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What happens if I overdose Helex?
Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include confusion; loss of consciousness; loss of coordination; severe drowsiness or deep sleep; slow reflexes.
Proper storage of Helex extended-release tablets:
Store Helex extended-release tablets at room temperature, between 59 and 86 degrees F (15 and 30 degrees C) in a tightly closed container, away from heat, moisture, and light. Do not store in the bathroom. Keep Helex extended-release tablets out of the reach of children and away from pets.
Overdose of Helex in details
Manifestations of Helex overdosage include somnolence, confusion, impaired coordination, diminished reflexes and coma. Death has been reported in association with overdoses of Helex 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 Helex, and alcohol; alcohol levels seen in some of these patients have been lower than those usually associated with alcohol-induced fatality.
The acute oral LD50 in rats is 331 to 2171 mg/kg. Other experiments in animals have indicated that cardiopulmonary collapse can occur following massive intravenous doses of Helex (over 195 mg/kg; 975 times the maximum recommended daily human dose of 10 mg/day). 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 Helex 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, a specific benzodiazepine receptor antagonist, 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-termbenzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert including CONTRAINDICATIONS, WARNINGS and PRECAUTIONS should be consulted prior to use.
What should I avoid while taking Helex?
Do not drink alcohol while taking Helex. This medication can increase the effects of alcohol. Helex can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert.
Grapefruit and grapefruit juice may interact with Helex and lead to potentially dangerous effects. Discuss the use of grapefruit products with your doctor. Do not increase or decrease the amount of grapefruit products in your diet without first talking to your doctor.
Dependence and Withdrawal Reactions, Including Seizures
Certain adverse clinical events, some life-threatening, are a direct consequence of physical dependence to Helex. These include a spectrum of withdrawal symptoms; the most important is seizure. Even after relatively short-term use at doses of ≤ 4 mg/day, there is some risk of dependence. Spontaneous reporting system data suggest that the risk of dependence and its severity appear to be greater in patients treated with doses greater than 4 mg/day and for long periods (more than 12 weeks). However, in a controlled postmarketing discontinuation study of panic disorder patients who received Helex tablets, the duration of treatment (3 months compared to 6 months) had no effect on the ability of patients to taper to zero dose. In contrast, patients treated with doses of Helex tablets greater than 4 mg/day had more difficulty tapering to zero dose than those treated with less than 4 mg/day.
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 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 Helex XR tablets has not been systematically studied. Experience in randomized placebo-controlled discontinuation studies of patients with panic disorder who received Helex 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 Helex tablets and where withdrawal symptoms were specifically sought, the following were identified as symptoms of withdrawal: heightened sensory perception, impaired concentration, dysosmia, clouded sensorium, paresthesias, muscle cramps, muscle twitch, diarrhea, blurred vision, appetite decrease, and weight loss. 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.
In two controlled trials of 6 to 8 weeks duration where the ability of patients to discontinue medication was measured, 71%–93% of patients treated with Helex tablets tapered completely off therapy compared to 89%–96% of placebo treated patients. In a controlled postmarketing discontinuation study of panic disorder patients treated with Helex tablets, the duration of treatment (3 months compared to 6 months) had no effect on the ability of patients to taper to zero dose.
Seizures were reported for three patients in panic disorder clinical trials with Helex XR. In two cases, the patients had completed 6 weeks of treatment with Helex XR6 mg/day before experiencing a single seizure. In one case, the patient abruptly discontinued Helex XR, and in both cases, alcohol intake was implicated. The third case involved multiple seizures after the patient completed treatment with Helex XR 4 mg/day and missed taking the medication on the first day of taper. All three patients recovered without sequelae.
Seizures have also been observed in association with dose reduction or discontinuation of Helex tablets, the immediate release form of Helex. Seizures attributable to Helex were seen after drug discontinuance or dose reduction in 8 of 1980 patients with panic disorder or in patients participating in clinical trials where doses of Helex greater than 4 mg/day for over 3 months were permitted. 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 Helex. The risk of seizure seems to be greatest 24–72 hours after discontinuation.
