P&T News: April 1999

Loading Doses of Warfarin

Linda M. Schrand, Pharm.D., Clinical Pharmacist
Peer Review Status: Internally Peer Reviewed by Steven Lentz, M.D., Division of Hematology/Oncology

As reported in the June 1998 issue of P&TNews, loading doses of warfarin are no longer recommended. A study by Harrison et al in 1997 compared the effects of 10 mg and 5 mg initial doses of warfarin by measuring surrogate laboratory markers. The 10 mg loading dose produced a rapid decrease in the activity of both factor VII and protein C within the first 48 hours of therapy. While the decrease in the activity of factor VII results in a rapid increase in the INR, the antithrombotic effect is delayed until the activity of both factors 11 and X is decreased which may take as long as 60 hours. In addition, the early increase in INR may be counteracted by increased procoagulant activity resulting from decreased activity of the vitamin K-dependent anticoagulant protein, protein C. The use of a 5 mg starting dose resulted in a reduction of factors 11 and X within approximately the same period as the 10 mg dose, but it did not have as rapid an effect on factor VII and protein C. At 60 hours, more patients in the 10 mg loading dose arm of the study had INRs greater than 3. Having both reduced levels of protein C and nearly normal levels of factors 11 and X may increase the chance of hypercoagulation within the first 48 hours of warfarin therapy, and excessive prolongation of the INR could increase the risk of bleeding events(1).

Recently, another prospective study(2) has been published that confirms the results outlined above. Fifty-three patients were randomized to receive either the 5 mg or 10 mg dosing protocol as had been used in the initial study done by Harrison and colleagues' to compare the relative efficacy of reaching a stable INR of 2 to 3 within the first 5 days of therapy. The randomization process had an underlying imbalance that resulted in 32 patients in the 5 mg study arm and 21 in the 10 mg arm. Patients receiving an initial dose of 5 mg had a greater proportion of INRs values between 2 and 3 at all time points in the study as compared to those in the 10 mg group. Additionally, 5 (24%) of the patients in the 10 mg group versus 2 (7%) in the 5 mg group had INRs that exceeded 3 on day 4 of the study. This study confirms the previous theory that a stable INR is not reached any sooner with a loading dose than it is with an initial dose of 5 mg and that patients are at a higher risk of having supratherapeutic INRs when given a loading dose at the initiation of warfarin therapy.

References
1. Ann Intern Med. 1997; 126: 133-6
2. Arch Intern Med. 1999; 159: 46-8
3. Ann Intern Med. 1997; 127: 332-3

Hepatitis B Vaccine
Joan M. Murhammer, R.Ph., Clinical Pharmacist, Drug Information Center, Department of Pharmaceutical Care

The CDC considers both Engerix-B[R] and Recombivax HB[R] to be safe and effective in the prevention of hepatitis B infections. I The immune response using one or two doses of a vaccine, followed by one or more subsequent doses from a different manufacturer, has been demonstrated to be comparable to a full vaccination series with a single product.(1) The products may be used interchangeably despite the mcg per dose differences, so patients who have started their immunization series with Engerix-B[R] can finish the series with the appropriate dose of Recombivax HB[R].

For children, the recommended dose for Recombivax HB[R] was changed in August 1998 to include the same dose (5 mcg) for all age groups. It was previously 2.5 mcg for children 0 to 10 years of age with HbsAG(-) mothers and 5 mcg for 0 to 10 years of age for HbsAG (+) mothers.

The chart below provides the recommended doses for both Engerix-B[R] and Recombivax HB[R].

Recombivax HB[R](3) Dose

Engerix-B[R](4) Dose

Infants and Children 0 to 19 years of age

5 mcg/0.5 ml

10 mcg/ 0.5 ml

Adults 20 or more years of age

10 mcg/ 1 ml

20 mcg/ 1 ml

Adult dialysis patients

40 mcg/ 1 ml

40 mcg/ 2 ml*

* given at 0, 1, 2, and 6 months

The recommended schedule for hepatitis B vaccine is a three-dose series given at 0, 1, and 6 months. The American Academy of Pediatrics and the Advisory Committee on Immunization Practices recommend that hepatitis B vaccination should be initiated at birth for all infants.' It can also be given in an accelerated schedule at 0, 1, 2 and 12 months for patients requiring more rapid induction of immunity or for postexposure prophylaxis. However, there is no clear-cut evidence that proves this four-dose regimen provides greater protection than the standard three-dose series.(5)

References
1. MMWR. 199 1; 40(RR- 13):1-24.
2. Committee on Infectious Disease. 1997 Red Book: Report of the Committee on Infectious diseases. Elk Grove Village, IL; American Academy of Pediatrics.
3. Merck & Co. Recombivax HB package insert. Philadelphia, PA: 1998 August.
4. SmithKline Beecham. Engerix-B package insert. Philadelphia, PA: 1995 April.
5. ACP Task Force on Adult Immunization and Infectious Disease Society of America. Guide for Adult Immunization. Philadelphia, PA; American College of Physicians: 1994.

