But hear me out, this report is pretty comprehensive. It was like I needed it every waking minute just to function. The high was satisfying. Along with this stage, is the inability to think as clearly and typing a neatly as I usually do. The most common veterinary use is probably the pro re nata treatment of panic disorder in dogs. After a brief lapse back into consciousness while the EMTs flushed the drugs out of my blood in the back of the ambulance, I woke up 12 hours later in the hospital. Although I cannot remember exact dates and times of my experiences, I do believe I have an informative experience with spice overall.
Difficult Experiences Bad Trips. Catnip - Nepeta cataria. Catuaba - Erythroxylum catuaba. Chamomile - Anthemis nobilis, Matricaria recutita. Chlorpheniramine Maleate - CPM. Glowing Experiences Families Medical Use. Chocolate - see also Cacao. Citicoline - CDP-Choline; cytidine 5-diphosphocholine. Clobazam - Klobazam; Urbanol; Frisium.
Clonazolam - see also Pharms - Clonazepam. Cloves - Syzygium aromaticum; Eugenia caryophyllus; E. Coca - Erythroxylum coca, see also Cocaine. Cocaine - see also Coca. Codeine - Tylenol 3. Coleus - Coleus blumei. Cytisus scoparius - Scotch Broom. Damiana - Turnera diffusa. Desmanthus illinoensis - Bundle Flower. Mystical Experiences Medical Use.
Diclazepam - Ro; Chlorodiazepam; 2'-chloro-diazepam, see also Pharms - Diazepam , Benzodiazepines. Dimenhydrinate - Dramamine; Motion Sickness Pills. Dimethocaine - DMC; larocaine. Diphenidine - 1- 1,2-diphenylethyl piperidine, see also Methoxphenidine. Diplopterys cabrerana - Chaliponga. DXM - dextromethorphan; Robitussin; Drixoral. Entada rheedii - African Dream Herb. Ephedra sinica - Ma Huang, see also Ephedrine. Ephenidine - N-Ethyl-1,2diphenylethylamine, see also Diphenidine , Methoxphenidine.
Escaline - 3,5-Dimethoxyethoxy-phenethylamine, see also Mescaline. Etaqualone - Aolan; Athinazone; Ethinazone, see also Methaqualone. Ether - see also Inhalants , Petroleum Ether. Ethylphenidate - see also Pharms - Methylphenidate. Etizolam - Etilaam; Sedekopan; Pasaden; Depas. Flunitrazolam - see also Pharms - Flunitrazepam. Fluorophenibut - F-Phenibut; 4-amino 4-fluorophenyl butanoic acid.
Frankincense - Boswellia spp. Furanylfentanyl - Fu-F, see also Pharms - Fentanyl. GABA - gamma-amino-butyric acid. Galantamine - Nivalin; Razadyne; Lycoremine; Galantamind. Garlic - Allium sativum. Health Benefits Families Medical Use. Glaucine - Yellow Horned Poppy; Glaucium flavum. Gotu Kola - Centella asiatica. Halothane - 2-bromochloro-1,1,1-trifluoro-ethane, see also Inhalants. Harmala Alkaloids - Harmine; Harmaline; Haoma. Heimia myrtifolia - Sinicuichi, see also Heimia salicifolia.
Heimia salicifolia - Sinicuichi. Heroin - Smack; Horse. Hops - Humulus lupulus. Huasca Group - Do Not Use. Huperzine - Huperzine A. Hydrocodone - Vicodin; Norco. Hydroxyzine - Atarax; Vistaril. Hyoscyamus niger - Henbane. Ibogaine - see also Tabernanthe iboga. Idebenone - Catena; Sovrima. Ilex guayusa - Guayusa. Ilex vomitoria - Yaupon. Indian Warrior - Pedicularis densiflora.
Kava - Kawa; Awa; Piper methisticum. Ketamine - Ketalar; Ketaset, see also Methoxetamine , Ketamine. Kratom - Mitragyna speciosa. Lady's Slipper - Cypripedium spp. Lagochilus inebrians - Intoxicating Mint; Turkistan Mint. Lemon Balm - Melissa officinalis. Leonotis leonurus - Lion's Tail; Wild Dagga. Leonotis nepetaefolia - Lion's Ear; cordon de fraile, see also Leonotis leonurus. Leonurus cardiaca - Motherwort.
Leonurus sibiricus - Marihuanilla, see also Leonotis leonurus. Levmetamfetamine - L-desoxyephedrine; Methamphetamine, see also Methamphetamine. Licorice Root - Glycyrrhiza glabra. Lorcaserin - Belviq; Lorquess. Mandrake - Atropa mandragora. Mystical Experiences What Was in That? Mansoa alliacea - Ajos Sacha; Garlic Vine. Bad Trips Health Problems. Mescaline - see also Cacti - columnar. Methallylescaline - MAL; 4-methallyloxy-3,5-dimethoxyphenethylamine. Methcathinone - see also Cathinone.
Methiopropamine - MPA; N-methyl thiophenyl propanamine. Glowing Experiences Health Benefits Families. Methocarbamol - Robaxin; Robaxacet. Methylmethaqualone - MMQ, see also Methaqualone. Metoprolol - Lopressor; Toprol. Milk Thistle - Silybum marianum. Modafinil - Provigil, see also Armodafinil , Adrafinil. Woodrose , Turbina corymbosa.
Morphine - see also Heroin , Opiates , Opium. MT - 1-cyclohexyl 1,2-diphenylethyl piperazine. Mucuna pruriens - Velvetbeans; Cowhage. Mugwort - Artemisia vulgaris. Mullein - Verbascum thapsus. Myrrh - Commiphora myrrha. Naloxone - Narcan; Suboxone, see also Naltrexone. Naproxen - Alieve; Anaprox. Napthylpyrovalerone - NRG-1; Naphyrone.
