News 14/04/2544

News 14/04/2544

PHARMACOLOGICAL INTERVENTIONS IN OLDER ADULTS
Pharmacological Interventions in Older Adults

VARDENAFIL SHOWN TO IMPROVE ERECTILE FUNCTION
Vardenafil has been shown to improve erections in up to 80% of men and increase their ability to complete sexual intercourse with ejaculation.

FDA EXPANDS INDICATION OF LOW-DOSE CLIMARA TO INCLUDE MENOPAUSE
Berlex Laboratories, the US affiliate of German pharmaceutical company Schering AG, reported on Monday that the US Food and Drug Administration has expanded the indication of the 0.025-mg formulation of its Climara patch to include the treatment of symptoms of menopause.

STATIN THERAPY NOT ASSOCIATED WITH REDUCED RISK OF FRACTURES
Contradicting the results of some previous studies, statin therapy does not reduce the risk of fractures, according to data reported in The Journal of the American Medical Association for April 11.

Pharmacological Interventions in Older Adults

Gary J. Kennedy, MD
[Geriatric Mental Health Care, Guilford Press, 2000]

Select Antidepressants For Older Adults

Generic Name	Trade Name	Initial Dose	Final Dose	Amnesia, Arrhythmia Potential	Hypotensive Potential	Sedative Potential	Precautions	Advantages
Tricyclic [TCA's]
Nortriptyline	Pamelor Aventyl	10-25	25-100	Moderate	Moderate	Moderate	Lower final dose, may be fatal in overdose, glaucoma, prostatic disease	Therapeutic window 80-120 mg/ml
Desipramine	Norpramin	10-25	25-150	Moderate	Moderate	Low	May be fatal in overdose, glaucoma, prostatic disease	Ther. level 125-300 mg/ml; Stimulant
Selective Serotonergic Reuptake Inhibitors [SSRI's]
Fluoxetine	Prozac	10 am	20-40	Low	Low	Low	Prolonged T 1/2, nausea, tremor, insomnia, drug interactions	Side effects not life threatening, liquid preparation available
Fluoxetine	ProzacWeekly	90 once a week	20-40	Low	Low	Low
Sertraline	Zoloft	25 am	100-200	Low	Low	Low	Nausea, tremor, insomnia	Few drug interactions
Paroxetine	Paxil	10 hs	20-40	Low	Low	Low	Nausea, tremor, drug interactions	Mild sedative effect
Citalopram	Celexa	10 am	20-40	Low	Low	Low	Nausea, tremor	Few drug interactions, T 1/2 longer than sertraline
Venlafaxine	Effexor	37.5 bid	75-225	Low	Low	Low	Mild hypertensive, headache, nausea, vomiting, do not stop abruptly, not for hypertensives	SSRI & SNRI, fewer drug interactions, sustained release prep
Venlafaxine	Effexor XR	37.5 bid	75-225	Low	Low	Low
Monoamine Oxidase Inhibitors [MAOI's]
Tranylcypromine	Parnate	10-20	30-60	Low	Moderate	Low	Life threatening diet & drug interactions	When depression resists TCA/SSRI, Stimulant, short T 1/2
Others
Bupropion	Wellbutrin	75 bid	150-300	Low	Low	Low	Dopaminergic, noradrenergic, agitation, insomnia, seizures, dose should be divided	Anxiolytic, for apathetic depression, when TCA/SSRI fail, sustained release preparation available
Bupropion	Wellbutrin SR	75 q am	150-300	Low	Low	Low
Nefazadone	Serzone	50 bid	200-400	Low	Mod	Mod	Dry mouth, give more at h.s. than a.m., drug interactions	Sedative, anxiolytic, promotes analgesics
Trazodone	Desyrel	25-50	100-400	Low	High	High	Very sedative, no partial response	For sleep disturbance
Mirtazapine	Remeron	7.5	15-30	Low	Low	Moderate	Prolonged T 1/2, renal clearance, dry mouth, weight gain	When depression resists TCA/SSRI, sedative
Hypericum perforatum	St. John's wort	300 bid	900 tid	Low	Low	Low	Use standardized, freeze dried extract 0.3% hypericin, drug interactions, latency of response	Low side effect profile, OTC
Stimulants
Methylphenidate	Ritalin	5	20 bid	Low	Low	Low	Anorexia, insomnia, daytime use only	Quick results, for the frail and apathetic