The medical event voluntary reporting system shows that withdrawal seizures have been reported in association with the discontinuation of Helex tablets. In most cases, only a single seizure was reported; however, multiple seizures and status epilepticus were reported as well.
Early morning anxiety and emergence of anxiety symptoms between doses of Helex tablets have been reported in patients with panic disorder taking prescribed maintenance doses. 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.
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 (eg, the patient forgets, the patient is admitted to a hospital). Therefore, the dosage of Helex XR should be reduced or discontinued gradually.
CNS Depression and Impaired Performance
Because of its CNS depressant effects, patients receiving Helex XR 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 Helex XR.
Risk of Fetal Harm
Benzodiazepines can potentially cause fetal harm when administered to pregnant women. If Helex 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, Helex 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 physicians about the desirability of discontinuing the drug.
Helex Interaction With Drugs That Inhibit Metabolism Via Cytochrome P450 3A
The initial step in Helex metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP3A). Drugs that inhibit this metabolic pathway may have a profound effect on the clearance of Helex. Consequently, Helex should be avoided in patients receiving very potent inhibitors of CYP3A. With drugs inhibiting CYP3A to a lesser but still significant degree, Helex should be used only with caution and consideration of appropriate dosage reduction. For some drugs, an interaction with Helex has been quantified with clinical data; for other drugs, interactions are predicted from in vitro data and/or experience with similar drugs in the same pharmacologic class.
The following are examples of drugs known to inhibit the metabolism of Helex and/or related benzodiazepines, presumably through inhibition of CYP3A.
Potent CYP3A Inhibitors
Azole antifungal agents — Ketoconazole and itraconazole are potent CYP3A inhibitors and have been shown in vivo to increase plasma Helex concentrations 3.98 fold and 2.70 fold, respectively. The coadministration of Helex with these agents is not recommended. Other azole-type antifungal agents should also be considered potent CYP3A inhibitors and the coadministration of Helex with them is not recommended.
Drugs demonstrated to be CYP3A inhibitors on the basis of clinical studies involving Helex (caution and consideration of appropriate Helex dose reduction are recommended during coadministration with the following drugs)
Nefazodone — Coadministration of nefazodone increased Helex concentration two-fold.
Fluvoxamine — Coadministration of fluvoxamine approximately doubled the maximum plasma concentration of Helex, decreased clearance by 49%, increased half-life by 71%, and decreased measured psychomotor performance.
Cimetidine — Coadministration of cimetidine increased the maximum plasma concentration of Helex by 86%, decreased clearance by 42%, and increased half-life by 16%.
HIV protease inhibitors — Interactions involving HIV protease inhibitors (eg, ritonavir) and Helex are complex and time dependent. Low doses of ritonavir resulted in a large impairment of Helex clearance, prolonged its elimination half-life and enhanced clinical effects. However, upon extended exposure to ritonavir, CYP3A induction offset this inhibition. This interaction will require a dose-adjustment or discontinuation of Helex.
Other Drugs Possibly Affecting Helex Metabolism
Other drugs possibly affecting Helex metabolism by inhibition of CYP3A are discussed in the PRECAUTIONS section.
What should I discuss with my healthcare provider before taking Helex?
