Alkala may be available in the countries listed below.
Ingredient matches for Alkala
Sodium Bicarbonate
Sodium Bicarbonate is reported as an ingredient of Alkala in the following countries:
- Germany
International Drug Name Search
Friday, 23 September 2016
Aciclovir Katwijk
Aciclovir Katwijk may be available in the countries listed below.
Ingredient matches for Aciclovir Katwijk
Acyclovir
Aciclovir is reported as an ingredient of Aciclovir Katwijk in the following countries:
- Netherlands
International Drug Name Search
Medovascin
Medovascin may be available in the countries listed below.
Ingredient matches for Medovascin
Lovastatin
Lovastatin is reported as an ingredient of Medovascin in the following countries:
- Greece
International Drug Name Search
Brevibloc
Generic Name: esmolol (ES moe lol)
Brand Names: Brevibloc
What is Brevibloc (esmolol)?
Esmolol is a beta 1-selective (cardioselective) adrenergic receptor blocking agent.
Esmolol is used for the rapid control of ventricular rate.
Esmolol may also be used for purposes other than those listed in this medication guide.
What is the most important information I should know about Brevibloc (esmolol)?
Esmolol should be administered by a healthcare provider. It is typically administered in a clinical setting where a healthcare provider can monitor vital signs (blood pressure, heart rates) and where an emergency situation can be handled properly.
Other drugs can interact with esmolol resulting in dangerous side effects and/or decreased effectiveness. Tell your doctor about any other prescription or over-the-counter medicines, including vitamins, minerals, and herbal products, you are taking.
Esmolol use has been associated with low blood pressure and other serious side effects. Talk to your doctor if you have questions regarding the potential side effects associated with esmolol use.
What should I discuss with my healthcare provider before using Brevibloc (esmolol)?
Tell your doctor about all prescription or over-the-counter medicines including vitamins, minerals, and herbal products that your are taking.
Esmolol is in the FDA pregnancy category C. This means that it is not known whether esmolol will be harmful to an unborn baby. Do not take this medication without first talking to your doctor if you are pregnant or could become pregnant during treatment. Do not use esmolol without first talking to your doctor if you are breast-feeding a baby.
How should I use Brevibloc (esmolol)?
Esmolol should be administered by a healthcare provider. It is typically administered in a clinical setting where a healthcare provider can monitor vital signs (blood pressure, heart rates) and where an emergency situation can be handled properly.
Your healthcare provider will store esmolol as directed by the manufacturer.
What happens if I miss a dose?
Since the medication will be administered by a healthcare provider, missing a dose should not occur.
What happens if I overdose?
Esmolol is typically administered by a healthcare provider in a clinical setting where an emergency situation or overdose can be handled properly.
What should I avoid while using Brevibloc (esmolol)?
Other drugs can interact with esmolol resulting in dangerous side effects and/or decreased effectiveness. Tell your doctor about any other prescription or over-the-counter medicines, including vitamins, minerals, and herbal products, you are taking.
Brevibloc (esmolol) side effects
Esmolol use has been associated with low blood pressure and other serious side effects.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
What other drugs will affect Brevibloc (esmolol)?
Other drugs can interact with esmolol resulting in dangerous side effects and/or decreased effectiveness. Tell your doctor about any other prescription or over-the-counter medicines, including vitamins, minerals, and herbal products, you are taking.
More Brevibloc resources
- Brevibloc Side Effects (in more detail)
- Brevibloc Use in Pregnancy & Breastfeeding
- Brevibloc Drug Interactions
- Brevibloc Support Group
- 0 Reviews for Brevibloc - Add your own review/rating
- Brevibloc Prescribing Information (FDA)
- Brevibloc MedFacts Consumer Leaflet (Wolters Kluwer)
- Brevibloc Monograph (AHFS DI)
- Brevibloc Advanced Consumer (Micromedex) - Includes Dosage Information
- Esmolol Prescribing Information (FDA)
Compare Brevibloc with other medications
- Atrial Fibrillation
- Atrial Flutter
- Intra- or Post-op SVT or Hypertension
- Supraventricular Tachycardia
Where can I get more information?
- Your pharmacist has additional information about esmolol written for health professionals that you may read.
See also: Brevibloc side effects (in more detail)
Thursday, 22 September 2016
Halcion
Halcion Tablets contain triazolam, a triazolobenzodiazepine hypnotic agent.
Triazolam is a white crystalline powder, soluble in alcohol and poorly soluble in water. It has a molecular weight of 343.21.
The chemical name for triazolam is 8-chloro-6-(o-chlorophenyl)-1-methyl-4H-s-triazolo-[4,3-α] [1,4] benzodiazepine.
The structural formula is represented below:
Each Halcion Tablet, for oral administration, contains 0.125 mg or 0.25 mg of triazolam. Inactive ingredients: 0.125 mg—cellulose, corn starch, docusate sodium, lactose, magnesium stearate, silicon dioxide, sodium benzoate; 0.25 mg—cellulose, corn starch, docusate sodium, FD&C Blue No. 2, lactose, magnesium stearate, silicon dioxide, sodium benzoate.
Halcion - Clinical Pharmacology
Triazolam is a hypnotic with a short mean plasma half-life reported to be in the range of 1.5 to 5.5 hours. In normal subjects treated for 7 days with four times the recommended dosage, there was no evidence of altered systemic bioavailability, rate of elimination, or accumulation. Peak plasma levels are reached within 2 hours following oral administration. Following recommended doses of Halcion, triazolam peak plasma levels in the range of 1 to 6 ng/mL are seen. The plasma levels achieved are proportional to the dose given.
Triazolam and its metabolites, principally as conjugated glucuronides, which are presumably inactive, are excreted primarily in the urine. Only small amounts of unmetabolized triazolam appear in the urine. The two primary metabolites accounted for 79.9% of urinary excretion. Urinary excretion appeared to be biphasic in its time course.
Halcion Tablets 0.5 mg, in two separate studies, did not affect the prothrombin times or plasma warfarin levels in male volunteers administered sodium warfarin orally.
Extremely high concentrations of triazolam do not displace bilirubin bound to human serum albumin in vitro.
Triazolam 14C was administered orally to pregnant mice. Drug-related material appeared uniformly distributed in the fetus with 14C concentrations approximately the same as in the brain of the mother.
In sleep laboratory studies, Halcion Tablets significantly decreased sleep latency, increased the duration of sleep, and decreased the number of nocturnal awakenings. After 2 weeks of consecutive nightly administration, the drug's effect on total wake time is decreased, and the values recorded in the last third of the night approach baseline levels. On the first and/or second night after drug discontinuance (first or second post-drug night), total time asleep, percentage of time spent sleeping, and rapidity of falling asleep frequently were significantly less than on baseline (predrug) nights. This effect is often called "rebound" insomnia.
The type and duration of hypnotic effects and the profile of unwanted effects during administration of benzodiazepine drugs may be influenced by the biologic half-life of administered drug and any active metabolites formed. When half-lives are long, the drug or metabolites may accumulate during periods of nightly administration and be associated with impairments of cognitive and motor performance during waking hours; the possibility of interaction with other psychoactive drugs or alcohol will be enhanced. In contrast, if half-lives are short, the drug and metabolites will be cleared before the next dose is ingested, and carry-over effects related to excessive sedation or CNS depression should be minimal or absent. However, during nightly use for an extended period pharmacodynamic tolerance or adaptation to some effects of benzodiazepine hypnotics may develop. If the drug has a short half-life of elimination, it is possible that a relative deficiency of the drug or its active metabolites (ie, in relationship to the receptor site) may occur at some point in the interval between each night's use. This sequence of events may account for two clinical findings reported to occur after several weeks of nightly use of rapidly eliminated benzodiazepine hypnotics: 1) increased wakefulness during the last third of the night and 2) the appearance of increased daytime anxiety after 10 days of continuous treatment.