SNRI = selective noradrenergic reuptake inhibitor; T 1/2 = half life, bid = twice daily

Select Agents Used for Anxiety Disorders in Older Adults

Generic Name	Trade Name	Initial Dose	Final Dose	Amnestic Potential	Hypotensive Potential	Sedative Potential	Precautions	Advantages
Benzodiazepines
Lorazepam	Ativan	0.5	3 bid	Moderate	Low	High	Falls, dependence, controlled substance	Immediate relief, short T 1/2, no active metabolite, good PRN, IM injection available
Oxazepam	Serax	10 bid	30 bid	Moderate	Low	High	Falls, dependence, controlled substance	Immediate relief, short T 1/2, no active metabolite, good PRN
Clonazepam	Klonopin	0.5 hs	2 bid	Moderate	Low	Moderate	Long T 1/2, falls, dependence, controlled substance	Immediate relief, qd dosing
Alprazolam	Xanax	0.25 bid	2 bid	Moderate	Low	Moderate	Falls, dependence, controlled substance	Immediate relief, FDA approved for Panic Disorder
Selective Serotonergic Reuptake Inhibitors
Nefazadone	Serzone	50 bid	400	Low	Moderate	Moderate	Dry mouth, give more at h.s. than a.m., drug interactions	Sedative SSRI
Sertraline	Zoloft	25 am	200	Low	Low	Low	Relief not immediate, nausea, tremor, insomnia	No sedation or dependence, fewer drug interactions, FDA approved for Panic Disorder, Obsessive Compulsive Disorder, Post-Traumatic Stress Disorder
Fluvoxamine	Luvox	25 am	25-100	Low	Low	Low	Relief not immediate, nausea, tremor, insomnia, drug interactions	FDA approved for Obsessive-Compulsive Disorder
Paroxetine	Paxil	10 hs	40	Low	Low	Moderate	Relief not immediate, nausea, tremor, drug interactions	Mild sedation, no dependence, FDA approved for Panic and, Obsessive Compulsive Disorder, Social Phobia
Venlafaxine	Effexor	37.5 bid	75-225	Low	Low	Low	Mild hypertensive, headache, nausea, vomiting, do not stop abruptly, not for hypertensives.	SSRI & SNRI, fewer drug interactions, sustained release prep FDA approved for GAD
Venlafaxine	Effexor XR	37.5 bid	75-225	Low	Low	Low
Tricyclic Antidepressant
Nortriptyline	Pamelor Aventyl	10 hs	100	Moderate	Moderate	Moderate	Life threatening side effects	Immediate relief, no dependence, therapeutic window 50-150 ng/ml
Others
Bupropion	Wellbutrin	75 bid	300	Low	Low	Low	Dopamienergic, noradrenergic, seizures, dose should be divided	No sedation or dependence
Buspirone	Buspar	10 bid	60	Low	Low	Low	Relief not immediate, not for benzodiazepine withdrawal	No sedation or dependence
Herbals, botanicals
Matricaria recutita	German chamomile	as tea at hs	TID	None	None	Low	Not FDA regulated, allergic reactions	Over-the-counter, no withdrawal, very mild
Valeriana officinalis	Valerian	150 mg bid	300 mg hs	None	None	Low	Not FDA regulated, products may vary and include other ingredients, delayed onset	Over-the-counter, no withdrawal, very mild

