; 133:340S-80S [PubMed 18574270]

28. Harrington RA, Becker RC, Cannon CP et al. Antithrombotic therapy for non ST-segment elevation acute coronary syndromes: American College of Chest Physicians evidence-based clinical practice guidelines (8th ed). Chest. 2008:133:670S-707S.

29. Goodman SG, Menon V, Cannon CP et al. Acute ST-segment elevation myocardial infarction: American College of Chest Physicians evidence-based clinical practice guidelines (8th ed). Chest. 2008; 133:708S-75S [PubMed 18574277]

30. Food and Drug Administration. Amended economic impact analysis of final rule requiring use of labeling on natural rubber containing devices. 21 CFR Part 801. Final rule. (Docket No. 96N-0119) Fed Regist. 1998; 63:50660-704.

31. Food and Drug Administration. Latex-containing devices; user labeling. 21 CFR Part 801. Proposed rule. (Docket No. 96N-0119) Fed Regist. 1996; 61:32617-21.

32. Antman EM, Anbe DT, Armstrong PW et al. 2007 Focused Update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Group to Review New Evidence and Update the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction). J Am Coll Cardiol. 2008; 51:210–47.

33. King SB III, Smith SC Jr, Hirschfeld JW Jr et al. 2007 Focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: American College of Cardiology/American Heart Association Task Force on Practice Guidelines, 2007 Writing Group to Review New Evidence and Update the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention. JACC. 2008; 51:172-209. [PubMed 18191745]

34. Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators, Yusuf S, Mehta SR et al. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med. 2006; 354:1464-76. [PubMed 16537663]

35. Mehta SR, Granger CB, Eikelboom JW et al. Efficacy and safety of fondaparinux versus enoxaparin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: results from the OASIS-5 trial. J Am Coll Cardiol. 2007; 50:1742-51. [PubMed 17964037]

36. Anderson JL, Adams CD, Antman EM et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-Elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol. 2007; 50:e1-e157. [PubMed 17692738]

b. Donat F, Duret JP, Santoni A et al. The pharmacokinetics of fondaparinux sodium in healthy volunteers. Clin Pharmacokinet. 2002; 41 Suppl 2:1-9. [PubMed 12383039]

More Fondaparinux Sodium resources

• Fondaparinux Sodium Side Effects (in more detail)
• Fondaparinux Sodium Use in Pregnancy & Breastfeeding
• Fondaparinux Sodium Drug Interactions
• Fondaparinux Sodium Support Group
• 3 Reviews for Fondaparinux Sodium - Add your own review/rating

• Arixtra Prescribing Information (FDA)


• Arixtra Concise Consumer Information (Cerner Multum)


• Arixtra Advanced Consumer (Micromedex) - Includes Dosage Information


• Arixtra MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Fondaparinux Sodium with other medications

• Deep Vein Thrombosis
• Deep Vein Thrombosis Prophylaxis after Abdominal Surgery
• Deep Vein Thrombosis Prophylaxis after Hip Replacement Surgery
• Deep Vein Thrombosis Prophylaxis after Knee Replacement Surgery
• Deep Vein Thrombosis, Prophylaxis
• Pulmonary Embolism

Foradil

Generic Name: Formoterol Fumarate
Class: Selective beta-2-Adrenergic Agonists
VA Class: RE102
Chemical Name: (±) - 2′ - Hydroxy - 5′ - [(R*) - 1 - hydroxy - 2 - [[(R*) - p - methoxy - α - methylphenethyl]amino]ethyl]formanilide fumarate
Molecular Formula: (C₁₉H₂₄N₂O₄)₂•C₄H₄O₄
CAS Number: 43229-80-7

Special Alerts:

[Posted 02/18/2010] FDA notified healthcare professionals and consumers that, due to safety concerns, FDA is requiring a risk management strategy (REMS) and class-labeling changes for all Long-Acting Beta-Agonists (LABAs). The REMS will require a revised Medication Guide written specifically for patients, and a plan to educate healthcare professionals about the appropriate use of LABAs. These changes are based on FDA's analyses of studies showing an increased risk of severe exacerbation of asthma symptoms, leading to hospitalizations in pediatric and adult patients as well as death in some patients using LABAs for the treatment of asthma.