In a study of elderly (62–83 years old) versus younger subjects (21–41 years old) who received Halcion at the same dose levels (0.125 mg and 0.25 mg), the elderly experienced both greater sedation and impairment of psychomotor performance. These effects resulted largely from higher plasma concentrations of triazolam in the elderly.
Indications and Usage for Halcion
Halcion is indicated for the short-term treatment of insomnia (generally 7–10 days). Use for more than 2–3 weeks requires complete reevaluation of the patient (see WARNINGS).
Prescriptions for Halcion should be written for short-term use (7–10 days) and it should not be prescribed in quantities exceeding a 1-month supply.
Contraindications
Halcion Tablets are contraindicated in patients with known hypersensitivity to this drug or other benzodiazepines.
Benzodiazepines may cause fetal damage when administered during pregnancy. An increased risk of congenital malformations associated with the use of diazepam and chlordiazepoxide during the first trimester of pregnancy has been suggested in several studies. Transplacental distribution has resulted in neonatal CNS depression following the ingestion of therapeutic doses of a benzodiazepine hypnotic during the last weeks of pregnancy.
Halcion is contraindicated in pregnant women. If there is a likelihood of the patient becoming pregnant while receiving Halcion, she should be warned of the potential risk to the fetus. Patients should be instructed to discontinue the drug prior to becoming pregnant. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered.
Halcion is contraindicated with ketoconazole, itraconazole, and nefazodone, medications that significantly impair the oxidative metabolism mediated by cytochrome P450 3A (CYP 3A) (see WARNINGS and PRECAUTIONS–Drug Interactions).
Warnings
Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Worsening of insomnia or the emergence of new thinking or behavior abnormalities may be the consequence of an unrecognized psychiatric or physical disorder. Such findings have emerged during the course of treatment with sedative-hypnotic drugs. Because some of the important adverse effects of sedative-hypnotics appear to be dose related (see Precautions and Dosage and Administration), it is important to use the smallest possible effective dose, especially in the elderly.
Complex behaviors such as "sleep-driving" (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported. These events can occur in sedative-hypnotic-naïve as well as in sedative-hypnotic-experienced persons. Although behaviors such as sleep-driving may occur with sedative-hypnotics alone at therapeutic doses, the use of alcohol and other CNS depressants with sedative-hypnotics appears to increase the risk of such behaviors, as does the use of sedative-hypnotics at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of sedative-hypnotics should be strongly considered for patients who report a "sleep-driving" episode.
Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with sleep-driving, patients usually do not remember these events.
Severe anaphylactic and anaphylactoid reactions
Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of sedative-hypnotics, including Halcion. Some patients have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis. Some patients have required medical therapy in the emergency department. If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with Halcion should not be rechallenged with the drug.
Central nervous system manifestations
An increase in daytime anxiety has been reported for Halcion after as few as 10 days of continuous use. In some patients this may be a manifestation of interdose withdrawal (see CLINICAL PHARMACOLOGY). If increased daytime anxiety is observed during treatment, discontinuation of treatment may be advisable.
A variety of abnormal thinking and behavior changes have been reported to occur in association with the use of benzodiazepine hypnotics including Halcion. Some of these changes may be characterized by decreased inhibition, eg, aggressiveness and extroversion that seem excessive, similar to that seen with alcohol and other CNS depressants (eg, sedative/hypnotics). Other kinds of behavioral changes have also been reported, for example, bizarre behavior, agitation, hallucinations, depersonalization. In primarily depressed patients, the worsening of depression, including suicidal thinking, has been reported in association with the use of benzodiazepines.
It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above is drug induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.
Because of its depressant CNS effects, patients receiving triazolam should be cautioned against engaging in hazardous occupations requiring complete mental alertness such as operating machinery or driving a motor vehicle. For the same reason, patients should be cautioned about the concomitant ingestion of alcohol and other CNS depressant drugs during treatment with Halcion Tablets.
As with some, but not all benzodiazepines, anterograde amnesia of varying severity and paradoxical reactions have been reported following therapeutic doses of Halcion. Data from several sources suggest that anterograde amnesia may occur at a higher rate with Halcion than with other benzodiazepine hypnotics.
Triazolam interaction with drugs that inhibit metabolism via cytochrome P450 3A
The initial step in triazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP 3A). Drugs that inhibit this metabolic pathway may have a profound effect on the clearance of triazolam. Consequently, triazolam should be avoided in patients receiving very potent inhibitors of CYP 3A. With drugs inhibiting CYP 3A to a lesser but still significant degree, triazolam should be used only with caution and consideration of appropriate dosage reduction. For some drugs, an interaction with triazolam 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 triazolam and/or related benzodiazepines, presumably through inhibition of CYP 3A.
Potent CYP 3A inhibitors
Potent inhibitors of CYP 3A that should not be used concomitantly with triazolam include ketoconazole, itraconazole, and nefazodone. Although data concerning the effects of azole-type antifungal agents other than ketoconazole and itraconazole on triazolam metabolism are not available, they should be considered potent CYP 3A inhibitors, and their coadministration with triazolam is not recommended (see CONTRAINDICATIONS).
Drugs demonstrated to be CYP 3A inhibitors on the basis of clinical studies involving triazolam (caution and consideration of dose reduction are recommended during coadministration with triazolam)
Macrolide Antibiotics
Coadministration of erythromycin increased the maximum plasma concentration of triazolam by 46%, decreased clearance by 53%, and increased half-life by 35%; caution and consideration of appropriate triazolam dose reduction are recommended. Similar caution should be observed during coadministration with clarithromycin and other macrolide antibiotics.
Cimetidine
Coadministration of cimetidine increased the maximum plasma concentration of triazolam by 51%, decreased clearance by 55%, and increased half-life by 68%; caution and consideration of appropriate triazolam dose reduction are recommended.
Other drugs possibly affecting triazolam metabolism
Other drugs possibly affecting triazolam metabolism by inhibition of CYP 3A are discussed in the PRECAUTIONS section (see PRECAUTIONS–Drug Interactions).
Precautions
General
In elderly and/or debilitated patients it is recommended that treatment with Halcion Tablets be initiated at 0.125 mg to decrease the possibility of development of oversedation, dizziness, or impaired coordination.
Some side effects reported in association with the use of Halcion appear to be dose related. These include drowsiness, dizziness, light-headedness, and amnesia.
The relationship between dose and what may be more serious behavioral phenomena is less certain. Specifically, some evidence, based on spontaneous marketing reports, suggests that confusion, bizarre or abnormal behavior, agitation, and hallucinations may also be dose related, but this evidence is inconclusive. In accordance with good medical practice it is recommended that therapy be initiated at the lowest effective dose (see DOSAGE AND ADMINISTRATION).
Cases of "traveler's amnesia" have been reported by individuals who have taken Halcion to induce sleep while traveling, such as during an airplane flight. In some of these cases, insufficient time was allowed for the sleep period prior to awakening and before beginning activity. Also, the concomitant use of alcohol may have been a factor in some cases.
Caution should be exercised if Halcion is prescribed to patients with signs or symptoms of depression that could be intensified by hypnotic drugs. Suicidal tendencies may be present in such patients and protective measures may be required. Intentional over-dosage is more common in these patients, and the least amount of drug that is feasible should be available to the patient at any one time.
The usual precautions should be observed in patients with impaired renal or hepatic function, chronic pulmonary insufficiency, and sleep apnea. In patients with compromised respiratory function, respiratory depression and apnea have been reported infrequently.
Information for patients
The text of a Medication Guide for patients is included at the end of this insert. To assure safe and effective use of Halcion, the information and instructions provided in this Medication Guide should be discussed with patients.
"Sleep-driving" and other complex behaviors
There have been reports of people getting out of bed after taking a sedative-hypnotic and driving their cars while not fully awake, often with no memory of the event. If a patient experiences such an episode, it should be reported to his or her doctor immediately, since "sleep-driving" can be dangerous. This behavior is more likely to occur when sedative-hypnotics are taken with alcohol or other central nervous system depressants (see WARNINGS). Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative hypnotic. As with sleep-driving, patients usually do not remember these events.