GAD=generalized anxiety disorder

Agents Used to Palliate the Cognitive Impairment of Dementia

Generic Name	Trade Name	Initial Dose	Final Dose	Arrhythmia Potential	Hypotensive Potential	Sedative Potential	Precautions	Advantages
Anticholinesterases
Donepezil	Aricept	5 mg qd	10 mg qd	Bradycardia	Low	Low	Transient, initial GI upset, abrupt withdrawal leads to abrupt decline	Once a day dosing, safety
Rivastigmine	Exelon	1.5 mg bid	6 mg bid	Low	Low	Low	Transient, initial GI upset, titrated up at 2 week intervals, abrupt withdrawal leads to abrupt decline, b.i.d. dosing	Wider dose range
Galantamine	Reminyl	4 mg bid	16 mg bid	Bradycardia	Low	Low	Transient, initial GI upset, titrated up at 2 week intervals, abrupt withdrawal leads to abrupt decline, b.i.d. dosing	Nicotinic receptor modulation
Antioxidants
Selegiline	Eldepryl	5 mg qd	5 mg bid	Low	Moderate	Low	Potentially life threatening diet & drug interactions are rare at recommended doses	Available as a transdermal patch
Alpha-tocopherol	vitamin E, (Hoffmann-LaRoche)	30 IU qd	1000 IU bid	NA	NA	NA	Liver toxicity, coagulopathy	Low toxicity, OTC
Others
Extract of Ginko biloba	Ginkgold	60 qd	60 qid	Low	Low	Low	q.i.d. dosing, an "herbal" not subject to FDA quality controls, little data available at max dose	Low toxicity, OTC
Extract of Ginko biloba	Tebonin forte	60 qd	60 qid	Low	Low	Low		Low toxicity, OTC

T 1/2 = half life, OTC = over the counter, FDA = Food and Drug Administration, NA not applicable; AD = Alzheimer's diseseae, VaD = vascular dementia

Selected Antipsychotics for Older Adults

Generic Name	Trade Name	Initial Dose	Final Dose	Movement Disorders Potential *	Hypotensive Potential	Sedative Potential	Precautions	Advantages
Sedative Antipsychotic
Thioridazine	Mellaril	10	100	Low	Dose related	Moderate to high	Hypotensive and amnestic as dose increases, quinidine like effects	Available as liquid. no EPS, sedative
Non-sedative Antipsychotics
Perphenazine	Trilafon	2	16	High	Low	Low	EPS, TD likely as dose increases, increases TCA level	Available as liquid and IM injection.
Haloperidol	Haldol	0.5	20	High	Low	Low	EPS, TD likely as dose increases	Available as liquid, IM & IV injection
Fluphenazine	Prolixin	0.5	20	High	Low	Low	EPS, TD likely as dose increases	Available as liquid, and IM injection
Extended Release Antipsychotics
Haloperidol decanoate	Haldol decanoate	12.5 IM q 14-28 days	200 IM q 28 days	Moderate	Low	Low	IM injection every 28 days, equal to 10 times oral dose, 90 days to steady state	Less EPS than oral, compliance
Fluphenazine enanthate	Prolixin enanthate	12.5 IM q 7-14 days	50 IM q 14-21 days	Moderate	Low	Low	IM injection every 14-21 days, 1:1 equivalence to oral dose, 20 days to steady state	Less EPS than oral, compliance
Atypical Antipsychotics
Resperidone	Risperdal	0.25	6	Low for TD, Moderate for EPS	Moderate, dose related	Moderate	EPS likely at doses above 2 mg, high potency, cost	Available in liquid from, depot form in development
Olanzapine	Zyprexa	2.5	15	Low	Moderate	Moderate	Anticholinergic as dose increases, high cost, weight gain, hyperglycemia	May produce less EPS, TD; FDA approved for acute mania
Quetiapine	Seroquel	25	750	Low	Moderate	More than moderate	Slit lamp exam for cataracts	Sedative, no anticholinergic effects, less EPS, TD
Clozapine	Clozaril	6.25	50	Low	Moderate	Moderate	Highly anticholinergic, monitor WBC weekly, withdraw drug if less than 3000	Proven benefit for patients with idiopathic Parkinson's disease

* Acute dystonias are rare in the elderly but acute extrapyramidal (Parkinsonian) symptoms and delayed tardive dyskinesias are frequent particularly with prolonged use of non-sedating antipsychotics.