Some medical conditions may interact with Helex solution. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:
- if you are pregnant, planning to become pregnant, or are breast-feeding
- if you are able to become pregnant
- if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement
- if you have allergies to medicines, foods, or other substances
- if you have a history of seizures, glaucoma or increased pressure in the eye, kidney or liver problems, lung or breathing problems (eg, chronic obstructive pulmonary disease [COPD], sleep apnea), myasthenia gravis, or a blood disorder known as porphyria
- if you have a history of other mental or mood problems (eg, depression), alcohol or other substance abuse or dependence, or suicidal thoughts or actions
- if you are in poor health, are very overweight, or are experiencing abnormal muscle movements
- if you drink alcoholic beverages or you smoke
Some MEDICINES MAY INTERACT with Helex solution. Tell your health care provider if you are taking any other medicines, especially any of the following:
- Methadone because it may increase the risk of serious and sometimes fatal breathing problems
- Amiodarone, azole antifungals (eg, itraconazole, ketoconazole), cimetidine, cyclosporine, delavirdine, diltiazem, ergot alkaloids (eg, ergotamine), fluoxetine, fluvoxamine, isoniazid, macrolide antibiotics (eg, clarithromycin, erythromycin), nefazodone, nicardipine, nifedipine, omeprazole, oral contraceptives (birth control pills), paroxetine, propoxyphene, protease inhibitors (eg, boceprevir, ritonavir), sodium oxybate (GHB), telithromycin, or valproic acid because they may increase the risk of Helex solution's side effects
- Carbamazepine, rifamycins (eg, rifampin), or St. John's wort because they may decrease Helex solution's effectiveness
- Hydantoins (eg, phenytoin) because the risk of their side effects may be increased and they may decrease Helex solution's effectiveness
- Clozapine or tricyclic antidepressants (eg, desipramine, imipramine) because the risk of their side effects may be increased by Helex solution
This may not be a complete list of all interactions that may occur. Ask your health care provider if Helex solution may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.
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.
Episodes of hypomania and mania have been reported in association with the use of Helex in patients with depression.
Helex 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 Helex.
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 Helex. A decreased systemic Helex elimination rate (eg, increased plasma half-life) has been observed in both alcoholic liver disease patients and obese patients receiving Helex.
Information for PatientsFor all users of Helex
To assure safe and effective use of benzodiazepines, all patients prescribed Helex should be provided 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. Benzodiazepines, even when used as recommended, may produce emotional and/or physical dependence.
- Do not stop taking this medication abruptly or decrease the dose without consulting your physician, since withdrawal symptoms can occur.
The use of Helex at doses greater than 4 mg/day, often necessary to treat panic disorder, is accompanied by risks that you need to carefully consider. When used at doses greater than 4 mg/day, which may or may not be required for your treatment, Helex has the potential to cause severe emotional and physical dependence in some patients and these patients may find it exceedingly difficult to terminate treatment. In two controlled trials of 6 to 8 weeks duration where the ability of patients to discontinue medication was measured, 7 to 29% of patients treated with Helex did not completely taper off therapy. In a controlled postmarketing discontinuation study of panic disorder patients, the patients treated with doses of Helex greater than 4 mg/day had more difficulty tapering to zero dose than patients treated with less than 4 mg/day. In all cases, it is important that your physician help you discontinue this medication in a careful and safe manner to avoid overly extended use of Helex.
In addition, the extended use at doses greater than 4 mg/day appears to increase the incidence and severity of withdrawal reactions when Helex is discontinued. 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 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.
Drug InteractionsUse with Other CNS Depressants
If Helex Tablets are to be combined with other psychotropic agents or anticonvulsant drugs, careful consideration should be given to the pharmacology of the agents to be employed, particularly with compounds which might potentiate the action of benzodiazepines. The benzodiazepines, including Helex, produce additive CNS depressant effects when co-administered with other psychotropic medications, anticonvulsants, antihistaminics, ethanol and other drugs which themselves produce CNS depression.
Use with Digoxin
Increased digoxin concentrations have been reported when Helex was given, especially in elderly (>65 years of age). Patients who receive Helex and digoxin should therefore be monitored for signs and symptoms related to digoxin toxicity.
Use with Imipramine and Desipramine
The steady state plasma concentrations of imipramine and desipramine have been reported to be increased an average of 31% and 20%, respectively, by the concomitant administration of Helex Tablets in doses up to 4 mg/day. The clinical significance of these changes is unknown.