Laboratory tests
Laboratory tests are not ordinarily required in otherwise healthy patients.
Drug interactions
Both pharmacodynamic and pharmacokinetic interactions have been reported with benzodiazepines. In particular, triazolam produces additive CNS depressant effects when coadministered with other psychotropic medications, anticonvulsants, antihistamines, ethanol, and other drugs which themselves produce CNS depression.
Drugs that inhibit triazolam metabolism via cytochrome P450 3A
The initial step in triazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP 3A). Drugs which inhibit this metabolic pathway may have a profound effect on the clearance of triazolam (see CONTRAINDICATIONS and WARNINGS for additional drugs of this type). Halcion is contraindicated with ketoconzaole, itraconazole, and nefazodone.
Drugs and other substances demonstrated to be CYP 3A inhibitors of possible clinical significance on the basis of clinical studies involving triazolam (caution is recommended during coadministration with triazolam)
Isoniazid
Coadministration of isoniazid increased the maximum plasma concentration of triazolam by 20%, decreased clearance by 42%, and increased half-life by 31%.
Oral contraceptives
Coadministration of oral contraceptives increased maximum plasma concentration by 6%, decreased clearance by 32%, and increased half-life by 16%.
Grapefruit juice
Coadministration of grapefruit juice increased the maximum plasma concentration of triazolam by 25%, increased the area under the concentration curve by 48%, and increased half-life by 18%.
Drugs demonstrated to be CYP 3A inhibitors on the basis of clinical studies involving benzodiazepines metabolized similarly to triazolam or on the basis of in vitro studies with triazolam or other benzodiazepines (caution is recommended during coadministration with triazolam)
Available data from clinical studies of benzodiazepines other than triazolam suggest a possible drug interaction with triazolam for the following: fluvoxamine, diltiazem, and verapamil. Data from in vitro studies of triazolam suggest a possible drug interaction with triazolam for the following: sertraline and paroxetine. Data from in vitro studies of benzodiazepines other than triazolam suggest a possible drug interaction with triazolam for the following: ergotamine, cyclosporine, amiodarone, nicardipine, and nifedipine. Caution is recommended during coadministration of any of these drugs with triazolam (see WARNINGS).
Drugs that affect triazolam pharmacokinetics by other mechanisms
Ranitidine
Coadministration of ranitidine increased the maximum plasma concentration of triazolam by 30%, increased the area under the concentration curve by 27%, and increased half-life by 3.3%. Caution is recommended during coadministration with triazolam.
Carcinogenesis, mutagenesis, impairment of fertility
No evidence of carcinogenic potential was observed in mice during a 24-month study with Halcion in doses up to 4,000 times the human dose.
Pregnancy
1. Teratogenic effects
Pregnancy category X (see CONTRAINDICATIONS).
2. Non-teratogenic effects
It is to be considered that the child born of a mother who is on benzodiazepines may be at some risk for withdrawal symptoms from the drug, during the postnatal period. Also, neonatal flaccidity has been reported in an infant born of a mother who had been receiving benzodiazepines.
Nursing mothers
Human studies have not been performed; however, studies in rats have indicated that Halcion and its metabolites are secreted in milk. Therefore, administration of Halcion to nursing mothers is not recommended.
Pediatric use
Safety and effectiveness of Halcion in individuals below 18 years of age have not been established.
Geriatric use
The elderly are especially susceptible to the dose related adverse effects of Halcion. They exhibit higher plasma triazolam concentrations due to reduced clearance of the drug as compared with younger subjects at the same dose. To minimize the possibility of development of oversedation, the smallest effective dose should be used (see CLINICAL PHARMACOLOGY, WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).
Tolerance/Withdrawal Phenomena
Some loss of effectiveness or adaptation to the sleep inducing effects of these medications may develop after nightly use for more than a few weeks and there may be a degree of dependence that develops. For the benzodiazepine sleeping pills that are eliminated quickly from the body, a relative deficiency of the drug may occur at some point in the interval between each night's use. This can lead to (1) increased wakefulness during the last third of the night, and (2) the appearance of increased signs of daytime anxiety or nervousness. These two events have been reported in particular for Halcion.
There can be more severe 'withdrawal' effects when a benzodiazepine sleeping pill is stopped. Such effects can occur after discontinuing these drugs following use for only a week or two, but may be more common and more severe after longer periods of continuous use. One type of withdrawal phenomenon is the occurrence of what is known as 'rebound insomnia'. That is, on the first few nights after the drug is stopped, insomnia is actually worse than before the sleeping pill was given. Other withdrawal phenomena following abrupt stopping of benzodiazepine sleeping pills range from mild unpleasant feelings to a major withdrawal syndrome which may include abdominal and muscle cramps, vomiting, sweating, tremor, and rarely, convulsions.
Adverse Reactions
During placebo-controlled clinical studies in which 1,003 patients received Halcion Tablets, the most troublesome side effects were extensions of the pharmacologic activity of triazolam, eg, drowsiness, dizziness, or light-headedness.
The figures cited below are estimates of untoward clinical event incidence among subjects who participated in the relatively short duration (i.e., 1 to 42 days) placebo-controlled clinical trials of Halcion. The figures 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 is 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 nondrug factors to the untoward event incidence rate in the population studied. Even this use must be approached cautiously, as a drug may relieve a symptom in one patient while inducing it in others. (For example, an anticholinergic, anxiolytic drug may relieve dry mouth [a sign of anxiety] in some subjects but induce it [an untoward event] in others.)
| Halcion | PLACEBO | |
|---|---|---|
| Number of Patients | 1003 | 997 |
| % Patients Reporting: | ||
| Central Nervous System | ||
| Drowsiness | 14.0 | 6.4 |
| Headache | 9.7 | 8.4 |
| Dizziness | 7.8 | 3.1 |
| Nervousness | 5.2 | 4.5 |
| Light-headedness | 4.9 | 0.9 |
| Coordination disorders/ataxia | 4.6 | 0.8 |
| Gastrointestinal | ||
| Nausea/vomiting | 4.6 | 3.7 |
In addition to the relatively common (i.e., 1% or greater) untoward events enumerated above, the following adverse events have been reported less frequently (i.e., 0.9% to0.5%): euphoria, tachycardia, tiredness, confusional states/memory impairment, cramps/pain, depression, visual disturbances.
Rare (i.e., less than 0.5%) adverse reactions included constipation, taste alterations, diarrhea, dry mouth, dermatitis/allergy, dreaming/nightmares, insomnia, paresthesia, tinnitus, dysesthesia, weakness, congestion, death from hepatic failure in a patient also receiving diuretic drugs.
In addition to these untoward events for which estimates of incidence are available, the following adverse events have been reported in association with the use of Halcion and other benzodiazepines: amnestic symptoms (anterograde amnesia with appropriate or inappropriate behavior), confusional states (disorientation, derealization, depersonalization, and/or clouding of consciousness), dystonia, anorexia, fatigue, sedation, slurred speech, jaundice, pruritus, dysarthria, changes in libido, menstrual irregularities, incontinence, and urinary retention. Other factors may contribute to some of these reactions, eg, concomitant intake of alcohol or other drugs, sleep deprivation, an abnormal premorbid state, etc.
Other events reported include: paradoxical reactions such as stimulation, mania, an agitational state (restlessness, irritability, and excitation), increased muscle spasticity, sleep disturbances, hallucinations, delusions, aggressiveness, falling, somnambulism, syncope, inappropriate behavior and other adverse behavioral effects. Should these occur, use of the drug should be discontinued.
The following events have also been reported: chest pain, burning tongue/glossitis/stomatitis.