Nimetazepam - Erimin; Hypnon. Nootka Lupine - Lupinus nootkatensis. Nutmeg - Myristica fragrans. Opioids - see also Oxycodone , Heroin. Opium - see also Poppies - Opium. Oxycodone - Oxycontin; Percodan; Percocet; Roxicodone. Passion Flower - Passiflora. PCP - angel dust; phencyclidine. Pennyroyal - Mentha pulegium; squawmint tickweed.
Pentedrone - 2- methylamino phenylpentanone; alpha-methylamino-valerophenone. Periwinkle - Vinca minor; Catharanthus rosea. Petroleum Ether - Naptha, see also Inhalants , Ether. Peyote - Lophophora williamsii, see also Cacti - columnar , Mescaline. Glowing Experiences Mystical Experiences Families. Pharms - Albuterol - Albuterol Inhaler. Pharms - Alprazolam - Xanax; Niravam. Pharms - Amitriptyline - Elavil; Tryptizol.
Pharms - Aripiprazole - Abilify. Pharms - Atenolol - Tenormin; benzeneacetamide, see also Pharms - Propranolol. Pharms - Atomoxetine - Strattera. Pharms - Baclofen - Kemstro; Lioresal. Pharms - Benzphetamine - Didrex; Inapetyl. Pharms - Bupropion - Wellbutrin; Zyban. Pharms - Buspirone - BuSpar. Pharms - Butorphanol - Stadol. Pharms - Carbamazepine - Tegretol. Pharms - Carisoprodol - Soma. Pharms - Chlordiazepoxide - Librium.
Pharms - Chlorpromazine - Thorazine. Pharms - Clonidine - Catapres; Dixarit; Haemiton. Pharms - Corticosteroid - Corticosteroids, see also Anabolic Steroids. Pharms - Cyclizine - Marezine, see also Dimenhydrinate. Pharms - Cyclobenzaprine - Flexeril. Pharms - Diazepam - Valium. Pharms - Dihydrocodeine - Panlor, see also Opiates. Pharms - Doxepin - Adapin; Sinequan.
Pharms - Doxycycline - Vibramycin, Monodox, Periostat. Pharms - Doxylamine - Unisom. Pharms - Escitalopram - Lexapro. Pharms - Ethchlorvynol - Placidyl. Pharms - Ethylmorphine - Codethyline; Dionine, see also Morphine. Pharms - Fenfluramine - Pondimin. Pharms - Flunitrazepam - Rohypnol. Pharms - Fluoxetine - Prozac. Pharms - Fluvoxamine - Luvox. Pharms - Haloperidol - Haldol. Pharms - Hydroxyzine - Atarax. Pharms - Ibuprofen - Advil.
Pharms - Lamotrigine - Lamictal. Central benzodiazepine receptors interact allosterically with GABA receptors, potentiating the effects of GABA and increasing the inhibition of the ascending reticular activating system. Benzodiazepines block the cortical and limbic arousal that occurs following stimulation of the reticular pathways. GABA is the most widely distributed inhibitory neurotransmitter in the central nervous system. The influx of Cl ions causes hyperpolarization of the neuron, subsequently inhibiting neuronal discharge.
GABA A is made up from 5 subunits out of a possible 19, and GABA A receptors made up of different combinations of subunits have different properties, different locations within the brain and importantly, different activities in regards to pharmacological and clinical effects. Benzodiazepines bind only to alpha subunits which contain a histidine amino acid residue i. For this reason benzodiazepines show no affinity for a 4 and a 6 subunits containing GABA A receptors, which contain an arginine instead of a histidine residue.
Other sites on the GABA A receptor also bind barbiturates, ethanol, furosemide, kavalactones, neurosteroids, picrotoxin and certain anesthetics. In order for GABA A receptors to be sensitive to the action of benzodiazepines they need to contain an a and a g subunit, where the benzodiazepine binds. Once bound, the benzodiazepine locks the GABA A receptor into a conformation where the neurotransmitter GABA has much higher affinity for the GABA A receptor, increasing the frequency of opening of the associated chloride ion channel and hyperpolarizing the neuron.
This potentiates the inhibitory effect of the available GABA leading to sedative and anxiolytic effects. As mentioned above, different benzodiazepines can have different affinities for GABA A receptors made up of different collection of subunits. Stimulation of peripheral nervous system PNS GABA receptors may cause decreased cardiac contractility, vasodilation and enhanced perfusion.
The action of hyperpolarization is reversed by the influx of calcium into the cell. The long-term pharmacodynamics interaction of benzodiazepines with GABA receptors is thought to be extremely complex. Long-term use of benzodiazepines is thought to result in down-regulation of inhibitory GABA receptors and configurational changes of the receptor-agonist complex, resulting in diminished agonist sensitivity. These changes are potential mechanisms of tolerance, dependence and withdrawal.
The abrupt cessation of benzodiazepines, as in the case of a patient discontinuing a benzodiazepine after long-term use, is thought to result in the classically described acute withdrawal symptoms as the inhibitory pressure is removed, leaving a relative excitatory state. The peak plasma concentration is reached about 1. When taken with water, mean T max occurs about 15 minutes earlier than when taken without water with no change in C max or AUC.
Plasma levels are proportional to the dose given; over the dose range of 0. Using a specific assay methodology, the mean plasma elimination half-life of alprazolam has been found to be approximately The bioavailability and pharmacokinetics of alprazolam following administration of alprazolam XR tablets are similar to that for alprazolam tablets, with the exception of a slower rate of absorption.
The slower absorption rate results in a relatively constant concentration that is maintained between 5 and 11 hours after the dosing. The pharmacokinetics of alprazolam and two of its major active metabolites 4-hydroxyalprazolam and a -hydroxyalprazolam are linear, and concentrations are proportional up to the recommended maximum daily dose of 10 mg given once daily.
