P&T News: May 1999
Kathryn A. Miller, Pharm.D., Clinical Pharmacist,
Pharmacotherapy Evaluation and Consultation Service, Department of
Pharmaceutical Care and Kim McDevitt, Pharm.D.*
Peer Review Status: Internally Peer Reviewed by
Steven Lentz, M.D., Ph.D., Associate Professor, Division of
Hematology/Oncology, Department of Internal Medicine.
* At the time the article was written, Dr. McDevitt was a Pharm.D. student, University of Iowa College of Pharmacy.
Management of the overanticoagulated patient with a supratherapeutic International Normalized Ratio (INR) depends upon specific patient considerations, such as the severity of bleeding and the urgency of reversing the anticoagulation (see Table 1). If a patient has an elevated INR (5.0 to 9.0) and does not have clinically significant bleeding, it is reasonable to reduce the INR to a safer level of less than 5.0 by holding the next 1 to 2 doses or administering vitamin K, (phytonadione). Ideally, administration of vitamin K1 should effectively lower the INR without overshooting to a subtherapeutic range in patients who need to have anticoagulation therapy maintained. Overshooting renders the patient resistant to warfarin therapy when it is re-started; this effect can last as long as one week when high doses (more than 5 mg) of vitamin K1 are used.1 New studies have confirmed that low doses (1 to 5 mg) of oral vitamin K1 are effective, and oral administration has the advantages of being safer and more convenient than parenteral administration. Reduction in the INR can be expected to occur within 24 hours after administration of oral vitamin K1. Vitamin K1 can also be given subcutaneously in non-emergent situations, although the response may be delayed and unpredictable.
Vitamin K1 is available as a 5 mg scored tablet; smaller oral doses can be supplied by either splitting the 5 mg tablet or through the use of injectable vitamin K1 administered orally. The injectable solution (AquaMephyton[R]-Merek) can be drawn up into an oral syringe and labeled "For oral use only." The solution must be protected from light until ready to administer. Anecdotally, the solution has been effectively mixed with orange juice, milk, or chocolate milk just prior to administration for increased palatability.
In emergent situations when the intravenous route of administration is desirable, caution should be used; rapid intravenous injection of vitamin K1 may cause severe hypotension, fever, chills, anaphylaxis and arrhythmias. Vitamin K1 should be diluted in 50 ml of normal saline and administered at a rate no greater than 1 mg/minute.
Guidelines for reversal of warfarin anticoagulation modified from the Fifth American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy are as follows:
| Table 1. Guidelines for Reversal of Warfarin Anticoagulation | |
|
INR and Patient Considerations |
Recommendations |
|
INR more than therapeutic range but less than 5.0, and Patient does not have clinically significant bleeding. |
Warfarin dose can be lowered or the next dose can be omitted and warfarin therapy can be resumed at a lower dose once the INR approaches the desired range. |
|
5.0 to 9.0, and Patient does not have clinically significant bleeding. |
If the patient has no additional risk factors for bleeding, the next I or 2 doses of warfarin can be omitted and therapy can be resumed at a lower dose once the INR approaches the desired range. If the patient is at increased risk of bleeding, the next dose of warfarin should be omitted and vitamin K1 (I to 2.5 mg) can be given orally. Therapy can be resumed at a lower dose once the INR approaches the desired range. |
|
INR more than 9.0, and Patient does not have clinically significant bleeding. |
Warfarin should be held, and vitamin K1 (2.5 to 5 mg) should be given orally; this treatment can be repeated after 24 to 48 hours, if necessary. |
|
Patient has major bleed or Rapid reversal of anticoagulant is required. |
Warfarin should be held, and vitamin K1, more than (10 mg) should be given by slow IV infusion. If necessary, fresh frozen plasma or prothrombin complex concentrate, can be administered. Vitamin K1 administration may be repeated every 12 hours, if necessary. |
References
1. Chest. 1998; 114 (suppl):445S-69S
2. Blood Coagul Fibrinolysis. 1995;4:739-41
3. Thromb Haemost. 1998;79:1116-8
4. Ann Intern Med. 1997; 125:959-62
5.Arch Intern Med. 1998;158:2136-40
THE LICENSED PRACTITIONER ISSUING THE ORDER MUST SIGN, TIME, AND DATE THE ORDER WITHIN 24 HOURS.
Nursing staff should flag the orders and the medical record to remind the licensed practitioner to sign them.
Additional information about dictating oral medication orders for UIHC inpatients may be found on pages 51 to 55 of the 1998 UIHC Formulary and Handbook in the section entitled, "Prescribing Medications for Hospitalized Patients."
In patients receiving celecoxib concurrently with warfarin, there have been infrequent post-marketing reports of increases in prothrombin time, sometimes associated with bleeding events, predominantly in the elderly. As you know, the warfarin label advises close and ongoing medical management of warfarin "whenever other medications are initiated, discontinued or taken irregularly," given the increased potential for bleeding. The warfarin label indicates potential interactions with more than a hundred compounds.Celecoxib is indicated for relief of the signs and symptoms of osteoarthritis (OA) and adult rheumatoid arthritis (RA).