Laboratory analyses were performed on all patients participating in the clinical program for Halcion. The following incidences of abnormalities were observed in patients receiving Halcion and the corresponding placebo group. None of these changes were considered to be of physiological significance.
| Halcion | PLACEBO | |||
|---|---|---|---|---|
| Number of Patients | 380 | 361 | ||
| % of Patients Reporting: | Low | High | Low | High |
| ||||
| Hematology | ||||
| Hematocrit | * | * | * | * |
| Hemoglobin | * | * | * | * |
| Total WBC count | 1.7 | 2.1 | * | 1.3 |
| Neutrophil count | 1.5 | 1.5 | 3.3 | 1.0 |
| Lymphocyte count | 2.3 | 4.0 | 3.1 | 3.8 |
| Monocyte count | 3.6 | * | 4.4 | 1.5 |
| Eosinophil count | 10.2 | 3.2 | 9.8 | 3.4 |
| Basophil count | 1.7 | 2.1 | * | 1.8 |
| Urinalysis | ||||
| Albumi | — | 1.1 | — | * |
| Sugar | — | * | — | * |
| RBC/HPF | — | 2.9 | — | 2.9 |
| WBC/HPF | — | 11.7 | — | 7.9 |
| Blood chemistry | ||||
| Creatinine | 2.4 | 1.9 | 3.6 | 1.5 |
| Bilirubin | * | 1.5 | 1.0 | * |
| SGOT | * | 5.3 | * | 4.5 |
| Alkaline phosphatase | * | 2.2 | * | 2.6 |
When treatment with Halcion is protracted, periodic blood counts, urinalysis, and blood chemistry analyses are advisable.
Minor changes in EEG patterns, usually low-voltage fast activity, have been observed in patients during therapy with Halcion and are of no known significance.
Drug Abuse and Dependence
Abuse and addiction are separate and distinct from physical dependence and tolerance. Abuse is characterized by misuse of the drug for non-medical purposes, often in combination with other psychoactive substances. Physical dependence is a state of adaptation that is manifested by a specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug and/or administration of an antagonist. Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug's effects over time. Tolerance may occur to both the desired and undesired effects of drugs and may develop at different rates for different effects.
Addiction is a primary, chronic, neurobiological disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common.
Controlled Substance
Triazolam is a controlled substance under the Controlled Substance Act, and Halcion Tablets have been assigned to Schedule IV.
Abuse, Dependence and Withdrawal
Withdrawal symptoms, similar in character to those noted with barbiturates and alcohol (convulsions, tremor, abdominal and muscle cramps, vomiting, sweating, dysphoria, perceptual disturbances and insomnia), have occurred following abrupt discontinuance of benzodiazepines, including Halcion. The more severe symptoms are usually associated with higher dosages and longer usage, although patients at therapeutic dosages given for as few as 1–2 weeks can also have withdrawal symptoms and in some patients there may be withdrawal symptoms (daytime anxiety, agitation) between nightly doses (see CLINICAL PHARMACOLOGY). Consequently, abrupt discontinuation should be avoided and a gradual dosage tapering schedule is recommended in any patient taking more than the lowest dose for more than a few weeks. The recommendation for tapering is particularly important in any patient with a history of seizure.
The risk of dependence is increased in patients with a history of alcoholism, drug abuse, or in patients with marked personality disorders. Such dependence-prone individuals should be under careful surveillance when receiving Halcion. As with all hypnotics, repeat prescriptions should be limited to those who are under medical supervision.
Overdosage
Because of the potency of triazolam, some manifestations of overdosage may occur at 2 mg, four times the maximum recommended therapeutic dose (0.5 mg).
Manifestations of overdosage with Halcion Tablets include somnolence, confusion, impaired coordination, slurred speech, and ultimately, coma. Respiratory depression and apnea have been reported with overdosages of Halcion. Seizures have occasionally been reported after overdosages.
Death has been reported in association with overdoses of triazolam 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 triazolam, and alcohol; benzodiazepine and alcohol levels seen in some of these cases have been lower than those usually associated with reports of fatality with either substance alone.
As in all cases of drug overdosage, respiration, pulse, and blood pressure should be monitored and supported by general measures when necessary. Immediate gastric lavage should be performed. An adequate airway should be maintained. Intravenous fluids may be administered.
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 resedation, 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. The complete flumazenil package insert including CONTRAINDICATIONS, WARNINGS and PRECAUTIONS should be consulted prior to use.
Experiments in animals have indicated that cardiopulmonary collapse can occur with massive intravenous doses of triazolam. This could be reversed with positive mechanical respiration and the intravenous infusion of norepinephrine bitartrate or metaraminol bitartrate. Hemodialysis and forced diuresis are probably of little value. As with the management of intentional overdosage with any drug, the physician should bear in mind that multiple agents may have been ingested by the patient.
The oral LD50 in mice is greater than 1,000 mg/kg and in rats is greater than 5,000 mg/kg.
Halcion Dosage and Administration
It is important to individualize the dosage of Halcion Tablets for maximum beneficial effect and to help avoid significant adverse effects.
The recommended dose for most adults is 0.25 mg before retiring. A dose of 0.125 mg may be found to be sufficient for some patients (e.g., low body weight). A dose of 0.5 mg should be used only for exceptional patients who do not respond adequately to a trial of a lower dose since the risk of several adverse reactions increases with the size of the dose administered. A dose of 0.5 mg should not be exceeded.
In geriatric and/or debilitated patients the recommended dosage range is 0.125 mg to 0.25 mg. Therapy should be initiated at 0.125 mg in these groups and the 0.25 mg dose should be used only for exceptional patients who do not respond to a trial of the lower dose. A dose of 0.25 mg should not be exceeded in these patients.
As with all medications, the lowest effective dose should be used.
How is Halcion Supplied
Halcion Tablets are available in the following strengths and package sizes:
| 0.125 mg (white, elliptical, imprinted Halcion 0.125): | |
| Reverse numbered | |
| Unit Dose (100) | NDC 0009-0010-32 |
| 10–10 Tablet Bottles | NDC 0009-0010-38 |
| Bottles of 500 | NDC 0009-0010-11 |
| 0.25 mg (powder blue, elliptical, scored, imprinted Halcion 0.25): | |
| Reverse numbered | |
| Unit Dose (100) | NDC 0009-0017-55 |
| 10–10 Tablet Bottles | NDC 0009-0017-59 |
| Bottles of 500 | NDC 0009-0017-02 |
Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].
Rx only
MEDICATION GUIDE
Halcion Tablets/ C-IV
Read this Medication Guide before you start taking Halcion and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your medical condition or treatment. You and your doctor should talk about the SEDATIVE-HYPNOTIC when you start taking it and at regular checkups.
What is the most important information I should know about Halcion?
After taking a SEDATIVE-HYPNOTIC, you may get up out of bed while not being fully awake and do an activity that you do not know you are doing. The next morning, you may not remember that you did anything during the night. You have a higher chance for doing these activities if you drink alcohol or take other medicines that make you sleepy with a SEDATIVE-HYPNOTIC. Reported activities include:
- driving a car ("sleep-driving")
- making and eating food
- talking on the phone
- having sex
- sleep-walking
Important:
- 1.
- Take Halcion exactly as prescribed
- Do not take more Halcion than prescribed.
- Take Halcion right before you get in bed, not sooner.
- 2.
- Do not take Halcion if you:
- drink alcohol
- take other medicines that can make you sleepy. Talk to your doctor about all of your medicines. Your doctor will tell you if you can take Halcion with your other medicines
- cannot get a full night's sleep
- are pregnant or considering becoming pregnant
- 3.
- Call your doctor right away if you find out that you have done any of the above activities after taking Halcion.
What are SEDATIVE-HYPNOTICS?
SEDATIVE-HYPNOTICs are sleep medicines. SEDATIVE-HYPNOTICS are used in adults for the treatment of the symptom of trouble falling asleep due to insomnia.
Halcion is not indicated for use in children.
Elderly patients are especially susceptible to dose related adverse effects when taking Halcion.
Halcion is a federally controlled substance (C-IV) because it can be abused or lead to dependence. Keep Halcion in a safe place to prevent misuse and abuse. Selling or giving away Halcion may harm others, and is against the law. Tell your doctor if you have ever abused or been dependent on alcohol, prescription medicines or street drugs.
Who should not take Halcion?