Multiple dose studies indicate that the metabolism and elimination of alprazolam are similar for the immediate-release and the extended-release products. Food has a significant influence on the bioavailability of alprazolam XR tablets. Serum albumin accounts for the majority of the binding. Metabolism Alprazolam is extensively metabolized in humans, primarily by cytochrome P 3A4 CYP3A4 , to two major metabolites in the plasma: A benzophenone derived from alprazolam is also found in humans.
Their half-lives appear to be similar to that of alprazolam. The pharmacokinetic parameters at steady-state for the two hydroxylated metabolites of alprazolam 4-hydroxyalprazolam and a -hydroxyalprazolam were similar for alprazolam and alprazolam XR tablets, indicating that the metabolism of alprazolam is not affected by absorption rate. The reported relative potencies in benzodiazepine receptor binding experiments and in animal models of induced seizure inhibition are 0.
Such low concentrations and the lesser potencies of 4-hydroxyalprazolam and a -hydroxyalprazolam suggest that they are unlikely to contribute much to the pharmacological effects of alprazolam. The benzophenone metabolite is essentially inactive. Elimination Alprazolam and its metabolites are excreted primarily in the urine as glucuronides. Some of the drug is also excreted in unchanged form.
Special populations Changes in the absorption, distribution, metabolism and excretion of benzodiazepines have been reported in a variety of disease states including alcoholism, impaired hepatic function and impaired renal function. Changes have also been demonstrated in geriatric patients. A mean half-life of alprazolam of The co-administration of oral contraceptives to healthy women increased the half-life of alprazolam as compared to that in healthy control women mean: There was a prolongation in the mean half-life of alprazolam from In patients with alcoholic liver disease the half-life of alprazolam ranged between 5.
In an obese group of subjects the half-life of alprazolam ranged between 9. Because of its similarity to other benzodiazepines, it is assumed that alprazolam undergoes transplacental passage and that it is excreted in human milk. Gender - Gender has no effect on the pharmacokinetics of alprazolam. Most of the interactions that have been documented with alprazolam are with drugs that inhibit or induce CYP3A4.
Compounds that are potent inhibitors of CYP3A would be expected to increase plasma alprazolam concentrations. Drug products that have been studied in vivo , along with their effect on increasing alprazolam AUC, are as follows: CYP3A inducers would be expected to decrease alprazolam concentrations and this has been observed in vivo. The oral clearance of alprazolam given in a 0.
The ability of alprazolam to induce human hepatic enzyme systems has not yet been determined. However, this is not a property of benzodiazepines in general. Further, alprazolam did not affect the prothrombin or plasma warfarin levels in male volunteers administered sodium warfarin orally. Alprazolam was significantly better than placebo at each of the evaluation periods of these four week studies as judged by the following psychometric instruments: In two of the three studies, alprazolam was superior to placebo on a variable defined as "change from baseline on the number of panic attacks per week" range, 3.
A subgroup of patients who were improved on alprazolam during short-term treatment in one of these trials was continued on an open basis up to 8 months, without apparent loss of benefit. The effectiveness of alprazolam XR was assessed on the basis of changes in various measures of panic attack frequency, on various measures of the Clinical Global Impression and on the Overall Phobia Scale.
In all, there were seven primary efficacy measures in these studies, and alprazolam XR was superior to placebo on all seven outcomes in both studies. The mean dose of alprazolam XR at the last treatment visit was 4. The longer-term efficacy of alprazolam XR in panic disorder has not been systematically evaluated. Analyses of the relationship between treatment outcome and gender did not suggest any differential responsiveness on the basis of gender.
These lesions did not appear until after 11 months of treatment. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. Generalized anxiety disorder is characterized by unrealistic or excessive anxiety and worry apprehensive expectation about two or more life circumstances, for a period of six months or longer, during which the person has been bothered more days than not by these concerns.
At least 6 of the following 18 symptoms are often present in these patients: Trembling, twitching or feeling shaky; muscle tension, aches or soreness; restlessness; easy fatigability. Shortness of breath or smothering sensations; palpitations or accelerated heart rate; sweating or cold clammy hands; dry mouth; dizziness or lightheadedness; nausea, diarrhea or other abdominal distress; flushes or chills; frequent urination; trouble swallowing. Feeling keyed up or on edge; exaggerated startle response; difficulty concentrating or 'mind going blank' because of anxiety; trouble falling or staying asleep; irritability.
These symptoms must not be secondary to another psychiatric disorder or caused by some organic factor. Anxiety associated with depression is responsive to alprazolam. Panic Disorder Alprazolam is also indicated for the treatment of panic disorder, with or without agoraphobia. Demonstrations of the effectiveness of alprazolam by systematic clinical study are limited to four months duration for anxiety disorder and four to ten weeks duration for panic disorder; however, patients with panic disorder have been treated on an open basis for up to eight months without apparent loss of benefit.
Periodically reassess the usefulness of the drug for the individual patient. Alprazolam may be used in patients with open angle glaucoma who are receiving appropriate therapy, but is contraindicated in patients with acute narrow angle glaucoma. Alprazolam is contraindicated with ketaconazole and itraconzole, since these medications significantly impair the oxidative metabolism mediated by cytochrome P 3A CYP3A.
Alprazolam should be used with extreme caution in patients with respiratory depression, pulmonary disease such as severe COPD chronic obstructive pulmonary disease or sleep apnea because the drug can exacerbate ventilatory failure. Alprazolam should be used with extreme caution in patients with myasthenia gravis because the drug can exacerbate this condition. Patients with late stage Parkinson's disease may experience worsening of their psychosis or impaired cognition with administration of benzodiazepines.
