dinoiii
March 10th, 2005, 07:15 AM
In regards to Ambien....its side effect reporting is what steers me away from its overprescribing to my patients.
Associated With Discontinuation Of Treatment
Approximately 4% of 1,701 patients who received zolpidem at all doses (1.25 to 90 mg) in U.S. pre-marketing clinical trial discontinued treatment because of an adverse clinical event. Events most commonly associated with discontinuation from U.S. trials were daytime drowsiness (0.5%), dizziness (0.4%), headache (0.5%), nausea (0.6%), and vomiting (0.5%).
Approximately 6% of 1320 patients who received zolpidem at all doses (5 to 50 mg) in similar foreign trials discontinued treatment because of an adverse event. Events most commonly associated with discontinuation from these trials were daytime drowsiness (1.6%), amnesia (0.6%), dizziness (0.6%), headache (0.6%), nausea (0.6%).
Data from a clinical study in which selective serotonin reuptake inhibitor- (SSRI) treated patients were given zolpidem revealed that four of the seven discontinuations during double-blind treatment with zolpidem (n=95) were associated with impaired concentration, continuing or aggravated depression, and manic reaction; one patient treated with placebo (n=97) was discontinued after an attempted suicide.
Incidence In Controlled Clinical Trials
Most Commonly Observed Adverse Events in Controlled Trials: During short-term treatment (up to 10 nights) with zolpidem tartrate at doses up to 10 mg, the most commonly observed adverse events associated with the use of zolpidem and seen at statistically significant differences from placebo-treated patients were drowsiness (reported by 2% of zolpidem patients), dizziness (1%), and diarrhea(1%). During longer- term treatment (28 to 35 nights) with zolpidem at doses up to 10 mg, the most commonly observed adverse events associated with the use of zolpidem and seen at statistically significant differences from placebo-treated patients were dizziness (5%) and drugged feelings (3%).
Adverse Events Observed at an Incidence of ³1% in Controlled Trials: TABLE 1 and TABLE 2 enumerate treatment-emergent adverse event frequencies that were observed at an incidence equal to 1% or greater among patients with insomnia who received zolpidem tartrate in U.S. placebo-controlled trials. Events reported by investigators were classified utilizing a modified World Health Organization (WHO) dictionary of preferred terms for the purpose of establishing event frequencies. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice, in which patient characteristics and other factors differ from those that prevailed in these clinical trials. Similarly, the cited frequencies cannot be compared with figure obtained from other clinical investigators involving related drug products and uses, since each group of drug trials is conducted under a different set of conditions. However, the cited figures provide the physician with a basis for estimating the relative contribution of drug and nondrug factors to the incidence of side effects in the population studied.
Dose Relationship For Adverse Events: There is evidence from dose comparison trials suggesting a dose relationship for many of the adverse events associated with zolpidem use, particularly for certain CNS and gastrointestinal adverse events.
Adverse event incidence across the entire preapproval database: Ambien (zolpidem tartrate) was administered to 3,660 subjects in clinical trials throughout the U.S., Canada, and Europe. Treatment-emergent adverse events associated with clinical trial participation were recorded by clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals experiencing treatment-emergent adverse events, similar types of untoward events were grouped into a smaller number of standardized event categories and classified utilizing a modified World Health Organization (WHO) dictionary of preferred terms. The frequencies presented, therefore, represent the proportions of the 3,660 individuals exposed to zolpidem, at all doses, who experienced an event of the type cited on at least one occasion while receiving zolpidem. All reported treatment-emergent adverse events are included, except those already listed in the table above of adverse events in placebo-controlled studies, those coding terms that are so general as to be uninformative, and those events where a drug cause was remote. It is important to emphasize that, although the events reported did occur during treatment with Ambien, they were not necessarily caused by it.
Adverse events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in greater than 1/100 subjects; infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; rare events are those occurring in less than 1/1,000 patients.
Autonomic nervous system: Infrequent: increased sweating, pallor, postural hypotension, syncope. Rare: abnormal accommodation, altered saliva, flushing, glaucoma, hypotension, impotence, increased saliva, tenesmus.
Body as a whole: Frequent: asthenia. Infrequent: edema, falling, fever, malaise, trauma. Rare: allergic reaction, allergy aggravated, abdominal body sensation, anaphylactic shock, face edema, hot flashes, increased ESR, pain, restless legs, rigors, tolerance increased, weight decrease.
Cardiovascular system: Infrequent: cerebrovascular disorder, hypertension, tachycardia. Rare: angina pectoris, arrhythmia, arteritis, circulatory failure, extrasystoles, hypertension aggravated, myocardial infarction, phlebitis, pulmonary embolism, pulmonary edema, varicose veins, ventricular tachycardia.