Do not take Halcion if you are allergic to anything in it. See the end of this Medication Guide for a complete list of ingredients in Halcion.
SEDATIVE-HYPNOTICS may not be right for you. Before starting SEDATIVE-HYPNOTICS, tell your doctor about all of your health conditions, including if you:
- have a history of depression, mental illness, or suicidal thoughts
- have a history of drug or alcohol abuse or addiction
- have kidney or liver disease
- have a lung disease or breathing problems
- are pregnant, planning to become pregnant, or breastfeeding
Tell your doctor about all of the medicines you take including prescription and nonprescription medicines, vitamins and herbal supplements. Medicines can interact, sometimes causing side effects. Do not take SEDATIVE-HYPNOTICS with other medicines that can make you sleepy.
Know the medicines you take. Keep a list of your medicines with you to show your doctor and pharmacist each time you get a new medicine.
Halcion should not be taken with potent inhibitors of CYP 3A including ketoconazole, itraconazole, nefazodone and possibly other azole-type antifungal agents.
How should I take Halcion?
- Take Halcion exactly as prescribed. Do not take more Halcion than prescribed for you.
- Take Halcion right before you get into bed. Or you can take the Halcion after you have been in bed and have trouble falling asleep.
- Do not take Halcion with or right after a meal.
- Do not take Halcion unless you are able to get a full night's sleep before you must be active again.
- Call your healthcare provider if your insomnia worsens or is not better within 7 to 10 days. This may mean that there is another condition causing your sleep problem.
- If you take too much Halcion or overdose, call your doctor or poison control center right away, or get emergency treatment.
What are the possible side effects of SEDATIVE-HYPNOTICS?
Serious side effects of SEDATIVE-HYPNOTICS include:
- getting out of bed while not being fully awake and doing an activity that you do not know you are doing. (See "What is the most important information I should know about SEDATIVE-HYPNOTICS?)
- abnormal thoughts and behavior. Symptoms include more outgoing or aggressive behavior than normal, confusion, agitation, hallucinations, worsening of depression, and suicidal thoughts or actions.
- memory loss, including "traveler's amnesia"
- anxiety
- severe allergic reactions. Symptoms include swelling of the tongue or throat, trouble breathing, and nausea and vomiting. Get emergency medical help if you get these symptoms after taking SEDATIVE-HYPNOTICS.
Call your doctor right away if you have any of the above side effects or any other side effects that worry you while using the SEDATIVE-HYPNOTIC.
Common side effects of Halcion include:
- drowsiness
- headache
- dizziness
- lightheadedness
- "pins and needles" feelings on your skin
- difficulty with coordination
- You may still
Carticaine
Carticaine may be available in the countries listed below.
Ingredient matches for Carticaine
Articaine
Carticaine (BAN) is known as Articaine in the US.
International Drug Name Search
Glossary
| BAN | British Approved Name |
Click for further information on drug naming conventions and International Nonproprietary Names.
Byetta
Generic Name: exenatide
Dosage Form: injection
FULL PRESCRIBING INFORMATION
Indications and Usage for Byetta
Type 2 Diabetes Mellitus
Byetta is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Important Limitations of Use
Byetta is not a substitute for insulin. Byetta should not be used for the treatment of type 1 diabetes or diabetic ketoacidosis, as it would not be effective in these settings.
The concurrent use of Byetta with prandial insulin has not been studied and cannot be recommended.
Based on postmarketing data Byetta has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. Byetta has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while using Byetta. Other antidiabetic therapies should be considered in patients with a history of pancreatitis.
Byetta Dosage and Administration
Recommended Dosing
Byetta should be initiated at 5 mcg administered twice daily at any time within the 60-minute period before the morning and evening meals (or before the two main meals of the day, approximately 6 hours or more apart). Byetta should not be administered after a meal. Based on clinical response, the dose of Byetta can be increased to 10 mcg twice daily after 1 month of therapy. Initiation with 5 mcg reduces the incidence and severity of gastrointestinal side effects. Each dose should be administered as a subcutaneous (SC) injection in the thigh, abdomen, or upper arm. Do not mix Byetta with insulin. Do not transfer Byetta from the pen to a syringe or a vial. No data are available on the safety or efficacy of intravenous or intramuscular injection of Byetta.
Use Byetta only if it is clear, colorless and contains no particles.
Dosage Forms and Strengths
Byetta is supplied as a sterile solution for subcutaneous injection containing 250 mcg/mL exenatide in the following packages:
- 5 mcg per dose, 60 doses, 1.2 mL prefilled pen
- 10 mcg per dose, 60 doses, 2.4 mL prefilled pen
Contraindications
Hypersensitivity
Byetta is contraindicated in patients with prior severe hypersensitivity reactions to exenatide or to any of the product components.
Warnings and Precautions
Acute Pancreatitis
Based on postmarketing data Byetta has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. After initiation of Byetta, and after dose increases, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting). If pancreatitis is suspected, Byetta should promptly be discontinued and appropriate management should be initiated. If pancreatitis is confirmed, Byetta should not be restarted. Consider antidiabetic therapies other than Byetta in patients with a history of pancreatitis.
Use with Medications Known to Cause Hypoglycemia
The risk of hypoglycemia is increased when Byetta is used in combination with a sulfonylurea. Therefore, patients receiving Byetta and a sulfonylurea may require a lower dose of the sulfonylurea to reduce the risk of hypoglycemia.
When Byetta is used in combination with insulin, the dose of insulin should be evaluated. In patients at increased risk of hypoglycemia consider reducing the dose of insulin [see Adverse Reactions (6.1)]. The concurrent use of Byetta with prandial insulin has not been studied and cannot be recommended. It is also possible that the use of Byetta with other glucose-independent insulin secretagogues (e.g. meglitinides) could increase the risk of hypoglycemia.
For additional information on glucose dependent effects see Mechanism of Action (12.1).
Renal Impairment
Byetta should not be used in patients with severe renal impairment (creatinine clearance < 30 mL/min) or end-stage renal disease and should be used with caution in patients with renal transplantation [see Use in Specific Populations (8.6)]. In patients with end-stage renal disease receiving dialysis, single doses of Byetta 5 mcg were not well-tolerated due to gastrointestinal side effects. Because Byetta may induce nausea and vomiting with transient hypovolemia, treatment may worsen renal function. Caution should be applied when initiating or escalating doses of Byetta from 5 mcg to 10 mcg in patients with moderate renal impairment (creatinine clearance 30 to 50 mL/min).
There have been postmarketing reports of altered renal function, including increased serum creatinine, renal impairment, worsened chronic renal failure and acute renal failure, sometimes requiring hemodialysis or kidney transplantation. Some of these events occurred in patients receiving one or more pharmacologic agents known to affect renal function or hydration status, such as angiotensin converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, or diuretics. Some events occurred in patients who had been experiencing nausea, vomiting, or diarrhea, with or without dehydration. Reversibility of altered renal function has been observed in many cases with supportive treatment and discontinuation of potentially causative agents, including Byetta. Exenatide has not been found to be directly nephrotoxic in preclinical or clinical studies.
Gastrointestinal Disease
Byetta has not been studied in patients with severe gastrointestinal disease, including gastroparesis. Because Byetta is commonly associated with gastrointestinal adverse reactions, including nausea, vomiting, and diarrhea, the use of Byetta is not recommended in patients with severe gastrointestinal disease.
Immunogenicity
Patients may develop antibodies to exenatide following treatment with Byetta. Antibody levels were measured in 90% of subjects in the 30-week, 24-week and 16-week studies of Byetta. In 3%, 4% and 1% of these patients, respectively, antibody formation was associated with an attenuated glycemic response. If there is worsening glycemic control or failure to achieve targeted glycemic control, alternative antidiabetic therapy should be considered [see Adverse Reactions (6.1)].
Hypersensitivity
There have been postmarketing reports of serious hypersensitivity reactions (e.g. anaphylaxis and angioedema) in patients treated with Byetta. If a hypersensitivity reaction occurs, the patient should discontinue Byetta and other suspect medications and promptly seek medical advice [see Adverse Reactions (6.2)].