Healthcare professionals are reminded that to ensure the safe use of these products:

• 
  

  Single-ingredient LABAs should only be used in combination with an asthma controller medication; they should not be used alone.

  
  


• 
  

  LABAs should only be used long-term in patients whose asthma cannot be adequately controlled on asthma controller medications.

  
  


• 
  

  LABAs should be used for the shortest duration of time required to achieve control of asthma symptoms and discontinued, if possible, once asthma control is achieved. Patients should then be maintained on an asthma controller medication.

  
  


• 
  

  Pediatric and adolescent patients who require the addition of a LABA to an inhaled corticosteroid should use a combination product containing both an inhaled corticosteroid and a LABA, to ensure compliance with both medications.

  
  

FDA has determined that the benefits of LABAs in improving asthma symptoms outweigh the potential risks when used appropriately with an asthma controller medication in patients who need the addition of LABAs. FDA believes the safety measures recommended will improve the safe use of these drugs. For more information visit the FDA website at: and .

REMS:

FDA approved a REMS for formoterol to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of formoterol and consists of the following: communication plan. See the FDA REMS page () or the ASHP REMS Resource Center ().

• 
  

  Possible increase in asthma-related deaths in patients receiving long-acting β₂-adrenergic bronchodilators (e.g., salmeterol) in addition to usual asthma therapy.^{1 40 41 a}

  
  


• 
  

  Reserve use of long-acting β₂-adrenergic agonists in patients with asthma for those whose disease is inadequately controlled with other anti-asthma therapy (e.g., low-to-medium dosage of inhaled corticosteroids) or whose disease severity warrants treatment with 2 maintenance therapies.^{1 39 40 41 42 a} (See Increased Risk of Asthma-related Death under Cautions.)

  
  

Introduction

Bronchodilator; a relatively selective, long-acting β₂-adrenergic agonist.¹

Uses for Foradil

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Bronchospasm in Asthma

Long-term prevention of bronchospasm in patients with reversible obstructive airway disease (e.g., asthma) whose symptoms are not adequately managed with other controller therapy (e.g., low-to-medium dosage of inhaled corticosteroids) or whose disease severity warrants treatment with 2 maintenance therapies.^{1 39 40 41 42} Not indicated in patients whose asthma can be successfully managed with occasional use of an inhaled, short-acting β₂-adrenergic agonist or in those whose asthma can be successfully managed by inhaled corticosteroids or other controller drugs accompanied by occasional use of an inhaled, short-acting β₂-adrenergic agonist.^{1 42} (See Increased Risk of Asthma-related Death under Cautions.)

Fixed combination of formoterol and budesonide recommended in patients whose symptoms are not adequately managed with other controller therapy (e.g., low-to-medium dosage of inhaled corticosteroids) or whose disease severity warrants treatment with 2 maintenance therapies.^{a e}

Formoterol should not be used as initial or sole therapy for asthma and is not a substitute for corticosteroids.^{1 40 44} Corticosteroid therapy should not be stopped or reduced in dosage when formoterol is initiated.^{1 40} (See Concomitant Anti-inflammatory Therapy under Cautions.)

Not to be used for immediate relief of bronchospasm or in patients with substantially worsening or acutely deteriorating asthma.^{1 40 42 a} (See Acute Exacerbations of Asthma under Cautions.)