Celecoxib, by itself, has no effect on platelet aggregation or bleeding time at therapeutic doses and may be an appropriate treatment option in patients taking warfarin, when anti-inflammatory therapy is indicated. It is important to note that celecoxib can be continued or initiated with warfarin when patients are monitored appropriately for changes in anticoagulant activity, particularly in the first few days. It is estimated that approximately one percent of patients on celecoxib also take warfarin, with a smaller subset of that group reporting increases in prothrombin time.
In order to communicate this important information to healthcare professionals, the warfarin section under the PRECAUTIONS heading in the revised package insert for celecoxib now reads:
Warfarin: Anticoagulant activity should be monitored, particularly in the first few days, after initiating or changing celecoxib therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding complications. The effect of celecoxib on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of 2 to 5 mg of warfarin. In these subjects, celecoxib did not alter the anticoagulant effect of warfarin as determined by prothrombin time. However, in post-marketing experience, bleeding events have been reported, predominantly in the elderly, in association with increases in prothrombin time in patients receiving celecoxib concurrently with warfarin.
"Dear Doctor Letter" Searl e/Pfiz er May 1999
DRUGS ADDED TO STOCK
AMPRENAVIR Capsules: 150 mg Amprenavir (Agenerase[R]-Glaxo Wellcome) is a protease inhibitor indicated for the treatment of HIV- I infection.
CEFUROXIME Tablets: 250 mg Oral Suspension: 250 mg per 5 ml Cefuroxime (Ceftin[R]-Glaxo Wellcome) is a secondgeneration cephalosporin. Due to its activity against Streptococcus pneumoniae, it has recently been recommended as a second-line therapy for otitis media caused by drug-resistant S. pneumoniae.
CELECOXIB Capsules: 100 mg, 200 mg Celecoxib (Celebrex[R] -more than Searle/Pfizer) is a nonsteroidal anti-inflammatory agent (NSAIA) that selectively inhibits cyclooxygenase-2 (COX-2). It is indicated for the treatment of signs and symptoms of osteoarthritis and rheumatoid arthritis. NOTE: Celecoxib has been designated a protocol drug. Criteria for use include: 1) documented intolerance to two previous trials of different multisource NSAIAs; 2) shortterm therapy in patients with prior history of GI bleed or ulcer disease, patients on high-dose corticosteroids, and patients with underlying bleeding disorders and/or platelet dysfunction; or 3) patients receiving celecoxib prior to admission for the management of osteoarthritis or rheumatoid arthritis, and the patient's preference to continue therapy.
CIPROFLOXACIN 0.2% WITH HYDROCORTISONE 1% Otic Solution: 10 ml This combination product (Cipro-HC[R] Otic- Bayer) is indicated for the treatment of acute otitis externa.
MEROPENEM Injection: 500 mg, 1 gram Meropenem (Merrem[R]-Zeneca) is a carbapenem antibiotic with moderate gram-positive coverage and excellent gram negative and anaerobic coverage.
NOTE: Meropenem has been designated a protocol drug. Criteria for use include: cystic fibrosis patients, patients intolerant of imipenem/cilastatin; patients in whom imipenem/cilastatin is contraindicated; and formal Infectious Diseases recommendation.
ROPINIROLE Tablets: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 5 mg Ropinirole (Requip[R] -Smith Kline Beecham) is a non ergot dopamine agonist indicated for the treatment of the signs and symptoms of Parkinson's disease.
VALRUBICIN Intravesical Powder for Solution: 200 mg Valrubicin (Valstar[R] -more than Medeva) is indicated for intravesical therapy of BCG-refractory carcinoma in situ of the urinary bladder in whom immediate cystectomy would be associated with unacceptable morbidity or mortality.
ADDITIONAL ACTIONS
AMPHOTERICIN B ORAL SUSPENSION A 100 mg per ml oral suspension is now commercially available and has been added to stock.
ENOXAPARIN INJECTION Two additional syringe sizes were added to stock: 80 mg per 0. 8 ml and 100 mg per I ml.
HEPATITIS B VIRUS VACCINE (RECOMBIVAX-HB[R]) The 40 mcg per I ml strength has been added to stock for the immunization of dialysis patients. -more than
LEUPROLIDE (LEUPRON{r} DEPOT) INJECTION The 30 mg strength has been added to stock. This product has a four-month duration of action and is indicated for the treatment of prostate cancer.
METRONIDAZOLE (NORITATE[R]) CREAM A I% cream has been added to stock.
METYRAPONE TABLETS A 250 mg tablet has been added to stock. This product is again commercially available. -more than -more than -more than -more than
MYCOPHENOLATE MOFETIL ORAL SUSPENSION A 200 mg per ml oral suspension is now commercially available and has been added to stock.
OCTREOTIDE (SANDOSTATIN[R] LAR DEPOT) DEPOT INJECTION The 10 mg, 20 mg, and 30 mg strengths have been added to stock. This product has a four-week duration of action.
SULFACETAMIDE SODIUM (KLARON[R]) TOPICAL LOTION A 10% topical lotion has been added to stock.
TACROLIMUS CAPSULES A 0.5 mg strength has been added to stock.
Note: The cost following each brief monograph is the UIHC inpatient acquisition cost.
DRUGS DELETED FROM STOCK
CORN OIL EMULSION (LIPOMUL[R]) Discontinued by the manufacturer.
RITONAVIR CAPSULES Discontinued by the manufacturer. Ritonavir oral solution is available.
SECRETIN (SECRETIN-KABI[R] INJECTION) Discontinued by the manufacturer.