Macrovascular Outcomes
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Byetta or any other antidiabetic drug.
Adverse Reactions
Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Hypoglycemia
Table 1 summarizes the incidence and rate of hypoglycemia with Byetta in six placebo-controlled clinical trials.
| Byetta | |||
|---|---|---|---|
| Placebo twice daily | 5 mcg twice daily | 10 mcg twice daily | |
| N = The number of Intent-to-Treat subjects in each treatment group. | |||
| |||
| Monotherapy (24 Weeks) | |||
| N | 77 | 77 | 78 |
| % Overall | 1.3% | 5.2% | 3.8% |
| Rate (episodes/patient-year) | 0.03 | 0.21 | 0.52 |
| % Severe | 0.0% | 0.0% | 0.0% |
| With Metformin (30 Weeks) | |||
| N | 113 | 110 | 113 |
| % Overall | 5.3% | 4.5% | 5.3% |
| Rate (episodes/patient-year) | 0.12 | 0.13 | 0.12 |
| % Severe | 0.0% | 0.0% | 0.0% |
| With a Sulfonylurea (30 Weeks) | |||
| N | 123 | 125 | 129 |
| % Overall | 3.3% | 14.4% | 35.7% |
| Rate (episodes/patient-year) | 0.07 | 0.64 | 1.61 |
| % Severe | 0.0% | 0.0% | 0.0% |
| With Metformin and a Sulfonylurea (30 Weeks) | |||
| N | 247 | 245 | 241 |
| % Overall | 12.6% | 19.2% | 27.8% |
| Rate (episodes/patient-year) | 0.58 | 0.78 | 1.71 |
| % Severe | 0.0% | 0.4% | 0.0% |
| With a Thiazolidinedione (16 Weeks) | |||
| N | 112 | not evaluated | 121 |
| % Overall | 7.1% | not evaluated | 10.7% |
| Rate (episodes/patient-years) | 0.56 | not evaluated | 0.98 |
| % Severe | 0.0% | not evaluated | 0.0% |
| With Insulin Glargine (30 Weeks) † | |||
| N | 122 | not evaluated | 137 |
| % Overall | 29.5% | not evaluated | 24.8% |
| Rate (episodes/patient-years) | 1.58 | not evaluated | 1.61 |
| % Severe | 0.8% | not evaluated | 0.0% |
Immunogenicity
Antibodies were assessed in 90% of subjects in the 30-week, 24-week and 16-week studies of Byetta. In the 30-week controlled trials of Byetta add-on to metformin and/or sulfonylurea, antibodies were assessed at 2- to 6-week intervals. The mean antibody titer peaked at week 6 and was reduced by 55% by week 30. Three hundred and sixty patients (38%) had low titer antibodies (<625) to exenatide at 30 weeks. The level of glycemic control (HbA1c) in these patients was generally comparable to that observed in the 534 patients (56%) without antibody titers. An additional 59 patients (6%) had higher titer antibodies (≥625) at 30 weeks. Of these patients, 32 (3% overall) had an attenuated glycemic response to Byetta; the remaining 27 (3% overall) had a glycemic response comparable to that of patients without antibodies [see Warnings and Precautions (5.5)].
In the 16-week trial of Byetta add-on to thiazolidinediones, with or without metformin, 36 patients (31%) had low titer antibodies to exenatide at 16 weeks. The level of glycemic control in these patients was generally comparable to that observed in the 69 patients (60%) without antibody titer. An additional 10 patients (9%) had higher titer antibodies at 16 weeks. Of these patients, 4 (4% overall) had an attenuated glycemic response to Byetta; the remaining 6 (5% overall) had a glycemic response comparable to that of patients without antibodies [see Warnings and Precautions (5.5)].
In the 24-week trial of Byetta used as monotherapy, 40 patients (28%) had low titer antibodies to exenatide at 24 weeks. The level of glycemic control in these patients was generally comparable to that observed in the 101 patients (70%) without antibody titers. An additional 3 patients (2%) had higher titer antibodies at 24 weeks. Of these patients, 1 (1% overall) had an attenuated glycemic response to Byetta; the remaining 2 (1% overall) had a glycemic response comparable to that of patients without antibodies [see Warnings and Precautions (5.5)].
Antibodies to exenatide were not assessed in the 30-week trial of Byetta used in combination with insulin glargine.
Two hundred and ten patients with antibodies to exenatide in the Byetta clinical trials were tested for the presence of cross-reactive antibodies to GLP-1 and/or glucagon. No treatment-emergent cross reactive antibodies were observed across the range of titers.
Other Adverse Reactions
Monotherapy
For the 24-week placebo-controlled study of Byetta used as a monotherapy, Table 2 summarizes adverse reactions (excluding hypoglycemia) occurring with an incidence ≥2% and occurring more frequently in Byetta-treated patients compared with placebo-treated patients.
| Monotherapy | Placebo BID N = 77 % | All Byetta BID N = 155 % |
|---|---|---|
| BID = twice daily. | ||
| ||
| Nausea | 0 | 8 |
| Vomiting | 0 | 4 |
| Dyspepsia | 0 | 3 |
Adverse reactions reported in ≥1.0 to <2.0% of patients receiving Byetta and reported more frequently than with placebo included decreased appetite, diarrhea, and dizziness. The most frequently reported adverse reaction associated with Byetta, nausea, occurred in a dose-dependent fashion.
Two of the 155 patients treated with Byetta withdrew due to adverse reactions of headache and nausea. No placebo-treated patients withdrew due to adverse reactions.
Combination Therapy
Add-on to metformin and/or sulfonylurea
In the three 30-week controlled trials of Byetta add-on to metformin and/or sulfonylurea, adverse reactions (excluding hypoglycemia) with an incidence ≥2% and occurring more frequently in Byetta-treated patients compared with placebo-treated patients [see Warnings and Precautions (5.2)] are summarized in Table 3.
| Placebo BID N = 483 % | All Byetta BID N = 963 % | |
|---|---|---|
| BID = twice daily. | ||
| ||
| Nausea | 18 | 44 |
| Vomiting | 4 | 13 |
| Diarrhea | 6 | 13 |
| Feeling Jittery | 4 | 9 |
| Dizziness | 6 | 9 |
| Headache | 6 | 9 |
| Dyspepsia | 3 | 6 |
| Asthenia | 2 | 4 |
| Gastroesophageal Reflux Disease | 1 | 3 |
| Hyperhidrosis | 1 | 3 |
Adverse reactions reported in ≥1.0 to <2.0% of patients receiving Byetta and reported more frequently than with placebo included decreased appetite. Nausea was the most frequently reported adverse reaction and occurred in a dose-dependent fashion. With continued therapy, the frequency and severity decreased over time in most of the patients who initially experienced nausea. Patients in the long-term uncontrolled open-label extension studies at 52 weeks reported no new types of adverse reactions than those observed in the 30-week controlled trials.
The most common adverse reactions leading to withdrawal for Byetta-treated patients were nausea (3% of patients) and vomiting (1%). For placebo-treated patients, <1% withdrew due to nausea and none due to vomiting.
Add-on to thiazolidinedione with or without metformin
For the 16-week placebo-controlled study of Byetta add-on to a thiazolidinedione, with or without metformin, Table 4 summarizes the adverse reactions (excluding hypoglycemia) with an incidence of ≥2% and occurring more frequently in Byetta-treated patients compared with placebo-treated patients.
| With a TZD or TZD/MET | Placebo N = 112 % | All Byetta BID N = 121 % |
|---|---|---|
| BID = twice daily. | ||
| ||
| Nausea | 15 | 40 |
| Vomiting | 1 | 13 |
| Dyspepsia | 1 | 7 |
| Diarrhea | 3 | 6 |
| Gastroesophageal Reflux Disease | 0 | 3 |
Adverse reactions reported in ≥1.0 to <2.0% of patients receiving Byetta and reported more frequently than with placebo included decreased appetite. Chills (n = 4) and injection-site reactions (n = 2) occurred only in Byetta-treated patients. The two patients who reported an injection-site reaction had high titers of antibodies to exenatide. Two serious adverse events (chest pain and chronic hypersensitivity pneumonitis) were reported in the Byetta arm. No serious adverse events were reported in the placebo arm.