Benzodiazepines may also cause incoordination or paradoxical reactions that may worsen symptoms of Parkinson's disease. The administration of alprazolam can exacerbate acute intermittent porphyria, so the drug should be used with caution in patients with this condition. Alprazolam is occasionally beneficial for patients with major depression, psychosis or suicidal ideation. The drug should be administered to these patients with careful monitoring. Alprazolam is classified as pregnancy category D because it could harm the fetus when administered to pregnant women.
Positive evidence of human fetal risk exists based on investigational, marketing or human studies, but the potential benefit to the mother may outweigh the potential risks to the fetus. Many benzodiazepines distribute into breast milk. Because of the potential for adverse effects in the nursing infant, such as sedation, feeding difficulties and weight loss, alprazolam generally is not recommended during breast-feeding.
Alprazolam should be administered cautiously to patients with severe hepatic disease because the elimination half-life of the drug can be prolonged, possibly resulting in toxicity. Patients with hepatic disease are more likely to experience adverse CNS reactions and should receive reduced initial dosages. Concomittant administration of alprazolam and potent inhibitors of CYP3A4 such as ketoconazole and itraconazole are contraindicated.
Concurrent administration of alprazolam and drugs that inhibit cytochrome P 3A CYP3A should be approached with caution. Patients with renal impairment should be carefully monitored during prolonged treatment with benzodiazepines to avoid the adverse reactions that may occur from drug accumulation. Delayed elimination can either intensify or prolong the actions of adverse reactions of the drug.
Benzodiazepines have been associated with falls in the elderly. The impairment of cognitive and motor function may be more marked in this patient group and lower initial dosage is recommended together with close monitoring. These include a spectrum of withdrawal symptoms; the most important is seizure. Even after relatively short-term use at the doses recommended for the treatment of transient anxiety and anxiety disorder i.
However, in a controlled postmarketing discontinuation study of panic disorder patients, the duration of treatment 3 months compared to 6 months had no effect on the ability of patients to taper to zero dose. The Importance Of Dose And The Risks Of Alprazolam As A Treatment For Panic Disorder Because the management of panic disorder often requires the use of average daily doses of alprazolam above 4 mg, the risk of dependence among panic disorder patients may be higher than that among those treated for less severe anxiety.
Experience in randomized placebo-controlled discontinuation studies of patients with panic disorder showed a high rate of rebound and withdrawal symptoms in patients treated with alprazolam compared to placebo treated patients. Relapse or return of illness was defined as a return of symptoms characteristic of panic disorder primarily panic attacks to levels approximately equal to those seen at baseline before active treatment was initiated. Rebound refers to a return of symptoms of panic disorder to a level substantially greater in frequency or more severe in intensity than seen at baseline.
Withdrawal symptoms were identified as those which baseline. Withdrawal symptoms were identified as those which were generally not characteristic of panic disorder and which occurred for the first time more frequently during discontinuation than at baseline. The rate of relapse, rebound and withdrawal in patients with panic disorder who received alprazolam tablets has not been systematically studied. Experience in randomized placebo-controlled discontinuation studies of patients with panic disorder who received alprazolam tablets showed a high rate of rebound and withdrawal symptoms compared to placebo treated patients.
In a controlled clinical trial in which 63 patients were randomized to alprazolam and where withdrawal symptoms were specifically sought, the following were identified as symptoms of withdrawal: Other symptoms, such as anxiety and insomnia, were frequently seen during discontinuation, but it could not be determined if they were due to return of illness, rebound or withdrawal. The ability of patients to completely discontinue therapy with alprazolam after long-term therapy has not been reliably determined.
However, in a controlled post marketing discontinuation study of panic disorder patients, the duration of treatment three months compared to six months had no effect on the ability to taper to zero dose. Seizures were reported for three patients in panic disorder clinical trials with alprazolam XR. In one case, the patient abruptly discontinued alprazolam XR, and in both cases, alcohol intake was implicated. All three patients recovered without sequelae.
Seizures have also been observed in association with dose reduction or discontinuation of alprazolam tablets, the immediate-release form of alprazolam. Five of these cases clearly occurred during abrupt dose reduction or discontinuation from daily doses of 2 to 10 mg. Three cases occurred in situations where there was not a clear relationship to abrupt dose reduction or discontinuation. In one instance, seizure occurred after discontinuation from a single dose of 1 mg after tapering at a rate of 1 mg every three days from 6 mg daily.
In two other instances, the relationship to taper is indeterminate; in both of these cases the patients had been receiving doses of 3 mg daily prior to seizure. The duration of use in the above 8 cases ranged from 4 to 22 weeks. There have been occasional voluntary reports of patients developing seizures while apparently tapering gradually from alprazolam. The risk of seizure seems to be greatest hours after discontinuation. Status Epilepticus The medical event voluntary reporting system shows that withdrawal seizures have been reported in association with the discontinuation of alprazolam.
In most cases, only a single seizure was reported; however, multiple seizures and status epilepticus were reported as well. Ordinarily, the treatment of status epilepticus of any etiology involves use of intravenous benzodiazepines plus phenytoin or barbiturates, maintenance of a patent airway and adequate hydration. For additional details regarding therapy, consultation with an appropriate specialist may be considered.
Interdose Symptoms Early morning anxiety and emergence of anxiety symptoms between doses of alprazolam have been reported in patients with panic disorder taking prescribed maintenance doses of alprazolam. These symptoms may reflect the development of tolerance or a time interval between doses, which is longer than the duration of clinical action of the administered dose. In either case, it is presumed that the prescribed dose is not sufficient to maintain plasma levels above those needed to prevent relapse, rebound or withdrawal symptoms over the entire course of the interdosing interval.
In these situations, it is recommended that the same total daily dose be given divided as more frequent administrations. Risk of Dose Reduction Withdrawal reactions may occur when dosage reduction occurs for any reason. This includes purposeful tapering, but also inadvertent reduction of dose e. Therefore, the dosage of alprazolam should be reduced or discontinued gradually. CNS Depression and Impaired Performance Because of its CNS depressant effects, patients receiving alprazolam should be cautioned against engaging in hazardous occupations or activities requiring complete mental alertness such as operating machinery or driving a motor vehicle.