EPS = extrapyramidal (Parkinsonian) symptoms, TD = tardive dyskinesia, IM = intramuscular, IV = intravenous

Agents Used to Stabilize Mood, Combat Mania or Aggression in Late Life

Generic Name	Trade Name	Initial Dose	Final Dose	Sedative Potential	Precautions	Advantages
Benzodiazepine
Clonazepam	Klonopin	0.5 bid	5 bid	Moderate	Prolonged T 1/2, falls, controlled substance, may exacerbate aggression or confusion in dementia	Rapid onset, fewer drug interactions, sedation
Lithium compounds
Lithium carbonate	Eskalith	300 qd	300 tid	Low	Renal clearance is sole route of elimination, toxicity may appear below therapeutic range. Tremor is a benign universal side effect. Nausea, vomiting are sings of toxicity. Risk of hypothryoidism	Patient preference otherwise none.
Controlled release	Eskalith CR	450 qd	450 bid	Low		Rx. Level 0.6-1.2 mEq/L
Anticonvulsants
Sodium valproate	Depakote	250 bid	1000 bid	Moderate	Delayed onset of action, drug interactions, GI upset, tremor, weight gain, edema, thrombocytopenia; CBC & chemistries at baseline, then every 6 months; inhibits hepatic enzymes and increases other drug levels	Better tolerated than carbamazepine, Rx. Level 50-100 µg/ml
Carbamazepine	Tegretol	100 bid	500 bid	Moderate	Delayed onset of action, drug interactions, dizziness, unsteady gait; CBC & chemistries at baseline, then every 6 months; enhances cytochrome P450 activity and decreases other drug levels	Rx. Level 4-12 µg/ml
Carbamazepine	Epitol	100 bid	500 bid	Moderate		Rx. Level 4-12 µg/ml
Gabapentin	Neurontin	200 hs	900 tid	Moderate	Wholly dependent on renal clearance for elimination, therapeutic range not established, little experience in the elderly	Not protein bound, liver toxicity and drug interactions unlikely
Lamotrigine	Lamictal	25 hs	200 qd	Moderate	Prolonged half life, appearance of rash calls for immediate cessation, therapeutic range not established, little used in the elderly	Does not alter P450 activity, drug interactions unlikely

T 1/2 = half life, bid = twice daily, GI = gastrointestinal

Select Agents Used for Sleep Disturbance in Older Adults

Generic Name	Trade Name	Initial Dose	Final Dose	Amnestic Potential	Hypotensive Potential	Sedative Potential	Precautions	Advantages
Short lived benzodiazepines
Lorazepam	Ativan	0.5	2	Moderate	Low	High	Falls, dependence, controlled substance	Short T 1/2, no active metabolite
Oxazepam	Serax	15	30	Moderate	Low	High	Falls, dependence, controlled substance	Short T 1/2, no active metabolite
Temazepam	Restoril	15	30	Moderate	Low	High	Falls, dependence, controlled substance	Short T 1/2, no active metabolite
Benzodiazepine "like" hypnotics
Zolpidem	Ambien	5	10	Low	Low	High	May not sustain sleep or be sufficient in major disorders, dependence	Ultra short T 1/2, no active metabolite
Zolpidem	Ambien	5	10	Low	Low	High		Level IV controlled substance
Zaleplon	Sonata	5	10	Low	Low	High	Very rapid onset, longer T 1/2	Level IV controlled substance
Sedative antipsychotics
Thioridazine	Mellaril	10	100	Dose related	Dose related	Moderate	Hypotensive and amnestic as dose increases, quinidine like effects	Available as liquid, not a controlled substance
Sedative antidepressants
Trazodone	Desyrel	25-50	300	Low	High	High	Hypotensive	No withdrawal, not a controlled substance
Nefazadone	Serzone	50	200	Low	Moderate	Moderate	Dry mouth	No withdrawal, not a controlled substance
Paroxetine	Paxil	10	40	Low	Low	Moderate	Nausea, tremor, drug interactions	No withdrawal, not a controlled substance
Mirtazapine	Remeron	7.5	15-30	Low	Low	Moderate	Prolonged T 1/2, renal clearance, dry mouth, weight gain	No withdrawal, not a controlled substance
Hormonal agents
Melatonin	several	2	2	Low	Low	Low	Not FDA regulated, preparations may vary and include other ingredients	Over-the-counter, no withdrawal
Herbals, botanicals
Matricaria recutita	German chamomile	as tea	TID	None	None	Low	Not FDA regulated, allergic reactions	Over-the-counter, no withdrawal, very mild
Matricaria recutita	German chamomile	at hs	TID	None	None	Low	Not FDA regulated, allergic reactions	Over-the-counter, no withdrawal, very mild
Valeriana officinalis	Valerian	150 mg bid	300 mg hs	None	None	Low	Not FDA regulated, products may vary and include other ingredients, delayed onset	Over-the-counter, no withdrawal, very mild