Exercise-induced Bronchospasm

Prevention of exercise-induced bronchospasm when administered on an occasional or as-needed basis.^{1 17}

Formoterol in fixed combination with budesonide is not indicated for prevention of exercise-induced bronchospasm.^a In patients receiving fixed combination, do not use additional formoterol or other long-acting β₂-adrenergic agonists (e.g., salmeterol) for prevention of exercise-induced bronchospasm or for any other reason.^a

COPD

Long-term treatment of bronchospasm associated with COPD, including chronic bronchitis and emphysema.^{1 19 23 24}

Use of long-acting β₂-adrenergic agonists with or without inhaled corticosteroids for acute exacerbations of COPD not evaluated.^f Use a short-acting inhaled β₂-adrenergic agonist intermittently (as needed) for acute symptoms of COPD.^{33 34 f}

Formoterol in fixed combination with budesonide is not indicated for treatment of COPD.^a

Foradil Dosage and Administration

General

• 
  

  When formoterol therapy alone or in fixed combination with budesonide is initiated, discontinue regular use of short-acting, inhaled β₂-adrenergic agonists; use such agents only for relief of acute symptoms of asthma or COPD that are not controlled by formoterol.^{1 a}

  
  


• 
  

  If a dose is missed, skip that dose and take the next dose at the usual time.^{11 44 e} Do not double the dose to replace the missed dose.^{11 44 e}

  
  


• 
  

  Failure to respond to a previously effective dosage may indicate seriously worsening asthma or destabilization of COPD that requires reevaluation.¹ Extra or increased doses are not recommended.^{1 6 10 11 40 41 a e} (See Acute Exacerbations of Asthma under Cautions.)

  
  


• 
  

  Administer a short-acting, inhaled β₂-adrenergic agonist if acute asthmatic symptoms arise despite maintenance therapy.^{1 a e} Administer a short-acting β₂-adrenergic agonist if routine therapy with formoterol is not effective for preventing exercise-induced bronchospasm.¹

  
  

Administration

Oral Inhalation

Administer oral inhalation powder using a special oral inhaler (Aerolizer) that delivers powdered drug from capsules.^{1 11} Do not take capsules orally.^{1 11 b}

Administer oral inhalation aerosol (Symbicort) using an aerosol inhaler device.^{a e}

Inhalation Powder

Administer twice daily, approximately every 12 hours (morning and evening).^{1 11 44}

For prevention of exercise-induced bronchospasm, administer ≥15 minutes before exercise, but not more often than once every 12 hours.^{1 11 44}

Do not use formoterol fumarate dry-powder capsules with any capsule inhaler other than Aerolizer.^{1 11 44} Do not swallow the dry-powder capsule.^{44 b}

If no improvement, ensure patient is using the inhaler rather than swallowing the dry-powder capsules.^b

Do not use spacer devices with the Aerolizer inhaler.⁴⁴

Inhalation Aerosol

Administer twice daily (morning and evening).^{a e}

Test spray 2 times before first use, if not used for >7 days, or if dropped.^{a e}

Shake well for 5 seconds immediately prior to use.^{a e} Clean inhaler every 7 days by wiping mouthpiece with a dry cloth.^{a e}

Use the actuator supplied with the product to administer formoterol in fixed combination with budesonide.^{a e}

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as formoterol fumarate dihydrate; dosage expressed in terms of anhydrous drug.¹ Available as fixed combination containing formoterol fumarate dihydrate and budesonide; dosage expressed in terms of the hydrated drug.^a

Each dry-powder capsule contains 12 mcg of formoterol fumarate.¹ During in vitro testing, each activation of the Aerolizer inhaler delivered about 10 mcg of drug; however, the precise amount of drug delivered to the lungs depends on factors such as the patient’s inspiratory flow.¹

Dosage of formoterol fumarate dihydrate in fixed combination with budesonide (Symbicort) inhalation aerosol is expressed in mcg delivered from the mouthpiece.^a Each actuation of the Symbicort inhalation aerosol delivers 5.1 mcg of formoterol fumarate dihydrate and 91 or 181 mcg of budesonide from the valve, and 4.5 mcg of formoterol fumarate dihydrate and 80 or 160 mcg of budesonide from the actuator per metered spray.^a The amount of drug delivered to the lungs depends on factors such as the patient’s inspiratory flow.^a The aerosol inhaler delivers 60 metered sprays per 6- or 6.9-g canister and 120 metered sprays per 10.2-g canister.^a