The most common adverse reactions leading to withdrawal for Byetta-treated patients were nausea (9%) and vomiting (5%). For placebo-treated patients, <1% withdrew due to nausea.
Add-on to insulin glargine with or without metformin and/or thiazolidinedione
For the 30-week placebo-controlled study of Byetta as add-on to insulin glargine with or without oral antihyperglycemic medications, Table 5 summarizes adverse reactions (excluding hypoglycemia) occurring with an incidence ≥2% and occurring more frequently in Byetta-treated patients compared with placebo-treated patients.
| With Insulin Glargine | Placebo N = 122 % | All Byetta BID N = 137 % |
|---|---|---|
| BID = twice daily. | ||
| ||
| Nausea | 8 | 41 |
| Vomiting | 4 | 18 |
| Diarrhea | 8 | 18 |
| Headache | 4 | 14 |
| Constipation | 2 | 10 |
| Dyspepsia | 2 | 7 |
| Asthenia | 1 | 5 |
| Abdominal Distention | 1 | 4 |
| Decreased Appetite | 0 | 3 |
| Flatulence | 1 | 2 |
| Gastroesophageal Reflux Disease | 1 | 2 |
The most frequently reported adverse reactions leading to withdrawal for Byetta-treated patients were nausea (5.1%) and vomiting (2.9%). No placebo-treated patients withdrew due to nausea or vomiting.
Post-Marketing Experience
The following additional adverse reactions have been reported during post-approval use of Byetta. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Allergy/Hypersensitivity: injection-site reactions, generalized pruritus and/or urticaria, macular or papular rash, angioedema, anaphylactic reaction [see Warnings and Precautions (5.6)].
Drug Interactions: International normalized ratio (INR) increased with concomitant warfarin use sometimes associated with bleeding [see Drug Interactions (7.2)].
Gastrointestinal: nausea, vomiting, and/or diarrhea resulting in dehydration; abdominal distension, abdominal pain, eructation, constipation, flatulence, acute pancreatitis, hemorrhagic and necrotizing pancreatitis sometimes resulting in death [see Limitations of Use (1.2) and Warnings and Precautions (5.1)].
Neurologic: dysgeusia; somnolence
Renal and Urinary Disorders: altered renal function, including increased serum creatinine, renal impairment, worsened chronic renal failure or acute renal failure (sometimes requiring hemodialysis), kidney transplant and kidney transplant dysfunction [see Warnings and Precautions (5.3)].
Skin and Subcutaneous Tissue Disorders: alopecia
Drug Interactions
Orally Administered Drugs
The effect of Byetta to slow gastric emptying can reduce the extent and rate of absorption of orally administered drugs. Byetta should be used with caution in patients receiving oral medications that have narrow therapeutic index or require rapid gastrointestinal absorption [see Adverse Reactions (6.2)]. For oral medications that are dependent on threshold concentrations for efficacy, such as contraceptives and antibiotics, patients should be advised to take those drugs at least 1 hour before Byetta injection. If such drugs are to be administered with food, patients should be advised to take them with a meal or snack when Byetta is not administered [see Clinical Pharmacology (12.3)].
Warfarin
There are postmarketing reports of increased INR sometimes associated with bleeding, with concomitant use of warfarin and Byetta [see Adverse Reactions (6.2)]. In a drug interaction study, Byetta did not have a significant effect on INR [see Clinical Pharmacology (12.3)]. In patients taking warfarin, prothrombin time should be monitored more frequently after initiation or alteration of Byetta therapy. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on warfarin.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies of Byetta use in pregnant women. In animal studies, exenatide caused cleft palate, irregular skeletal ossification and an increased number of neonatal deaths. Byetta should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Female mice given SC doses of 6, 68, or 760 mcg/kg/day beginning 2 weeks prior to and throughout mating until gestation day 7 had no adverse fetal effects. At the maximal dose, 760 mcg/kg/day, systemic exposures were up to 390 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC [see Nonclinical Toxicology (13.3)].
In developmental toxicity studies, pregnant animals received exenatide subcutaneously during organogenesis. Specifically, fetuses from pregnant rabbits given SC doses of 0.2, 2, 22, 156, or 260 mcg/kg/day from gestation day 6 through 18 experienced irregular skeletal ossifications from exposures 12 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC. Moreover, fetuses from pregnant mice given SC doses of 6, 68, 460, or 760 mcg/kg/day from gestation day 6 through 15 demonstrated reduced fetal and neonatal growth, cleft palate and skeletal effects at systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC [see Nonclinical Toxicology (13.3)].
Lactating mice given SC doses of 6, 68, or 760 mcg/kg/day from gestation day 6 through lactation day 20 (weaning), experienced an increased number of neonatal deaths. Deaths were observed on postpartum days 2-4 in dams given 6 mcg/kg/day, a systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC [see Nonclinical Toxicology (13.3)].
Pregnancy Registry
Amylin Pharmaceuticals, Inc. maintains a Pregnancy Registry to monitor pregnancy outcomes of women exposed to exenatide during pregnancy. Physicians are encouraged to register patients by calling 1-800-633-9081.
Nursing Mothers
It is not known whether exenatide is excreted in human milk. However, exenatide is present at low concentrations (less than or equal to 2.5% of the concentration in maternal plasma following subcutaneous dosing) in the milk of lactating mice. Many drugs are excreted in human milk and because of the potential for clinically significant adverse reactions in nursing infants from exenatide, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account these potential risks against the glycemic benefits to the lactating woman. Caution should be exercised when Byetta is administered to a nursing woman.
Pediatric Use
Safety and effectiveness of Byetta have not been established in pediatric patients.
Geriatric Use
Population pharmacokinetic analysis of patients ranging from 22 to 73 years of age suggests that age does not influence the pharmacokinetic properties of exenatide [see Clinical Pharmacology (12.3)]. Byetta was studied in 282 patients 65 years of age or older and in 16 patients 75 years of age or older. No differences in safety or effectiveness were observed between these patients and younger patients. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in the elderly based on renal function.
Renal Impairment
Byetta is not recommended for use in patients with end-stage renal disease or severe renal impairment (creatinine clearance < 30 mL/min) and should be used with caution in patients with renal transplantation. No dosage adjustment of Byetta is required in patients with mild renal impairment (creatinine clearance 50 to 80 mL/min). Caution should be applied when initiating or escalating doses of Byetta from 5 mcg to 10 mcg in patients with moderate renal impairment (creatinine clearance 30 to 50 mL/min) [see Clinical Pharmacology (12.3)].
Hepatic Impairment
No pharmacokinetic study has been performed in patients with a diagnosis of acute or chronic hepatic impairment. Because exenatide is cleared primarily by the kidney, hepatic dysfunction is not expected to affect blood concentrations of exenatide [see Clinical Pharmacology (12.3)].
Overdosage
In a clinical study of Byetta, three patients with type 2 diabetes each experienced a single overdose of 100 mcg SC (10 times the maximum recommended dose). Effects of the overdoses included severe nausea, severe vomiting, and rapidly declining blood glucose concentrations. One of the three patients experienced severe hypoglycemia requiring parenteral glucose administration. The three patients recovered without complication. In the event of overdose, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms.
Byetta Description
Byetta (exenatide) is a synthetic peptide that was originally identified in the lizard Heloderma suspectum. Exenatide differs in chemical structure and pharmacological action from insulin, sulfonylureas (including D-phenylalanine derivatives and meglitinides), biguanides, thiazolidinediones, alpha-glucosidase inhibitors, amylinomimetics and dipeptidyl peptidase-4 inhibitors.