Acknowledgements

From Geriatric Mental Health Care by Gary J. Kennedy, MD, Guilford Press, 2000 (Used with permission)

Vardenafil Shown to Improve Erectile Function

New York - Vardenafil, a phosphodiesterase-5 (PDE-5) inhibitor, has been shown to improve erections in up to 80% of men and increase their ability to complete sexual intercourse with ejaculation, according to a presentation at the XVI annual European Association of Urology (EAU) meeting in Geneva, Switzerland. The study was the first large-scale patient trial of vardenafil, which is made by Bayer.

"Vardenafil improved erectile function in these men, regardless of their age, cause, or severity of their problem. This improvement occurred even at the lowest dose of 5 mg," said Dr. Irwin Goldstein, Boston University School of Medicine, a co-author of the study and a member of the international Vardenafil Study Group. "There was another important finding as well," continued Goldstein. "In the overall study, vardenafil not only helped most men achieve erections, they also were able to sustain their erections and successfully complete intercourse."

The analyses involved 580 patients, aged 21-70 years, in stable heterosexual relationships, from 39 treatment centers in the United States, Belgium, France, Germany, the Netherlands, Poland, and South Africa. The patients had experienced difficulty with erectile function of organic, psychogenic, or mixed etiology for an average of 2.8 years. They were randomized into 4 groups and received vardenafil in 5 mg, 10 mg, 20 mg doses, or placebo on demand, but not more than once a day.

In subanalyses, effects of vardenafil were evaluated by patients' responses to 2 key questions of the International Index of Erectile Function (IIEF) questionnaire: the ability to penetrate (question 3 [Q3]) and the ability to maintain an erection during intercourse (question 4 [Q4]). The scoring was based on a 5-point scale, with one being the most severe.

Those with a baseline Q3 score of 1.0 (ie, with very little ability to penetrate) increased their score to a mean of 1.8 with placebo and to 3.0, 3.1, and 3.7 with 5 mg, 10 mg, and 20 mg of vardenafil, respectively. Those with a starting score of 4.0 on Q3 deteriorated to a mean score of 3.4 with placebo, but increased to a mean of 4.4, 4.7, or 4.4 for the same increasing doses of vardenafil.

For Q4, the results were similar. Those with a score of 1.0 (ie, with very little ability to maintain an erection and complete intercourse) increased their score to a mean of 2.0 with placebo and to scores of 3.3, 3.1, and 3.5 with increasing doses of vardenafil. Those with a relatively mild degree of severity starting with a score of 4.0 had a decreased mean of 3.6 on placebo, but reached a score of 4.0, 4.3, or 4.7 with increasing doses of vardenafil.

Having an organic or psychogenic etiology of erectile dysfunction did not influence the efficacy of vardenafil. The mean changes in score of Q3 for organic and psychogenic erectile dysfunction were: 0.3 and 0.3 for placebo, 1.2 and 1.4 for 5 mg, 1.5 and 1.1 for 10 mg, and 1.3 and 1.4 for 20 mg doses of vardenafil, respectively. Similar responses were seen for Q4.

