Consultant Pharmacist/Forum

With the onset of cool weather, those of us working in long-term care turn our thoughts to influenza immunization. The Centers for Disease Control and Prevention (CDC) recommend that long-term care facilities immunize all eligible residents (those with no contraindications and who accept the vaccine). Health care workers coming in contact with elderly residents are also urged to accept the influenza vaccine. During the late summer (or even earlier), pharmacy providers should order the current vaccine and work with infection control to plan for the prescribing and distribution of the vaccine. But despite the best immunization plans, what happens when in the middle of winter, an outbreak of influenza A occurs in a facility? It is for this circumstance that pharmacy must be prepared. We must be ready to quickly dispense the appropriate dose of antiviral agent, either amantadine or rimantadine, to all residents at risk.

Each year the CDC publishes guidelines for the prevention and treatment of influenza in their Morbidity and Mortality Weekly Report. The following is a summary of the May 1, 1998, guidelines.¹ Amantadine and rimantadine are antiviral agents with specific activity against influenza A. When given within 48 hours of the onset of influenza A, these agents can reduce the severity and duration of the symptoms of the illness. When given prophylactically during an outbreak, they are 70%-90% effective in preventing influenza. These agents are not a substitute for vaccination but are to be used in the event of an outbreak.

Who Should Receive Chemoprophylaxis?
Nursing facilities should have a surveillance program so that staff report "flu-like" illnesses to the infection control officer. If influenza is suspected, a nasopharyngeal swab can be tested for influenza A by the rapid antigen test and a swab should also be sent for a viral culture. If influenza A is confirmed, or even if outbreaks are suspected in a nursing facility, the CDC recommends that all residents, whether immunized or not, receive amantadine or rimantadine. If influenza A is confirmed residents should receive amantadine or rimantadine for at least two weeks or until approximately one week after the end of the outbreak.¹ Non-vaccinated staff should receive antiviral therapy, and it should be offered even to those staff members who received the vaccine, particularly if a variant strain is suspected.

Dosage
The treatment and prophylactic dose for both amantadine and rimantadine are essentially the same. Each medication is renally eliminated, and dosage adjustment based on renal function is essential to minimize the risk of adverse effects (Table 1). Rarely will an elderly patient require more than 100 mg/day of either drug. The CDC recommends that the dose for patients ≥65 years not exceed this level. One study found that 62.9% of the patients in a nursing facility required an amantadine dose of less than 100 mg/day.² Even with 100 mg/day, side effects, particularly central nervous system (CNS) effects have been reported in elderly patients. With amantadine, it has been suggested that elderly patients may tolerate 50 mg b.i.d. better than 100 mg q.d. This dosing regimen will avoid high peak serum concentrations, which have been associated with adverse effects.^3,4

Another method of dosing is by trough amantadine serum concentrations. In young, healthy adults receiving 200 mg/day, the average trough steady-state serum concentration is 300 ng/ml. A study of amantadine pharmacokinetics in healthy elderly men found that a dose of 1.4 mg/kg/day would be necessary to achieve this same concentration.⁵ This dosing regimen has been recommended by some clinicians.

Adverse Effects
Both amantadine and rimantadine can cause CNS and gastrointestinal side effects, though amantadine seems to cause CNS effects more often than rimantadine. The CNS effects consist of confusion, dizziness, hallucinations, insomnia, tremors, and excitability. The most serious side effects occurred in elderly patients receiving 200 mg/day, patients with renal insufficiency, and patients with high amantadine serum levels.⁶ Amantadine can also cause anticholinergic effects. Livedo reticularis, a reddish-purple mottling of the skin, is usually not seen with short-term use.

Special Precautions
An increased incidence of seizures with amantadine has been reported in patients with a history of seizures. These patients should be observed closely when given chemoprophylaxis with amantadine. No data are available on rimantadine use in patients with a history of seizure disorder, but it has caused seizure activity in patients with a history of seizures who were not taking an anticonvulsant.¹

Increased toxicity is seen when amantadine and triamterene are used in combination. Caution should be taken when amantadine is used with anticholinergic agents and medications that affect the CNS.

Amantadine or Rimantadine?
Amantadine and rimantadine appear to be equally effective against influenza A. As mentioned earlier, rimantadine seems to cause fewer CNS effects than amantadine, though there is not much information on its use in the nursing facility population. Rimantadine is much more expensive than amantadine. The syrup is approximately three times as expensive as amantadine syrup, and the tablets are approximately 12 times as expensive as generic amantadine capsules.

Pharmacy's Role
The major role the pharmacist can play is to be ready in the event of an outbreak of influenza. This goes beyond having enough of the antiviral agent of choice in stock. Time is a factor, and the correct dosing to minimize adverse effects is crucial. At the beginning of the influenza season, we need to update our patient profiles with a recent serum creatinine level in order to estimate creatinine clearance. This can be done using an equation such as the Cockcroft-Gault equation (Table 1). Some facilities will have contingency plans for pre-approved orders for amantadine dosing as per pharmacy calculations or orders ready for the physicians or medical director to sign. Elliott and Zubick² described a program for quickly estimating amantadine dosing during an outbreak of influenza A. In their situation, after the dosing calculations were made, the nursing staff contacted all the physicians to have the appropriate prescriptions written. The pharmacist should also ensure that new residents admitted to the facility during the time of chemoprophylaxis also receive a two-week course of antiviral medication.