For the same reason, patients should be cautioned about the simultaneous ingestion of alcohol and other CNS depressant drugs during treatment with alprazolam. Risk of Fetal Harm Benzodiazepines can potentially cause fetal harm when administered to pregnant women. If alprazolam is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Because of experience with other members of the benzodiazepine class, alprazolam is assumed to be capable of causing an increased risk of congenital abnormalities when administered to a pregnant woman during the first trimester.
Because use of these drugs is rarely a matter of urgency, their use during the first trimester should almost always be avoided. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. Patients should be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their prescriber about the desirability of discontinuing the drug.
Drugs that inhibit this metabolic pathway may have a profound effect on the clearance of alprazolam. Consequently, alprazolam should be avoided in patients receiving very potent inhibitors of CYP3A. With drugs inhibiting CYP3A to a lesser but still significant degree, alprazolam should be used only with caution and consideration of appropriate dosage reduction.
Ketoconazole and itraconazole are potent CYP3A inhibitors and have been shown in vivo to increase plasma alprazolam concentrations 3. The co-administration of alprazolam with these agents is not recommended. Other azole-type antifungal agents should also be considered potent CYP3A inhibitors and the co-administration of alprazolam with them is not recommended.
Drugs demonstrated to be CYP3A inhibitors on the basis of clinical studies involving alprazolam caution and consideration of appropriate alprazolam dose reduction are recommended during co-administration with the following drugs: Co-administration of nefazodone increased alprazolam concentration twofold. Suicide As with other psychotropic medications, the usual precautions with respect to administration of the drug and size of the prescription are indicated for severely depressed patients or those in whom there is reason to expect concealed suicidal ideation or plans.
Panic disorder has been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients. Mania Episodes of hypomania and mania have been reported in association with the use of alprazolam in patients with depression. Uricosuric Effect Alprazolam has a weak uricosuric effect. Although other medications with weak uricosuric effect have been reported to cause acute renal failure, there have been no reported instances of acute renal failure attributable to therapy with alprazolam.
Use in Patients with Concomitant Illness It is recommended that the dosage be limited to the smallest effective dose to preclude the development of ataxia or oversedation, which may be a particular problem in elderly or debilitated patients. The usual precautions in treating patients with impaired renal, hepatic or pulmonary function should be observed. There have been rare reports of death in patients with severe pulmonary disease shortly after the initiation of treatment with alprazolam.
A decreased systemic alprazolam elimination rate e. Information for Patients To assure safe and effective use of alprazolam, the physician should provide the patient with the following guidance. Inform your physician about any alcohol consumption and medicine you are taking now, including medication you may buy without a prescription. Alcohol should generally not be used during treatment with benzodiazepines.
Not recommended for use in pregnancy. Therefore, inform your physician if you are pregnant, if you are planning to have a child, or if you become pregnant while you are taking this medication. Inform your physician if you are nursing. Until you experience how this medication affects you, do not drive a car or operate potentially dangerous machinery, etc.
Do not increase the dose even if you think the medication "does not work anymore" without consulting your physician. Do not stop taking this medication abruptly or decrease the dose without consulting your physician, since withdrawal symptoms can occur. Some patients may find it very difficult to discontinue treatment with alprazolam due to severe emotional and physical dependence. It is important that you seek advice from your physician to discontinue treatment in a careful and safe manner.
Proper discontinuation will help to decrease the possibility of withdrawal reactions that can range from mild reactions to severe reactions such as seizure. In all cases, it is important to have a physician's help in discontinuing this medication in a careful and safe manner to avoid overly extended use of alprazolam. These are generally minor but seizure can occur, especially if you reduce the dose too rapidly or discontinue the medication abruptly.
Seizure can be life-threatening. Laboratory Tests Laboratory tests are not ordinarily required in otherwise healthy patients. However, when treatment is protracted, periodic blood counts, urinalysis and blood chemistry analyses are advisable in keeping with good medical practice. The benzodiazepines, including alprazolam, produce additive CNS depressant effects when co-administered with other psychotropic medications, anticonvulsants, antihistaminics, ethanol and other drugs which themselves produce CNS depression.
Drugs Affecting Salivary Flow and Stomach pH Because alprazolam disintegrates in the presence of saliva and the formulation requires an acidic environment to dissolve, concomitant drugs or diseases that cause dry mouth or raise stomach pH might slow disintegration or dissolution, resulting in slowed or decreased absorption. The clinical significance of these changes is unknown. Drugs that inhibit alprazolam metabolism via cytochrome P 3A: Drugs which inhibit this metabolic pathway may have a profound effect on the clearance of alprazolam.
Drugs demonstrated to be CYP3A inhibitors of possible clinical significance on the basis of clinical studies involving alprazolam caution is recommended during co-administration with alprazolam: May increase serum digoxin levels, increasing toxicity. An interaction between digoxin with alprazolam has been reported. Digoxin toxicity has occurred in a patient receiving alprazolam and digoxin. Pending further clarification of this interaction, patients receiving alprazolam and digoxin concurrently should be monitored for increased serum digoxin levels.
Drugs and other substances demonstrated to be CYP3A inhibitors on the basis of clinical studies involving benzodiazepines metabolized similarly to alprazolam or on the basis of in vitro studies with alprazolam or other benzodiazepines caution is recommended during co-administration with alprazolam: Available data from clinical studies of benzodiazepines other than alprazolam suggest a possible drug interaction with alprazolam for the following: Data from in vitro studies of alprazolam suggest a possible drug interaction with alprazolam for the following: Data from in vitro studies of benzodiazepines other than alprazolam suggest a possible drug interaction for the following: Drugs demonstrated to be inducers of CYP3A Carbamazepine can increase alprazolam metabolism and therefore can decrease plasma levels of alprazolam.