Central and peripheral nervous system: Frequent: ataxia, confusion, euphoria, insomnia, vertigo. Infrequent: agitation, decreased cognition, detached, difficulty concentrating, dysarthria, emotional lability, hallucination, hypoesthesia, illusion, leg cramps, migraine, paresthesia, sleeping (after daytime dosing), speech disorder, stupor, tremor. Rare: abnormal gait, abnormal thinking, aggressive reaction, apathy, appetite increased, decreased libido, delusion, dementia, depersonalization, dysphasia, feeling strange, hypokinesia, hypotonia, hysteria, intoxicated feeling, manic reaction, neuralgia, neuritis, neuropathy, neurosis, panic attacks, paresis, personality disorder, somnambulism, suicide attempts, tetany, yawning.
Gastrointestinal system: Frequent: hiccup. Infrequent: constipation, dysphagia, flatulence, gastroenteritis. Rare: enteritis, eructation, esophagospasm, gastritis, hemorrhoids, intestinal obstruction, rectal hemorrhage, tooth caries.
Hematologic and lymphatic system: Rare: anemia, hyperhemoglobinemia, leukopenia, lymphadenopathy, macrocytic anemia, purpura, thrombosis.
Immunologic system: Rare: abscess, herpes simplex, herpes zoster, otitis externa, otitis media.
Liver and biliary system: Infrequent: abnormal hepatic function, increased SGPT. Rare: bilirubinemia, increased SGOT.
Metabolic and nutritional: Infrequent: hyperglycemia, thirst. Rare: gout, hypercholesteremia, hyperlipidemia, increased alkaline phosphatase, increased BUN, periorbital edema.
Musculoskeletal system: Infrequent: arthritis. Rare: arthrosis, muscle weakness, sciatica, tendinitis.
Reproductive system: Infrequent: menstrual disorder, vaginitis. Rare: breast fibroadenosis, breast neoplasm, breast pain.
Respiratory system: Infrequent: bronchitis, coughing, dyspnea. Rare: bronchospasm, epistaxis, hypoxia, laryngitis, pneumonia.
Skin and appendages: Infrequent: pruritus. Rare: acne, bullous eruption, dermatitis, furunculosis, injection-site inflammation, photosensitivity reaction, urticaria.
Special senses: Frequent: diplopia, vision abnormal. Infrequent: eye irritation, eye pain, scleritis, taste perversion, tinnitus. Rare: conjunctivitis, corneal ulceration, lacrimation abnormal, parosmia, photopsia.
Urogenital system: Infrequent: cystitis, urinary incontinence. Rare: acute renal failure, dysuria, micturition frequency, nocturia, polyuria, pyelonephritis, renal pain, urinary retention.
DRUG ABUSE AND DEPENDENCE
Controlled Substance: Zolpidem tartrate is classified as a Schedule IV controlled substance by federal regulation.
Studies of abuse potential in former drug abusers found that the effects of single doses of zolpidem tartrate 40 mg were similar, but not identical, to diazepam 20 mg, while zolpidem tartrate 10 mg was difficult to distinguish from placebo.
Sedative/hypnotics have produced withdrawal signs and symptoms following abrupt discontinuation. These reported symptoms range from mild dysphoria and insomnia to a withdrawal syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremors, and convulsions. The U.S. clinical trial experience from zolpidem does not reveal any clear evidence for withdrawal syndrome. Nevertheless, the following adverse events included in DSM-III-R criteria for uncomplicated sedative/hypnotic withdrawal were reported during U.S. clinical trials following placebo substitution occurring within 48 hours following last zolpidem treatment: fatigue, nausea, flushing, lightheadedness, uncontrolled crying, emesis, stomach cramps, panic attack, nervousness, and abdominal discomfort. These reported adverse events occurred at an incidence of 1% or less. However, available data cannot provide a reliable estimate of the incidence, if any, of dependency, or the relationship of any dependency to dose and duration of treatment.
Because individuals with a history of addiction to, or abuse of, drugs or alcohol are at risk of habituation and dependence, they should be under careful supervision when receiving zolpidem or any other hypnotic.
DRUG INTERACTIONS
CNS-Active Drugs
Zolpidem tartrate was evaluated in healthy volunteers in single-dose interaction studies for several CNS drugs. A study involving haloperidol and zolpidem revealed no effect of haloperidol on the pharmacokinetics or pharmacodynamics of zolpidem. Imipramine in combination with zolpidem produced no pharmacokinetic interaction other a 20% decrease in peak levels of imipramine, but there was an additive effect of decreased alertness. Similarly, chlorpromazine in combination with zolpidem produced no pharmacokinetic interaction, but there was an additive effect of decreased alertness and psychomotor performance. The lack of a drug interaction following single-dose administration does not predict a lack following chronic administration.
An additive effect on psychomotor performance between alcohol and zolpidem was demonstrated.
A single-dose interaction study with zolpidem 10 mg and fluoxetine 20 mg at steady-state levels in male volunteers did not demonstrate any clinically significant pharmacokinetic or pharmacodynamic interactions. When multiple doses of zolpidem and fluoxetine at steady-state concentrations were evaluated in healthy females, the only significant change was a 17% increase in the zolpidem half-life. There was no evidence of an additive effect in psychomotor performance.