TABLE 1. Recommended Antiviral Dosing
Amantadine
Creatinine Clearance		Dose
>80 ml/min		100 mg b.i.d.
51-79 ml/min		100 mg b.i.d. alternating with 100 mg q.d.
3 1-50 ml/min		100 mg q.d.
15-30 ml/min		100 mg every other day
<15 ml/min		200 mg/day every 7 days
Rimantadine
Adults		100 mg b.i.d.
Elderly nursing facility residents		100 mg q.d.
Severe hepatic dysfunction		100 mg q.d.
Creatinine clearance £10 ml/min		100 mg q.d.
Cockcroft-Gault Equation Used to Estimate Creatinine Clearance
(140 - Age) X Wt	= CrCl (men)	CrCl (men) X 0.85 = CrCl (women)
72 X Scr
Wt = weight (lean body weight) Scr = serum creatinine

Immunization During an Outbreak
Residents and health care workers who were not initially immunized with the influenza vaccine and who are not allergic to it should receive the vaccine, even after an outbreak of influenza A has begun. These people still need to receive prophylaxis with an antiviral agent, since antibodies to the vaccine do not develop for two weeks.

Conclusion
Influenza A can be a serious illness in elderly nursing facility residents. Widespread immunization, coupled with good infection control surveillance to catch suspected cases early, can limit the incidence of this illness. In the event of an outbreak, prompt treatment and prophylaxis with antiviral agents can minimize the spread of the illness. With the input of pharmacy, appropriate antiviral dosing can help avoid serious adverse effects.

Judith L. Beizer, PharmD, FASCP
College of Pharmacy & Allied Health Professions
St. John's University
Jamaica, New York

References
1. Prevention and control of influenza; Recommendations of the Advisory Committee on Immunization Practices (ACIP). Centers for Disease Control and Prevention. MMWR 1998;47(RR-6):1-26.
2. Elliott DP, Zubick S. Amantadine dosage estimation for an influenza outbreak in a long-term care facility. Consult Pharm 1993;8:1277-80.
3. Somani SK, Degelau J, Cooper SL et al. Comparison of pharmacokinetic and safety profiles of amantadine 50- and 100-mg daily doses in elderly nursing home residents. Pharmacotherapy 1991;11:460-6.
4. Degelau J, Somani S, Cooper SL et al. Occurrence of adverse effects and high amantadine concentrations with influenza prophylaxis in the nursing home. J Am Geriatr Soc 1990;38:428-32.
5. Aoki FY, Sitar DS. Amantadine kinetics in healthy elderly men: Implications for influenza prevention. Clin Pharmacol Ther ]985;37:137-44.
6. Guay DRP. Amantadine and rimantadine prophylaxis of influenza A in nursing homes: A tolerability perspective. Drugs Aging 1994,5:8-19.

For many years, the management of urinary incontinence has been accomplished through non-specific drug therapy, exercises, and incontinence products. Over the last several months, new medications and products have been marketed in this area.

Tolterodine is a bladder-selective muscarinic receptor antagonist indicted for the treatment of patients with an overactive bladder with symptoms of urinary frequency, urgency, or urge incontinence.¹ Tolterodine works to inhibit contractions of the detrusor (bladder) muscle. The initial recommended dose is 2 mg twice daily. The dose may be lowered to 1 mg twice daily on the basis of individual response and tolerability. The lower dose is also recommended for patients who have significantly reduced hepatic function or who are currently taking drugs that are inhibitors of cytochrome p450 3A4, such as the macrolide antibiotics (erythromycin and clarithromycin) or antifungal agents (ketoconazole, itraconazole, and miconazole).

Studies are currently under way to evaluate the effect of tolterodine on the pharmacokinetics of drugs metabolized by cytochrome p450 2D6, such as flecanide, vinblastine, carbamazepine, and tricyclic antidepressants. Fluoxetine, a selective serotonin re-uptake inhibitor and an inhibitor of cytochrome p450 2D6, has been shown to inhibit the metabolism of tolterodine in some patients. Currently, there is no dosage adjustment required for patients receiving both tolterodine and fluoxetine.

Tolterodine differs from the previously available anticholinergic/antispasmodic agent, oxybutynin, in that tolterodine's action is targeted more specifically to the bladder, therefore reducing the incidence of anticholinergic effects such as dry mouth and constipation. Tolterodine is being directly marketed to consumers seeking solutions for symptoms of urinary frequency or urgency. Duloxetine, a serotonin and norepinephrine re-uptake inhibitor proposed to increase bladder storage capacity, is currently undergoing phase III clinical trials.