Pregnancy Category D - Positive evidence of risk. It should be considered that the child born of a mother who is receiving benzodiazepines may be at some risk for withdrawal symptoms from the drug during the postnatal period. Also, neonatal flaccidity and respiratory problems have been reported in children born of mothers who have been receiving benzodiazepines. Labor and Delivery Alprazolam has no established use in labor or delivery. Nursing Mothers Benzodiazepines are known to be excreted in human milk.
It should be assumed that alprazolam is as well. Chronic administration of diazepam to nursing mothers has been reported to cause their infants to become lethargic and to lose weight. As a general rule, nursing should not be undertaken by mothers who must use alprazolam. Pediatric Use Safety and effectiveness of alprazolam in individuals below 18 years of age have not been established. Geriatric Use The elderly may be more sensitive to the effects of benzodiazepines.
They exhibit higher plasma alprazolam concentrations due to reduced clearance of the drug as compared with a younger population receiving the same doses. The smallest effective dose of alprazolam should be used in the elderly to preclude the development of ataxia and oversedation. In the usual patient, the most frequent side effects are likely to be an extension of the pharmacological activity of alprazolam e.
The data cited in the two tables below are estimates of untoward clinical event incidence among patients who participated under the following clinical conditions: These data cannot be used to predict precisely the incidence of untoward events in the course of usual medical practice where patient characteristics and other factors often differ from those in clinical trials. These figures cannot be compared with those obtained from other clinical studies involving related drug products and placebo as each group of drug trials are conducted under a different set of conditions.
Comparison of the cited figures, however, can provide the prescriber with some basis for estimating the relative contributions of drug and non-drug factors to the untoward event incidence in the population studied. Even this use must be approached cautiously, as a drug may relieve a symptom in one patient but induce it in others. For example, an anxiolytic drug may relieve dry mouth a symptom of anxiety in some subjects but induce it an untoward event in others.
Therefore, the same precaution must be exercised when using the higher doses of alprazolam in treating patients with panic disorders as is exercised with the use of any psychotropic drug in treating depressed patients or those in whom there is reason to expect concealed suicidal ideation or plans. Laboratory analyses were performed on patients participating in the clinical program for alprazolam. The following incidences of abnormalities shown below were observed in patients receiving alprazolam and in patients in the corresponding placebo group.
Few of these abnormalities were considered to be of physiological significance. Minor changes in EEG patterns, usually low-voltage fast activity have been observed in patients during therapy with alprazolam and are of no known significance. Adverse event reports were elicited either by general inquiry or by checklist, and were recorded by clinical investigators using terminology of their own choosing. The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed.
An event was considered treatment emergent if it occurred for the first time or worsened during therapy following baseline evaluation. In the tables and tabulations that follow, standard MedDRA terminology version 4. The most common events leading to discontinuation and considered to be drug-related i. Similarly, the cited frequencies cannot be compared with event incidence obtained from other clinical investigations involving different treatments, uses, and investigators.
The cited values, however, do provide some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied. All potentially important reported events are included except those already listed in the above table or elsewhere in labeling, those events for which a drug cause was remote, those event terms that were so general as to be uninformative, and those events that occurred at rates similar to background rates in the general population.
It is important to emphasize that, although the events reported occurred during treatment with alprazolam XR, they were not necessarily caused by the drug. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: Nevertheless, the types of adverse events reported in the clinical trials with alprazolam tablets were generally the same as those reported in the clinical trials with alprazolam XR tablets. It is suggested that the daily dosage of alprazolam be decreased by no more than 0.
Some patients may require an even slower dosage reduction. In a controlled postmarketing discontinuation study of panic disorder patients which compared this recommended taper schedule with a slower taper schedule, no difference was observed between the groups in the proportion of patients who tapered to zero dose; however, the slower schedule was associated with a reduction in symptoms associated with a withdrawal syndrome.
As with all benzodiazepines, paradoxical reactions such as stimulation, increased muscle spasticity, sleep disturbances, hallucinations and other adverse behavioral effects such as agitation, rage, irritability, and aggressive or hostile behavior have been reported rarely. Should any of the above events occur, alprazolam should be discontinued. Isolated published reports involving small numbers of patients have suggested that patients who have borderline personality disorder, a prior history of violent or aggressive behavior or alcohol or substance abuse may be at risk for such events.
Instances of irritability, hostility and intrusive thoughts have been reported during discontinuation of alprazolam in patients with posttraumatic stress disorder. Post Introduction Reports Various adverse drug reactions have been reported in association with the use of alprazolam since market introduction. The majority of these reactions were reported through the medical event voluntary reporting system. Because of the spontaneous nature of the reporting of medical events and the lack of controls, a causal relationship to the use of alprazolam cannot be readily determined.
While the usual daily dosages given below will meet the needs of most patients, there will be some who require higher doses. In such cases, dosage should be increased cautiously to avoid adverse effects. Alprazolam XR tablets may be administered once daily, preferably in the morning. The tablets should be taken intact; they should not be chewed, crushed or broken. Anxiety Disorders and Transient Symptoms of Anxiety Treatment for patients with anxiety should be initiated with a dose of 0.
The dose may be increased to achieve a maximum therapeutic effect, at intervals of 3 to 4 days, to a maximum daily dose of 4 mg, given in divided doses. The lowest possible effective dose should be employed and the need for continued treatment reassessed frequently. The risk of dependence may increase with dose and duration of treatment. Panic Disorder The successful treatment of many panic disorder patients has required the use of alprazolam at doses greater than 4 mg daily.