Following five consecutive nightly doses of zolpidem 10 mg in the presence of sertraline 50 mg (17 consecutive daily doses, at 7:00 am, in healthy female volunteers), zolpidem C max was significantly higher (43%) and T max was significantly decreased (53%). Pharmacokinetics of sertraline and N-desmethylsertraline were unaffected by zolpidem.
Since the systemic evaluation of zolpidem tartrate in combination with other CNS-active drugs have been limited, careful consideration should be given to the pharmacology of any CNS-active drug to be used with zolpidem. Any drug with CNS-depressant effects could potentially enhance the CNS- depressant effects of zolpidem.
Drugs that affect drug metabolism via cytochrome P450: A randomized, double-blind, crossover interaction study in ten healthy volunteers between itraconazole (200 mg once daily for 4 days) and a single dose of zolpidem (10 mg) given 5 hours after the last dose of itraconazole resulted in a 34% increase in AUC0->∞ of zolpidem. There were no significant pharmacodynamic effects of zolpidem on subjective drowsiness, postural sway, or psychomotor performance.
A randomized, placebo-controlled, crossover interaction study in eight healthy female volunteers between 5 consecutive daily doses of rifampin (600 mg) and a single dose of zolpidem (20 mg) given 17 hours after the last dose of rifampin showed significant reductions of the AUC (–73%), Cmax (–58%), and T1/2 (–36%) of zolpidem together with significant reductions in the pharmacodynamic effects of zolpidem.
Other Drugs
A study involving cimetidine/zolpidem and ranitidine/zolpidem combinations revealed no effect of either drug on the pharmacokinetics or pharmacodynamics of zolpidem. Zolpidem had no effect on digoxin kinetics and did not effect prothrombin time when given with warfarin in normal subjects. Zolpidem's sedative/hypnotic effect was reversed by flumazenil; however, no significant alterations in zolpidem pharmacokinetics were found.
pbk
March 10th, 2005, 02:36 PM
Hi Dinoiii, and everyone else. For the most part I certainly agree with everything you said about LR and Knockout. I guess we agree to disagree on the taste and cost. Your description of the taste of LR actually had me laughing....kind of funny as I tried to imagine you "swilling" your "shot" down, as I happily downed a whole cup and then smacked my lips in satisfaction. (Imaginary scene, of course, of you and me together. Boy, I bet I would go to sleep quickly and sleep like a baby if I drank that much.)
As I said, amazing how we all have different tastes. I am not sure of what pure lab alcohol would taste like? I would think that it would really burn when going down. Anyway, I do not care for the taste of alcohol....I don't drink alcoholic beverages...don't even like wine....most of it taste like Listerine to me....yech. Well, to be fair, I do kind of like the taste of an ice cold lager, but to me there is not much alcohol taste there....but I don't drink it either. (Not to worry boys...I DID get my fair share of it in my more youthful days.) But LR does not remind me of alcohol at all, but more like a tangy, fruity drink.
I too agree that I would not want to use melatonin on any regular basis. I seldom use the Knockout, a bottle will last me a year or more. Too bad they don't make a version without the melatonin. On the other hand, I think I could handle the LR everyday, but probably would not want to do this either, in case I might would get too dependent on it.
Last night I finished off my last two capfuls...had not used any for a couple of weeks....felt really relaxed when I went to bed, but still did not go to sleep right away. Well actually, I think that I did, but was so relaxed that upon the "fall" into sleep, I snorted or snored loudly, and woke myself back up. Then my wife started snoring and, well, you know how it goes. Laid there awhile, but I was relaxed.
Sounds like LR is just "what the doctor ordered" for you Dinoiii. Helping you to rest after those long stressful days, or nights. I tell you, I do not know how you guys (medical students, interns and hospital doctors) do it. Hey, you work hard for your $ and deserve a little Liquid Relaxation now and then. All the long hours and stress, and lots of nights of just a couple hours of sleep.
Actually, I did go through a similar schedule and stress for about 6 years up until a year ago. It was during that time that I was introduced to Ambien by my doctor. I commuted 4 hours a day through stressful traffic, and worked 8 to 12 hours in a very stressful environment in computer technology support. I suffered more heath setbacks and aging in 6 years than anytime in my life.
Thanks Dinoiii for the info on Ambien. Wow! That was a lot of stuff to read. It kind of made my head spin...couldn't take it all in, but I focused on certain things of interest. Anyway, I do NOT particularly like taking any prescriptive drugs. I try to avoid them like the plague. BTW, mine are only 5 mg and I use them VERY sparingly. I don't want to say more here, as this thread is really about the LR. I am sending you an email.
vBulletin v3.6.2, Copyright ©2000-2009, Jelsoft Enterprises Ltd.