Estring, an estradiol-containing vaginal ring, is indicated for the management of stress incontinence in post-menopausal women.² The ring contains 2 mg of 17-B-estradiol, the estrogen normally produced by the pre-menopausal woman. The ring is inserted into the upper vagina, where it releases 50%-60% of the estradiol over a three-month period, at which time it should be replaced. An advantage of the ring is that it delivers estrogen directly to the urogenital tissues and improves atrophy and related symptoms such as vaginal dryness, pruritus, dysuria, and urinary urgency. Estring has been reported as a positive alternative to oral estrogen therapy when the side effects may be problematic to the patient; to the patches, which may be irritating to the skin; and to vaginal creams, which are associated with compliance problems.

Desmopressin (DDAVP) delivered via an intranasal spray has been shown to improve the nocturnal polyuria syndrome, characterized by an increased nocturnal urine output.³ In this syndrome, the diurnal rhythm of the antidiuretic hormone (ADH) is absent, and often there is no detectable ADH in the plasma during the night, causing patients to awaken frequently to void or have urinary incontinence. Desmopressin is a synthetic form of ADH that causes the kidneys to resorb fluid and reduce urine output. In three small studies conducted in Europe, desmopressin doses of 20 and 40 mcg delivered as a nasal solution reduced the nocturnal urine output in elderly patients. Desmopressin tablets are also available for oral treatment of bedwetting in children. The usual oral dose is 0.2 mg at bedtime and can be increased to 0.6 mg if needed. Patients should not consume large amounts of fluid while using desmopressin, as excessive water retention may lead to seizures.

Tamsulosin is an alpha-blocker approved for treatment of benign prostatic hypertrophy (BPH).⁴ It is in the same class with terazosin and doxazosin, but it is more selective for the genitourinary tract. This class of medications has been shown to significantly increase urinary flow rates and to decrease outflow obstruction and irritation symptoms, such as frequency, nocturia, urgency, and urge incontinence associated with BPH. Tamsulosin is reported to be as effective as the other agents for the management of enlarged prostate, but it has very little effect on blood pressure. At the recommended oral dose of 0.4 mg once daily, tamsulosin has shown modest improvement in micturition disturbances such as irritative or obstructive symptoms in men with BPH.

The Reliance Urinary Control Insert is a balloon-tipped device that is inserted into the urethra and inflated with the use of a removable applicator. When it is time to urinate, the patient deflates the balloon and removes the insert. The insert is promoted for easy and reliable control of female stress incontinence, defined as occasional urine leakage when the patient laughs, coughs, or sneezes.

The Impress Softpatch is promoted as a simple solution for urine leakage due to stress incontinence.⁵ The patch itself does not absorb urine, but instead is designed to work as a barrier to odor and wetness, and ultimately to keep urine within the bladder. The small, triangular patch is made of foam, coated with adhesive on one side, and is created to fit comfortably over the urethra. It is designed for one-time use only and should be replaced with a fresh patch following urination.

The Neocontrol Pelvic Floor Therapy System is a special chair developed by Neotonus, Inc. It is described as a new treatment for bladder control that is simple, safe, and painless.⁶ The Neocontrol system was recently approved by the Food and Drug Administration for the treatment of stress, urge, and mixed urinary incontinence due to pelvic floor weakness in women. The most common causes of pelvic floor weakness are childbirth, surgery, injury, or hormonal changes during menopause. With the Neocontrol system, women sit fully clothed for 20-30 minutes twice a week in a chair that has magnetic technology imbedded in the seat. Pulsating magnetic fields induce muscle contractions in the pelvic floor to build strength. The patient feels her muscle tighten, but experiences no pain. A complete course of treatment may take eight weeks or more. The treatment works much the same as the Kegal exercises, which involve contracting the anal sphincter in the same manner as to prevent a bowel movement or urine flow. The exercises must be repeated several times during the day and are often done either incorrectly or not at all. Half the patients completing clinical trials of the system report being "completely dry" after eight weeks of therapy, and over 80% reported significant improvement in their continence. The Neocontrol system is currently available in selected areas, and it should be available nationwide in the near future.

Urinary incontinence affects more than one-third of older individuals. It is important that patients with complaints of urinary frequency or urgency undergo a thorough screening and clinical work-up. New medications and technologies may be effective in reducing or eliminating the symptoms of urinary incontinence and, in turn, improving the quality of life for these individuals.

Susan W. Miller, PharmD, FASCP
Department of Pharmacy Practice
Mercer University
Atlanta, Georgia

References
1. Detrol (tolterodine) package insert. Pharmacia & Upjohn, Kalamazoo, MI. April 1998.
2. Estring (17-B-estradiol) package insert. Pharmacia & Upjohn, Kalamazoo, MI. October 1996.
3. Asplund R, Aberg H. Desmopressin in elderly subjects with increased nocturnal diuresis. A two-month treatment study. Scand J Urol Nephrol 1993;27(1):77-82.
4. Flomax (tamsulosin) package insert. Boehringer-Ingelheim, Ridgefield, CT. March 1998.
5. www.uromed.com October 22, 1998.
6. www.neocontrol.com October 22, 1998.