In controlled trials conducted to establish the efficacy of alprazolam in panic disorder, doses in the range of 1 to 10 mg daily were used. The mean dosage employed was approximately 5 to 6 mg daily. Occasional patients required as much as 10 mg a day to achieve a successful response. Dosing in Special Populations In elderly patients, in patients with advanced liver disease, or in patients with debilitating disease, the usual starting dose is 0.
This may be gradually increased if needed and tolerated. The elderly may be especially sensitive to the effects of benzodiazepines. If side effects occur at the recommended starting dose, the dose may be lowered. Dose Titration Treatment may be initiated with a dose of 0. Depending on the response, the dose may be increased at intervals of 3 to 4 days in increments of no more than 1 mg per day. Slower titration to the higher dose levels may be advisable to allow full expression of the pharmacodynamic effect of alprazolam.
To lessen the possibility of interdose symptoms, the times of administration should be distributed as evenly as possible throughout the waking hours, that is, on a three or four times per day schedule. Generally, therapy should be initiated at a low dose to minimize the risk of adverse responses in patients especially sensitive to the drug. Dose should be advanced until an acceptable therapeutic response i.
Because of the danger of withdrawal, abrupt discontinuation of treatment should be avoided. The necessary duration of treatment for panic disorder patients responding to alprazolam is unknown. Dose Reduction Because of the danger of withdrawal, abrupt discontinuation of treatment should be avoided. In all patients, dosage should be reduced gradually when discontinuing therapy or when decreasing the daily dosage.
Although there are no systematically collected data to support a specific discontinuation schedule, it is suggested that the daily dosage be decreased by no more than 0. In any case, reduction of dose must be undertaken under close supervision and must be gradual. If significant withdrawal symptoms develop, the previous dosing schedule should be reinstituted and, only after stabilisation, should a less rapid schedule of discontinuation be attempted.
It is suggested that the dose be reduced by no more than 0. Some patients may prove resistant to all discontinuation regimens. Switch from Alprazolam immediate-release Tablets to Alprazolam XR extended-release Tablets Patients who are currently being treated with divided doses of alprazolam immediate-release tablets, for example 3 to 4 times a day, may be switched to alprazolam XR tablets at the same total daily dose taken once daily.
If the therapeutic response after switching is inadequate, the dosage may be titrated as outlined above. Immediately place the alprazolam orally disintegrating tablet on top of the tongue where it will disintegrate and be swallowed with saliva. Administration with liquid is not necessary. Discard any cotton that was included in the bottle and reseal the bottle tightly to prevent introducing moisture that might cause the tablets to disintegrate. Proper Use of an Intensol An Intensol is a concentrated oral solution as compared to standard oral liquid medications.
It is recommended that an Intensol be mixed with liquid or semi-solid food such as water, juices, soda or soda-like beverages, applesauce and puddings. Use only the calibrated dropper provided with this product. Draw into the dropper the amount prescribed for a single dose. Then squeeze the dropper contents into a liquid or semi-solid food. Stir the liquid or food gently for a few seconds.
The Intensol formulation blends quickly and completely. The entire amount of the mixture, of drug and liquid or drug and food, should be consumed immediately. Do not store for future use. Death has been reported in association with overdoses of alprazolam by itself, as it has with other benzodiazepines. In addition, fatalities have been reported in patients who have overdosed with a combination of a single benzodiazepine, including alprazolam and alcohol; alcohol levels seen in some of these patients have been lower than those usually associated with alcohol-induced fatality.
Animals could be resuscitated with positive mechanical ventilation and the intravenous infusion of norepinephrine bitartrate. Animal experiments have suggested that forced diuresis or hemodialysis are probably of little value in treating overdosage. General Treatment of Overdose Overdosage reports with alprazolam tablets are limited. As in all cases of drug overdosage, respiration, pulse rate and blood pressure should be monitored. General supportive measures should be employed, along with immediate gastric lavage.
Intravenous fluids should be administered and an adequate airway maintained. If hypotension occurs, it may be combated by the use of vasopressors. Dialysis is of limited value. As with the management of intentional overdosing with any drug, it should be borne in mind that multiple agents may have been ingested. Flumazenil Mazicon , a specific benzodiazepine receptor antagonist at central GABA-ergic receptors, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected.
Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation and intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for re-sedation, respiratory depression and other residual benzodiazepine effects for an appropriate period after treatment.
The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. Flumazenil is a short-acting drug; therefore, sedation after an initial awakening may recur. If necessary, this can be treated by repeating doses at minute intervals. Although it effectively reverses the CNS effects of benzodiazepine overdose, its use in clinical practice is rarely indicated.
Use of flumazenil is specifically contraindicated when there is history of co-ingestion of tricyclic antidepressants or other drugs capable of producing seizures including aminophylline and cocaine , benzodiazepine dependence or in patients taking benzodiazepines as an anticonvulsant agent. In such situations, administration of flumazenil may precipitate seizures.
It must be used with some caution; in some cases, it has not completely reversed respiratory depression. Adverse effects associated with flumazenil include hypertension, tachycardia, anxiety, nausea, vomiting and benzodiazepine withdrawal syndrome. The complete flumazenil prescribing information should be consulted prior to use. The symptoms can range from mild dysphoria and insomnia to a major syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremors and convulsions.
Distinguishing between withdrawal emergent signs and symptoms and the recurrence of illness is often difficult in patients undergoing dose reduction. The long-term strategy for treatment of these phenomena will vary with their cause and the therapeutic goal. When necessary, immediate management of withdrawal symptoms requires re-institution of treatment at doses of alprazolam sufficient to suppress symptoms. There have been reports of failure of other benzodiazepines to fully suppress these withdrawal symptoms.