Pediatric Patients

Asthma

Oral Inhalation Powder

Children ≥5 years of age and adolescents: 12 mcg (contents of one capsule) twice daily.^{1 11}

Formoterol/Budesonide Fixed-combination Therapy

Oral Inhalation Aerosol

Adolescents ≥12 years of age not currently receiving an orally inhaled corticosteroid: Initially, 9 mcg of formoterol fumarate dihydrate and 160 or 320 mcg of budesonide twice daily, depending on asthma severity.^a

Adolescents ≥12 years of age inadequately controlled with low-to-medium dosages of an inhaled corticosteroid: Initially, 9 mcg of formoterol fumarate dihydrate and 160 mcg of budesonide twice daily.^a

Adolescents ≥12 years of age inadequately controlled with medium-to-high dosages of an inhaled corticosteroid: Initially, 9 mcg of formoterol fumarate dihydrate and 320 mcg of budesonide twice daily.^a

If control of asthma is inadequate after 1–2 weeks of therapy at the lower dosage, a higher strength (higher strengths contain higher dosages of budesonide only) may provide additional asthma control.^a

Exercise-induced Bronchospasm

Oral Inhalation Powder

Children ≥5 years of age and adolescents: 12 mcg (contents of one capsule) administered ≥15 minutes before exercise but not more often than once every 12 hours.^{1 11}

Adults

Asthma

Oral Inhalation Powder

12 mcg (contents of one capsule) twice daily.^{1 11}

Formoterol/Budesonide Fixed-combination Therapy

Oral Inhalation Aerosol

Patients not currently receiving an orally inhaled corticosteroid: Initially, 9 mcg of formoterol fumarate dihydrate and 160 or 320 mcg of budesonide twice daily, depending on asthma severity.^a

Patients inadequately controlled with low-to-medium dosages of an inhaled corticosteroid: Initially, 9 mcg of formoterol fumarate dihydrate and 160 mcg of budesonide twice daily.^a

Patients inadequately controlled with medium-to-high dosages of an inhaled corticosteroid: Initially, 9 mcg of formoterol fumarate dihydrate and 320 mcg of budesonide twice daily.^a

If control of asthma is inadequate after 1–2 weeks of therapy at the lower dosage, a higher strength (higher strengths contain higher dosages of budesonide only) may provide additional asthma control.^a

Exercise-induced Bronchospasm

Oral Inhalation Powder

12 mcg (contents of one capsule) administered ≥15 minutes before exercise but not more often than once every 12 hours.^{1 11}

COPD

Oral Inhalation Powder

12 mcg (contents of one capsule) twice daily.¹

Prescribing Limits

Pediatric Patients

Asthma

Oral Inhalation Powder

Children ≥5 years of age and adolescents: Maximum 24 mcg daily (12 mcg every 12 hours).^{1 11}

Formoterol/Budesonide Fixed-combination Therapy

Oral Inhalation Aerosol

Adolescents ≥12 years of age: Maximum 9 mcg of formoterol fumarate dihydrate and 320 mcg of budesonide twice daily.^a

Exercise-induced Bronchospasm

Oral Inhalation Powder

Children ≥5 years of age and adolescents: Maximum 24 mcg daily (12 mcg every 12 hours).¹

Adults

Asthma

Oral Inhalation Powder

Maximum 24 mcg daily (12 mcg every 12 hours).^{1 11}

Formoterol/Budesonide Fixed-combination Therapy

Oral Inhalation Aerosol

Maximum 9 mcg of formoterol fumarate dihydrate and 320 mcg of budesonide twice daily.^a

Exercise-induced Bronchospasm

Oral Inhalation Powder

Maximum 24 mcg daily (12 mcg every 12 hours).¹

COPD

Oral Inhalation Powder

Maximum 24 mcg daily (12 mcg every 12 hours).¹

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.^{1 a} (See Special Populations under Pharmacokinetics.)