The patients were divided into 4 age groups: younger than 45 years, 45-55 years, 55-65 years, and older than 65 years. For Q4, the mean increases in score for placebo-treated patients ranged between 0.2 and 0.8 in each age group. For vardenafil-treated patients, a statistically significant treatment effect was found for all doses with mean increases ranging between 0.8 and 1.9, but no one age group had a superior response to vardenafil.

"Our study also demonstrated that vardenafil was well tolerated, with few patients reporting any adverse events," Dr. Goldstein reported. The most frequent adverse events, whether related to the drug or not, were headache (7-15%), flushing (10-11%), rhinitis (3-7%), and dyspepsia (1-7%). The events were generally mild in intensity and related to dosage.

In preclinical studies, the pro-erectile activity of vardenafil was greater than sildenafil at equivalent dosing. In a separate study, vardenafil was found to be highly selective at targeting the PDE-5 enzyme, which is believed to be responsible for inducing erections. Vardenafil is now being evaluated in Phase III trials to better understand if these characteristics will translate into clinical benefits for patients. Results are expected for publication later this year, with completion of the Food and Drug Administration (FDA) review in the second half of 2002. Current estimates suggest that more than half of all men in the United States older than 40 years experience some difficulty with erectile function.

FDA Expands Indication of Low-Dose Climara to Include Menopause

WESTPORT, CT (Reuters Health) Apr 09 - Berlex Laboratories, the US affiliate of German pharmaceutical company Schering AG, reported on Monday that the US Food and Drug Administration has expanded the indication of the 0.025-mg formulation of its Climara patch to include the treatment of symptoms of menopause.

Climara, a transdermal estradiol patch, won FDA approval as a prophylactic for osteoporosis in March 1999. The drug, which is also marketed in 0.05 mg, 0.075 mg and 0.1 mg strengths, was initially approved to treat menopausal symptoms in 1994.

Low-dose estrogen is more tolerable in some patients and is beneficial for long-term health maintenance, Montville, New Jersey-based Berlex said in a news release.

Statin Therapy Not Associated With Reduced Risk of Fractures

WESTPORT, CT (Reuters Health) Apr 10 - Contradicting the results of some previous studies, statin therapy does not reduce the risk of fractures, according to data reported in The Journal of the American Medical Association for April 11.

Using the General Practice Research Database in the UK, Dr. Cyrus Cooper, from Southampton General Hospital, and colleagues reviewed data on 81,880 patients, 50 years of age or older, who had a fracture of the vertebrae, clavicle, humerus, radius/ulna, carpus, hip, ankle or foot. The patients were compared with 81,880 age-, sex- and practice-matched controls.

The adjusted odds ratio for fracture among current statin users was 1.01 compared with nonusers. For forearm fractures it was 1.01, for hip fractures it was 0.59 and for vertebral fractures it was 1.15, the researchers report.

There was no reduction in fracture risk among patients using higher statin dosages. For a dose of less than 20 mg/day the adjusted odds ratio for fracture was 1.13 relative to nonuse, for doses of 20 to 39.9 mg/day it was 1.07, and for doses of 40 mg/day or more it was 0.85.

Neither was long-term statin use protective. Statin use for 3 months or less was associated with an adjusted odds ratio for fracture of 0.71, whereas for those who used statins for 3 to 6 months it was 1.31. For those using statins for 6 to 12 months, the adjusted odds ratio was 1.14 and for those using statins for more than 12 months, it was 1.17.

"Our results do not support those of earlier epidemiological reports that suggest that statins may prevent fracture," Dr. Cooper and colleagues conclude.

In an editorial, Dr. Sean Hennessy, from the Agency for Healthcare Research and Quality, Rockville, Maryland, and Dr. Brian L. Strom, from the University of Pennsylvania in Philadelphia, comment that until data from randomized trials are more convincing, "the evidence supports the conclusion of the editorialists who commented on the first such article in this journal: 'In the meantime, patients with osteoporosis should be treated with agents that have been proven to reduce the risk of fractures.' "

JAMA 2001;285:1850-1855,1888-1889.