Drugs that inhibit Helex metabolism via cytochrome P450 3A
The initial step in Helex metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP3A). Drugs which inhibit this metabolic pathway may have a profound effect on the clearance of Helex.
Drugs demonstrated to be CYP3A inhibitors of possible clinical significance on the basis of clinical studies involving Helex (caution is recommended during coadministration with Helex)
Coadministration of fluoxetine with Helex increased the maximum plasma concentration of Helex by 46%, decreased clearance by 21%, increased half-life by 17%, and decreased measured psychomotor performance.
Coadministration of propoxyphene decreased the maximum plasma concentration of Helex by 6%, decreased clearance by 38%, and increased half-life by 58%.
Coadministration of oral contraceptives increased the maximum plasma concentration of Helex by 18%, decreased clearance by 22%, and increased half-life by 29%.
Drugs and other substances demonstrated to be CYP 3A inhibitors on the basis of clinical studies involving benzodiazepines metabolized similarly to Helex or on the basis of in vitro studies with Helex or other benzodiazepines (caution is recommended during coadministration with Helex)
Available data from clinical studies of benzodiazepines other than Helex suggest a possible drug interaction with Helex for the following: diltiazem, isoniazid, macrolide antibiotics such as erythromycin and clarithromycin, and grapefruit juice. Data from in vitro studies of Helex suggest a possible drug interaction with Helex for the following: sertraline and paroxetine. However, data from an in vivo drug interaction study involving a single dose of Helex 1 mg and steady state dose of sertraline (50 to 150 mg/day) did not reveal any clinically significant changes in the pharmacokinetics of Helex. Data from in vitro studies of benzodiazepines other than Helex suggest a possible drug interaction for the following: ergotamine, cyclosporine, amiodarone, nicardipine, and nifedipine. Caution is recommended during the coadministration of any of these with Helex.
Drugs demonstrated to be inducers of CYP3A
Carbamazepine can increase Helex metabolism and therefore can decrease plasma levels of Helex.
Drug/Laboratory Test Interactions
Although interactions between benzodiazepines and commonly employed clinical laboratory tests have occasionally been reported, there is no consistent pattern for a specific drug or specific test.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of carcinogenic potential was observed during 2-year bioassay studies of Helex in rats at doses up to 30 mg/kg/day (150 times the maximum recommended daily human dose of 10 mg/day) and in mice at doses up to 10 mg/kg/day (50 times the maximum recommended daily human dose).
Helex was not mutagenic in the rat micronucleus test at doses up to 100 mg/kg, which is 500 times the maximum recommended daily human dose of 10 mg/day. Helex also was not mutagenic in vitro in the DNA Damage/Alkaline Elution Assay or the Ames Assay.
Helex produced no impairment of fertility in rats at doses up to 5 mg/kg/day, which is 25 times the maximum recommended daily human dose of 10 mg/day.
Pregnancy Category D
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
Helex has no established use in labor or delivery.
Benzodiazepines are known to be excreted in human milk. It should be assumed that Helex 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 Helex.
Safety and effectiveness of Helex in individuals below 18 years of age have not been established.
The elderly may be more sensitive to the effects of benzodiazepines. They exhibit higher plasma Helex concentrations due to reduced clearance of the drug as compared with a younger population receiving the same doses. The smallest effective dose of Helex should be used in the elderly to preclude the development of ataxia and oversedation.
What happens if I miss a dose of Helex?
Take the missed dose as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at your next regularly scheduled time. Do not take extra medicine to make up the missed dose.
- DailyMed. "ALPRAZOLAM: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
- DrugBank. "alprazolam". http://www.drugbank.ca/drugs/DB00404 (accessed September 17, 2018).
- MeSH. "Hypnotics and Sedatives". https://www.ncbi.nlm.nih.gov/mesh/68... (accessed September 17, 2018).
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Information checked by Dr. Sachin Kumar, MD Pharmacology