Renal Impairment

No specific dosage recommendations at this time.^{1 a}

Geriatric Patients

Fixed-combination therapy with budesonide: No dosage adjustment required.^a

Cautions for Foradil

Contraindications

• 
  

  Known hypersensitivity to formoterol fumarate or any ingredient in the formulation.^{1 a}

  
  

Warnings/Precautions

Warnings

Increased Risk of Asthma-related Death

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Large safety study (Salmeterol Multicenter Asthma Research Trial [SMART]) suggests increased risk of asthma-related life-threatening events, including death, in patients receiving long-acting β₂-adrenergic agonist salmeterol.^{29 30 36 37 38 41 a} While studies currently available do not show an increased risk of asthma-related death with formoterol, small clinical studies suggest a higher incidence of serious worsening of asthma with formoterol therapy compared with placebo.^{1 41 a} Consider possibility that all long-acting β₂-adrenergic agonists may be associated with increased risk of asthma-related death given similar basic mechanism of action.^{1 29 39 40 41 a} Long-acting β₂-adrenergic agonist bronchodilators such as formoterol should be added to asthma therapy only in case of inadequate response to other controller drugs (e.g., low- or medium-dose corticosteroids) or in patients whose disease severity warrants treatment with 2 maintenance therapies.^{40 41 42 a}

It is not known whether the rate of death is increased in patients with COPD receiving long-acting β₂-adrenergic agonists.¹

Acute Exacerbations of Asthma

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Do not initiate therapy in patients with acutely deteriorating or substantially worsening asthma, which may be life-threatening; fatalities have been reported with orally inhaled sympathomimetic drugs.^{1 7 40 41 a}

Failure to respond to a previously effective dosage may indicate substantially worsening asthma.^{1 a} Promptly reevaluate asthma therapy if inadequate control of symptoms persists despite supplemental short-acting β₂-agonist bronchodilator therapy (i.e., need to increase dose or frequency of administration).^{1 41 a} May require adjustment of dosage of inhaled corticosteroid or initiation of systemic corticosteroids.^{1 a} Do not use extra doses of formoterol alone or in fixed combination with budesonide or other long-acting inhaled β₂-adrenergic agonists (e.g., salmeterol) for any reason.^{44 a}

If asthma deteriorates in patients receiving formoterol in fixed combination with budesonide, prompt reevaluation of asthma therapy is required.^a Consider increasing the strength of the fixed combination (higher strengths contain higher dosages of budesonide only), adding additional inhaled corticosteroids, or initiating systemic corticosteroids.^a

Excessive Doses

Possible fatalities and/or serious exacerbations of asthma associated with excessive use of inhaled sympathomimetic drugs.^{1 a}

Patients receiving formoterol alone or in fixed combination with budesonide should not use additional formoterol or other long-acting inhaled β₂-adrenergic agonists^{1 44 a} for any reason.^{44 a}

Concomitant Anti-inflammatory Therapy

Formoterol therapy is not a substitute for inhaled or oral corticosteroids.^{1 40} Use formoterol only in patients with asthma whose symptoms are not adequately managed with other controller therapy (e.g., low-to-medium dosage of inhaled corticosteroids) or whose disease severity warrants treatment with 2 maintenance therapies.^{1 39 40 41 42}

Do not discontinue or reduce dosage of corticosteroids when formoterol therapy is initiated.^{1 40} Continue corticosteroid therapy even if patient feels better as a result of initiating or increasing formoterol dosage.¹ Changes in corticosteroid dosage recommended only after clinical evaluation of the patient.¹

Cardiovascular Effects

Possible clinically important changes in SBP and/or DBP, heart rate, and ECG (e.g., flattening of the T wave, prolongation of the QT_c interval, ST-segment depression) changes.^{1 7 17 a} May require discontinuance of the drug.¹ Use with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.^{1 a}

Nervous System Effects

Use with caution in patients with seizure disorders.^{1 a}

Paradoxical Bronchospasm

Possible acute, life-threatening bronchospasm may occur immediately upon inhalation of formoterol.^{1 a} Discontinue therapy immediately and institute alternative therapy.^{1 a}