These failures have been attributed to incomplete cross-tolerance but may also reflect the use of an inadequate dosing regimen of the substituted benzodiazepine or the effects of concomitant medications. While it is difficult to distinguish withdrawal and recurrence for certain patients, the time course and the nature of the symptoms may be helpful. A withdrawal syndrome typically includes the occurrence of new symptoms, tends to appear toward the end of taper or shortly after discontinuation and will decrease with time.
In recurring panic disorder, symptoms similar to those observed before treatment may recur either early or late and they will persist. While the severity and incidence of withdrawal phenomena appear to be related to dose and duration of treatment, withdrawal symptoms, including seizures, have been reported after only brief therapy with alprazolam at doses within the recommended range for the treatment of anxiety e.
Signs and symptoms of withdrawal are often more prominent after rapid decrease of dosage or abrupt discontinuance. Patients, especially individuals with a history of seizures or epilepsy, should not be abruptly discontinued from any CNS depressant agent, including alprazolam. It is recommended that all patients on alprazolam who require a dosage reduction be gradually tapered under close supervision. Psychological dependence is a risk with all benzodiazepines, including alprazolam.
The risk of psychological dependence may also be increased at higher doses and with longer-term use and this risk is further increased in patients with a history of alcohol or drug abuse. Some patients have experienced considerable difficulty in tapering and discontinuing from alprazolam, especially those receiving higher doses for extended periods. Addiction-prone individuals should be under careful surveillance when receiving alprazolam. As with all anxiolytics, repeat prescriptions should be limited to those who are under medical supervision.
What do alprazolam tablets do? This medication has a calming effect. It is used to relieve anxiety, nervousness and tension in the treatment of anxiety disorders and panic disorder, with or without agoraphobia. Primarily for short-term relief of mild to moderate anxiety and nervous tension. Alprazolam is also effective in the treatment of alcohol withdrawal, specific phobias, psychogenic headaches, anticipatory anxiety, hypersensitivity, hyperventilation or panic attacks. It can be useful in treating irritable bowel syndrome, to manage spasticity in Lesch-Nyhan syndrome, anxiety associated with depression, anxiety related to symptoms of esophageal motility disorders, anxiety comorbid with hypochondriasis and anxiety due to a neurosis as well.
What do they do to the brain? People with serious forms of anxiety demonstrate chronic over-activity in the areas of the brain associated with fear or nervousness. An inhibitory neurotransmitter, gamma-aminobutyric acid GABA works in these areas to diminish this excessive nerve cell activity. It was not until that researchers showed that benzodiazepines cause an increase in the activity of GABA, thereby returning the system to a normal level and reducing the associated symptoms of anxiety.
In it was discovered that the benzodiazepines bind to a specific receptor on the GABA A receptor complex, which facilitates the binding of GABA to its specific receptor site. Benzodiazepine binding causes increased frequency of opening of the chloride channel complexed with the GABA A receptor. Chloride channel opening results in membrane hyperpolarization, which inhibits cellular excitation. Enhanced GABA neurotransmission results in sedation, striated muscle relaxation, anxiolysis and anticonvulsant effects.
They are also believed to decrease the turnover rate of the neurotransmitters, serotonin and norepinephrine. What are the names of the benzodiazepines? Several thousand different benzodiazepines have been synthesized since the first benzodiazepine chlordiazepoxide in , of which about 50 are currently marketed throughout the world. The benzodiazepines used most often include alprazolam Xanax, Niravam ; bromazepam Lexotan ; chlordiazepoxide Librium, Librax, Libritabs ; clobazam Frisium ; clonazepam Klonopin ; clorazepate Tranxene ; diazepam Valium ; estazolam Prosom ; flunitrazepam Rohypnol ; flurazepam Dalmane ; halazepam Paxipam ; ketazolam Anxon ; lorazepam Ativan ; midazolam Versed ; nitrazepam Mogadon ; oxazepam Serax ; prazepam Centrax ; quazepam Doral ; temazepam Restoril ; triazolam Halcion.
Their generic names are easy to recognize because many of them end in the suffixes -zepam for 1,4-benzodiazepines, -zolam for 1,4-triazolo-benzodiazepines, -bazam for 1,5-benzodiazepines and -sopam for 2,3-benzodiazepines. How fast do they take effect? Like the barbiturates, benzodiazepines differ from one another in how fast they take effect and how long the effects last. The lipophilic fat-soluble benzodiazepines, including alprazolam, usually are absorbed more rapidly and produce a faster onset of action than the hydrophilic water-soluble benzodiazepines.
Absorption is especially rapid when ethanol is present and the stomach is empty. After a single dose, the lipophilic benzodiazepines have a shorter duration of action than the hydrophilic benzodiazepines because of a rapid redistribution from the CNS to peripheral sites e. Alprazolam is well absorbed from the gastrointestinal tract after oral doses, peak plasma concentrations being achieved within hours of a dose.
The mean plasma half-life ranges from hours. Metabolites include a -hydroxyalprazolam, which is reported to be about half as active as the parent compound, 4-hydroxyalprazolam, and an inactive benzophenone. Plasma concentrations of metabolites are very low. Alprazolam is excreted in urine as unchanged form and metabolites. Short-acting benzodiazepines, with half-life values of less than 5 hours, include midazolam Versed and triazolam Halcion. Intermediate-acting benzodiazepines, with half-life values of hours, include alprazolam Xanax, Niravam ; bromazepam Lexotan ; clonazepam Klonopin ; estazolam ProSom ; lorazepam Ativan ; nitrazepam Mogadon ; oxazepam Serax ; temazepam Restoril.
Long-acting benzodiazepines, with half-life values usually exceeding 24 hours especially through formation of active metabolites , include chlordiazepoxide Librium, Librax, Libritabs ; clobazam Frisium ; clorazepate Tranxene ; diazepam Valium ; flunitrazepam Rohypnol ; flurazepam Dalmane ; halazepam Paxipam ; ketazolam Anxon ; prazepam Centrax ; quazepam Dormalin.