PHARMACY AND THERAPEUTICS SUBCOMMITTEE ACTIONS

DRUGS ADDED TO STOCK

ABACAVIR Tablets: 300 mg Oral Solution: 20 mg per ml Abacavir (Ziagen[R]- Glaxo Wellcome) is a reverse transcriptase inhibitor indicated for use in combination with other antiretroviral agents for the treatment of HIV- I infection.

ANTI-THYMOCYTE GLOBULIN, RABBIT Injection: 25 mg per vial Anti-thymocyte globulin (Thymoglobulln[R]- SangStat) is indicated for the treatment of acute renal transplant rejection in conjunction with concomitant immunosuppression.

DORNASE ALFA Inhalation Solution: 2.5 mg per 2.5 ml ampul Dornase alfa (Pulmozyme[R] - Genentech) is indicated for the management of cystic fibrosis patients to reduce the frequency of respiratory infections and improve pulmonary function. NOTE: The prescribing of dornase alfa is restricted to cystic fibrosis patients with attending staff physician signature.

FENOFIBRATE Capsules: 67 mg Fenofibrate (Tricor[R] - Abbott) is indicated as an adjunct to diet for the treatment of very high serum triglyceride levels in patients who are at risk of pancreatitis.

GENTAMICIN Irrigation Solution: 0.04%, 120 ml bottle This product is used as a bladder irrigant. It replaces neomycin topicalibladder irrigation.

LEFLUNOMIDE Tablets: 10 mg, 20 mg, 100 mg Leflunomide (Arava[R] - Hoechst Marion Roussel) is an immunomodulating agent indicated for the treatment of acute rheumatoid arthritis.

LYME DISEASE VACCINE Injection: 30 mcg per 0.5 ml Lyme disease vaccine (Lymerix[R] - Smith Kline Beecham) is indicated for active immunization against Lyme disease in patients 15 to 70 years of age. The vaccine provides approximately 78% efficacy for prevention of definite Lyme disease after completion of the three-dose series.

SIBUTRAMINE Capsules: 5 mg, 10 mg, 15 mg Sibutramine (Merldia[R] - Knoll) is indicated for the management of obesity in conjunction with a reduced calorie diet in patients with a body mass index of ~30 kg/ml.

SIMETHICONE-COATED CELLULOSE Oral Suspension: 7.5 mg per ml, 400 ml bottle Simethicone-coated cellulose (SonoRx[R] - Bracco) is used to enhance the delineation of upper abdominal anatomy in conjunction with ultrasound imaging.

ADDITIONAL ACTIONS

ENOXAPARIN INJECTION A 60 mg per 0.6 ml prefilled syringe has been added to stock.

PYRIDOSTIGMINE INJECTION A 5 mg per ml injection has been added to stock.

TESTOSTERONE TRANSDERMAL PATCH A 5 mg patch has been added to stock. Note: The cost following each brief monograph is the UIHC inpatient acquisition cost.

DRUGS DELETED FROM STOCK

ATRACURIUM INJECTION Deleted due to low use. Other neuromuscular blocking agents are available.

CHOLINE SALICYLATE ORAL SOLUTION (ARTHROPAN&) Deleted due to low use. Salsalate tablets are available.

CHLORPROMAZINE 100 mg/ml ORAL SYRUP Deleted due to low use. Chlorpromazine 30 mg/ml oral syrup is available.

DIATRIZOATE SODIUM POWDER Deleted due to low use. Other contrast dye agents are available.

DIATRIZOATE SODIUM SOLUTION 50 g/120 ml Deleted due to low use. Other contrast dye agents are available.

ECHOTHIOPHATE 0.06%,0.125%, AND 0.25% OPHTHALMIC SOLUTION

Deleted due to low use. Other agents for the treatment of glaucoma are available.

ESTRADIOL VALERATE 20 mg/ml INJECTION Deleted due to low use. Estradiol valerate 10 mg/ml injection is available.

GLATIRAMER INJECTION (COPAXONE-) Deleted due to low use. Interferon beta la and interferon beta 1b injections are available.

METHYLDOPA ORAL SUSPENSION Deleted due to low use. Methyldopa tablets are available.

NEOMYCIN 1% TOPICAL/IRRIGATION SOLUTION Deleted due to concerns of nephrotoxicity and ototoxicity. Neosporin' GU irrigant, gentamicin 0.04% irrigation solution, and acetic acid 0.25% irrigation solution are available.

NILUTAMIDE TABLETS (NILANDRONO) Deleted due to low use. Bicalutamide tablets (Casodex[R]) are available.

PILOCARPINE 4% OPHTHALMIC SOLUTION, 1 ML Deleted due to low use. Pilocarpine 4% Ophthalmic Solution 15 ml is available.

PROGESTERONE INTRAUTERINE INSERT (PROGESTASERV) Deleted due to low use. Other contraceptive devices are available.

TOLCAPONE 100 mg TABLETS Deleted due to low use. Tolcapone 200 mg tablets are available.

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