Sensitivity Reactions

Immediate hypersensitivity reactions (e.g., anaphylaxis, urticaria, angioedema, rash, bronchospasm) reported.^{1 a}

General Precautions

Metabolic Effects

Possible clinically important changes in blood glucose; possible clinically important decreases in serum potassium.^{1 a} Hypokalemia is usually transient, not requiring supplementation.^{1 a}

Use with caution in patients with thyrotoxicosis, untreated hypokalemia, and in those who are unusually responsive to sympathomimetic amines.^{1 a}

Use of Fixed Combinations

When used in fixed combination with budesonide, consider the cautions, precautions, and contraindications associated with budesonide.^a

Specific Populations

Pregnancy

Category C.^{1 a}

May interfere with uterine contractility.^{1 a} Carefully weigh benefit versus risk in labor.^{1 a}

Lactation

Distributed into milk in rats.¹ Not known whether formoterol is distributed into human milk.¹ Use with caution in nursing women.¹

Formoterol in fixed combination with budesonide: Discontinue nursing or the drug.^a

Pediatric Use

Formoterol: Safety and efficacy not established in children <5 years of age.¹

Formoterol in fixed combination with budesonide: Efficacy not established in children <12 years of age.^a Safety not established in children <6 years of age.^a

Geriatric Use

Formoterol: No substantial differences in safety and efficacy relative to younger adults.¹

Formoterol in fixed combination with budesonide: No substantial differences in safety relative to younger adults.^a

Common Adverse Effects

Bronchitis,¹ chest infection,¹ dyspnea,¹ chest pain,¹ tremor (dose-related),^{1 7 12} dizziness (dose-related),¹ insomnia,¹ tonsillitis,¹ rash,¹ dysphonia (dose-related).¹

Interactions for Foradil

Metabolized in the liver by CYP isoenzymes 2D6, 2C19, 2C9 and 2A6.^{1 a}

Specific Drugs

Drug	Interaction	Comments
Antidepressants, tricyclic	Potential pharmacodynamic interaction (prolongation of the QTc interval and increased risk of ventricular arrhythmias)1 a	Extreme caution is recommended during concomitant therapy1 18 a or within 2 weeks following discontinuance of a tricyclic antidepressanta
β-Adrenergic blocking agents (including ophthalmic agents)	Potential pharmacologic interaction (antagonism of pulmonary effects resulting in severe bronchospasm in asthmatic patients)1 18 a	If concomitant therapy is required, consider cautious use of cardioselective β-adrenergic blocking agents1 18 a
Corticosteroids	Potential pharmacodynamic interaction (increased risk of hypokalemia)1
Diuretics, nonpotassium-sparing	Potential pharmacodynamic interaction (additive hypokalemia and/or ECG changes), especially when the recommended β-agonist dose is exceeded1 18 a	Cautious use is recommended1 18 a
MAO Inhibitors	Potential pharmacodynamic interaction (prolongation of the QTc interval and increased risk of ventricular arrhythmias))1 a	Extreme caution is recommended during concomitant therapy1 18 a or within 2 weeks following discontinuance of an MAO inhibitora
Sympathomimetic agents	Potential pharmacodynamic interaction (additive pharmacologic and adverse effects)1	Caution recommended for concomitant use of formoterol and sympathomimetic agents administered by any route1
Xanthine derivatives	Potential pharmacodynamic interaction (increased risk of hypokalemia)1

Foradil Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following inhalation; peak plasma concentrations usually attained within 5–10 minutes.^{1 a}

Onset

Maximum improvement in forced expiratory volume in 1 second (FEV₁): 1–3 hours.¹

Duration

12 hours.¹

Distribution

Extent

Distributed into milk in animals.¹ Not known if the drug crosses the placenta or distributes into milk in humans.¹

Plasma Protein Binding

46–64% bound to plasma proteins; binding to serum albumin is 31–38%.^{1 a}

Elimination

Metabolism

Metabolized in the liver by CYP isoenzymes 2D6, 2C19, 2C9 and 2A6.^{1 a}

Elimination Route

Eliminated in feces (24–34%) and in urine (59–62%).^{1 a}

Half-life

7.9–10 hours.^{1 a}

Special Populations

In severe hepatic impairment, increased exposure possible.^a

Stability

Storage

Oral Inhalation

Powder

20–25°C in a dry place; protect from excessive moisture.^{1 44} Do not remove capsules of dry powder from their foil package until just before use.⁴⁴ Discard inhaler and dry powder capsules at 4 months or by date indicated on the package, whichever is sooner; use the new inhaler provided with each new prescription.⁴⁴

Aerosol

20–25°C with mouthpiece down.^{a e}

Do not puncture aerosol containers, use or store near heat or an open flame, expose to temperatures >49°C, or place into a fire or incinerator for disposal.^{a e} Discard inhaler ≤3 months after removal from foil package.^{a e}

Actions

• 
  

  Synthetic sympathomimetic amine.^{1 6 7 15}

  
  


• 
  

  Long-acting, selective β₂-receptor agonist.^{1 6 7 15 a}

  
  


• 
  

  Stimulates β₂-adrenergic receptors with little or no effect on β₁-^{1 6 7 a} or α-adrenergic receptors.⁷

  
  


• 
  

  Activates adenyl cyclase and stimulates production of cyclic adenosine-3′,5′-monophosphate (cAMP).^{1 a} Increased concentrations of cAMP relax bronchial smooth muscle and inhibit release of proinflammatory mast-cell mediators (e.g., histamine, leukotrienes).^{1 a}

  
  


• 
  

  Inhibits allergen-induced infiltration of eosinophils into airways and reduces extravasation of plasma proteins (e.g., albumin).^{1 2 7 13 a} Does not possess clinically important anti-inflammatory effects.^{1 6 13 15}

  
  


• 
  

  Prolonged therapy at greater than recommended dosages may be associated with development of tolerance to the bronchodilatory effects.^{1 17 a}

  
  

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• 
  

  Importance of patient reading medication guide before initiating therapy and each time the prescription is refilled.^{1 40 41 44 a}

  
  


• 
  

  Advise of potential for increased risk of asthma-related death.^{1 40 41 44 a e}

  
  


• 
  

  Importance of pediatric patients receiving therapy under adult supervision.⁴⁴

  
  


• 
  

  Importance of adequate understanding of proper storage, preparation, and use of inhalation delivery systems.^{1 11 a e}

  
  


• 
  

  Importance of correct procedure for administering formoterol-containing therapy and concomitant therapy (e.g., a short-acting β₂-adrenergic agonist).^{1 11 a b} Importance of not breathing into inhaler.^{1 44}

  
  


• 
  

  Advise patients not to swallow dry-powder capsules; use only with provided inhaler; never place capsules into inhaler mouthpiece.^{44 b}

  
  


• 
  

  Importance of adherence to dosing schedules of formoterol and concomitant therapy, including not altering the dose or frequency of use of such drugs unless otherwise instructed by a clinician.^{1 11 44 e}

  
  


• 
  

  Importance of advising patients that if a dose of formoterol alone or in fixed combination with budesonide is missed, the next dose should be taken at the regularly scheduled time; the dose should not be doubled.^{11 44 e}

  
  


• 
  

  Importance of not using formoterol as sole therapy for asthma.^{40 44} Importance of using drug only when asthma is inadequately controlled with other controller drugs (e.g., inhaled corticosteroid) or when asthma is of sufficient severity to warrant treatment with 2 maintenance therapies.^{1 44 a e}

  
  


• 
  

  Importance of all patients being provided with a short-acting, inhaled β₂-adrenergic bronchodilator as supplemental therapy for acute asthma symptoms.^{44 a e}

  
  


• 
  

  Importance of discontinuing regular use of a short-acting, inhaled β-adrenergic bronchodilator when initiating maintenance formoterol therapy and instituting intermittent use of a short-acting bronchodilator to relieve acute symptoms of asthma.^{1 11 44 a e}

  
  


• 
  

  Importance of contacting a clinician if asthma symptoms do not improve after 1 week of therapy.^{44 e}

  
  


• 
  

  Importance of not using formoterol-containing therapy to relieve acute symptoms of asthma.^{1 5 6 8 11 40 41 a e}

  
  


• 
  

  Importance of contacting a clinician immediately if breathing problems worsen quickly or peak flow meter results decrease.^{1 44 e}

  
  


• 
  

  Importance of contacting a clinician or obtaining medical care immediately if decreased effectiveness of a short-acting β₂-adrenergic agonist (requiring use of ≥4 inhalations for ≥2 consecutive days or 1 canister in 8 weeks) for acute symptoms occurs.^{1 44 e}

  
  


• 
  

  Importance of contacting a clinician if respiratory symptoms worsen over time while using usual dosage of formoterol fumarate.^{1 44 e}

  
  


• 
  

  Importance of advising patients who are receiving formoterol-containing preparations not to use additional formoterol or other long-acting inhaled β₂-adrenergic agonists for any reason.^{1 11 44 e}

  
  


• 
  

  Importance of patients not discontinuing or changing any medications used to control breathing problems without medical supervision, since worsening of asthma may occur.^{1 44 a e}

  
  


• 
  

  Importance of administering formoterol ≥15 minutes prior to exercise for prevention of exercise-induced bronchospasm.^{1 11} Importance of not using additional doses for exercise-induced asthma while receiving maintenance therapy (twice daily) with formoterol.^{1 11 44}

  
  


• 
  

  Advise of potential for adverse effects, such as palpitations, rapid heart rate, tremor, nervousness, or chest pain.^{1 a e}

  
  


• 
  

  Importance of promptly contacting a clinician or seeking emergency medical care if symptoms of a serious allergic reaction such as rash; hives; swelling of the face, tongue, or mouth; or breathing problems develop.^{44 e}

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., heart disease, hypertension, seizures, thyroid disease, diabetes, drug or food allergies).^{1 11 44 e}

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{1 11 a e}

  
  


• 
  

  Importance of informing patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Formoterol Fumarate (Dihydrate)

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral Inhalation	Powder for inhalation (contained in capsules)	12 mcg (of formoterol fumarate) per capsule	Foradil Aerolizer Inhaler	Schering

Formoterol Fumarate (Dihydrate) Combinations

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral Inhalation	Aerosol	4.5 mcg (of formoterol fumarate dihydrate) with Budesonide 80 mcg per metered spray	Symbicort (with hydrofluoroalkane propellant and povidone)	AstraZeneca
		4.5 mcg (of formoterol fumarate dihydrate) with Budesonide 160 mcg per metered spray	Symbicort (with hydrofluoroalkane propellant and povidone)	AstraZeneca

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Dulera 100-5MCG/ACT Aerosol (SCHERING): 13/$219.00 or 39/$636.94

Dulera 200-5MCG/ACT Aerosol (SCHERING): 13/$229.99 or 39/$659.98

Foradil Aerolizer 12MCG Capsules (SCHERING): 60/$175.99 or 180/$485.95

Symbicort 160-4.5MCG/ACT Aerosol (ASTRAZENECA LP): 10/$229.99 or 31/$659.93

Symbicort 80-4.5MCG/ACT Aerosol (ASTRAZENECA LP): 10/$196.99 or 31/$569.98

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

Only references cited for selected revisions after 1984 are available electronically.

1. Schering. Foradil (formoterol fumarate) aerolizer inhalation powder prescribing information. Kenilworth, NJ; 2006 Jun.

2. Wallin A, Sandstrom T, Soderberg M et al. The effects of regular inhaled formoterol, budesonide, and placebo on mucosal inflammation and clinical indices in mild asthma. Am J Respir Crit Care Med. 1999; 159:79-86. [IDIS 421471] [PubMed 9872822]

3. National Asthma Education and