Exenatide is a 39-amino acid peptide amide. Exenatide has the empirical formula C184H282N50O60S and molecular weight of 4186.6 Daltons. The amino acid sequence for exenatide is shown below.
H - His - Gly - Glu - Gly - Thr - Phe - Thr - Ser - Asp - Leu - Ser - Lys - Gln - Met - Glu - Glu - Glu - Ala - Val - Arg - Leu - Phe - Ile - Glu - Trp - Leu - Lys - Asn - Gly - Gly - Pro - Ser - Ser - Gly - Ala - Pro - Pro - Pro - Ser - NH2
Byetta is supplied for SC injection as a sterile, preserved isotonic solution in a glass cartridge that has been assembled in a pen-injector (pen). Each milliliter (mL) contains 250 micrograms (mcg) synthetic exenatide, 2.2 mg metacresol as an antimicrobial preservative, mannitol as a tonicity-adjusting agent, and glacial acetic acid and sodium acetate trihydrate in water for injection as a buffering solution at pH 4.5. Two prefilled pens are available to deliver unit doses of 5 mcg or 10 mcg. Each prefilled pen will deliver 60 doses to provide for 30 days of twice daily administration (BID).
Byetta - Clinical Pharmacology
Mechanism of Action
Incretins, such as glucagon-like peptide-1 (GLP-1), enhance glucose-dependent insulin secretion and exhibit other antihyperglycemic actions following their release into the circulation from the gut. Byetta is a GLP-1 receptor agonist that enhances glucose-dependent insulin secretion by the pancreatic beta-cell, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying.
The amino acid sequence of exenatide partially overlaps that of human GLP-1. Exenatide has been shown to bind and activate the human GLP-1 receptor in vitro. This leads to an increase in both glucose-dependent synthesis of insulin, and in vivo secretion of insulin from pancreatic beta cells, by mechanisms involving cyclic AMP and/or other intracellular signaling pathways.
Byetta improves glycemic control by reducing fasting and postprandial glucose concentrations in patients with type 2 diabetes through the actions described below.
Pharmacodynamics
Glucose-dependent insulin secretion: Byetta has acute effects on pancreatic beta-cell responsiveness to glucose leading to insulin release predominantly in the presence of elevated glucose concentrations. This insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia. However, Byetta does not impair the normal glucagon response to hypoglycemia.
First-phase insulin response: In healthy individuals, robust insulin secretion occurs during the first 10 minutes following intravenous (IV) glucose administration. This secretion, known as the "first-phase insulin response," is characteristically absent in patients with type 2 diabetes. The loss of the first-phase insulin response is an early beta-cell defect in type 2 diabetes. Administration of Byetta at therapeutic plasma concentrations restored first-phase insulin response to an IV bolus of glucose in patients with type 2 diabetes (Figure 1). Both first-phase insulin secretion and second-phase insulin secretion were significantly increased in patients with type 2 diabetes treated with Byetta compared with saline (p <0.001 for both).
Figure 1: Mean (+SEM) Insulin Secretion Rate During Infusion of Byetta or Saline in Patients With Type 2 Diabetes and During Infusion of Saline in Healthy Subjects
Glucagon secretion: In patients with type 2 diabetes, Byetta moderates glucagon secretion and lowers serum glucagon concentrations during periods of hyperglycemia. Lower glucagon concentrations lead to decreased hepatic glucose output and decreased insulin demand.
Gastric emptying: Byetta slows gastric emptying, thereby reducing the rate at which meal-derived glucose appears in the circulation.
Food intake: In both animals and humans, administration of exenatide has been shown to reduce food intake.
Postprandial Glucose
In patients with type 2 diabetes, Byetta reduces postprandial plasma glucose concentrations (Figure 2).
Figure 2: Mean (+SEM) Postprandial Plasma Glucose Concentrations on Day 1 of Byettaa Treatment in Patients With Type 2 Diabetes Treated With Metformin, a Sulfonylurea, or Both (N = 54)
Fasting Glucose
In a single-dose crossover study in patients with type 2 diabetes and fasting hyperglycemia, immediate insulin release followed injection of Byetta. Plasma glucose concentrations were significantly reduced with Byetta compared with placebo (Figure 3).
Figure 3: Mean (+SEM) Serum Insulin and Plasma Glucose Concentrations Following a One-Time Injection of Byettaa or Placebo in Fasting Patients With Type 2 Diabetes (N = 12)
Cardiac Electrophysiology
The effect of exenatide 10 µg subcutaneously on QTc interval was evaluated in a randomized, placebo-, and active-controlled (moxifloxacin 400 mg) crossover thorough QTc study in 62 healthy subjects. In this study with demonstrated ability to detect small effects, the upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc was below 10 ms. Thus, Byetta (10 mcg single dose) was not associated with clinically meaningful prolongation of the QTc interval.
Pharmacokinetics
Absorption
Following SC administration to patients with type 2 diabetes, exenatide reaches median peak plasma concentrations in 2.1 h. The mean peak exenatide concentration (Cmax) was 211 pg/mL and overall mean area under the time-concentration curve (AUC0-inf) was 1036 pg∙h/mL following SC administration of a 10-mcg dose of Byetta. Exenatide exposure (AUC) increased proportionally over the therapeutic dose range of 5 mcg to 10 mcg. The Cmax values increased less than proportionally over the same range. Similar exposure is achieved with SC administration of Byetta in the abdomen, thigh, or upper arm.
Distribution
The mean apparent volume of distribution of exenatide following SC administration of a single dose of Byetta is 28.3 L.
Metabolism and Elimination
Nonclinical studies have shown that exenatide is predominantly eliminated by glomerular filtration with subsequent proteolytic degradation. The mean apparent clearance of exenatide in humans is 9.1 L/h and the mean terminal half-life is 2.4 h. These pharmacokinetic characteristics of exenatide are independent of the dose. In most individuals, exenatide concentrations are measurable for approximately 10 h post-dose.
Drug Interactions
Acetaminophen
When 1000 mg acetaminophen elixir was given with 10 mcg Byetta (0 h) and 1 hour, 2 hours, and 4 hours after Byetta injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively; Tmax was increased from 0.6 hour in the control period to 0.9 hour, 4.2 hours, 3.3 hours, and 1.6 hours, respectively. Acetaminophen AUC, Cmax and Tmax were not significantly changed when acetaminophen was given 1 hour before Byetta injection.
Digoxin
Administration of repeated doses of Byetta (10 mcg BID) 30 minutes before oral digoxin (0.25 mg QD) decreased the Cmax of digoxin by 17% and delayed the Tmax of digoxin by approximately 2.5 hours; however, the overall steady-state pharmacokinetic exposure (e.g., AUC) of digoxin was not changed.
Lovastatin
Administration of Byetta (10 mcg BID) 30 minutes before a single oral dose of lovastatin (40 mg) decreased the AUC and Cmax of lovastatin by approximately 40% and 28%, respectively, and delayed the Tmax by about 4 hours compared with lovastatin administered alone. In the 30-week controlled clinical trials of Byetta, the use of Byetta in patients already receiving HMG CoA reductase inhibitors was not associated with consistent changes in lipid profiles compared to baseline.
Lisinopril
In patients with mild to moderate hypertension stabilized on lisinopril (5 to 20 mg/day), Byetta (10 mcg BID) did not alter steady-state Cmax or AUC of lisinopril. Lisinopril steady-state Tmax was delayed by 2 hours. There were no changes in 24-h mean systolic and diastolic blood pressure.
Oral Contraceptives
The effect of Byetta (10 mcg BID) on single and on multiple doses of a combination oral contraceptive (30 mcg ethinyl estradiol plus 150 mcg levonorgestrel) was studied in healthy female subjects. Repeated daily doses of the oral contraceptive (OC) given 30 minutes after Byetta administration decreased the Cmax of ethinyl estradiol and levonorgestrel by 45% and 27%, respectively and delayed the Tmax of ethinyl estradiol and levonorgestrel by 3.0 hours and 3.5 hours, respectively, as compared to the oral contraceptive administered alone. Administration of repeated daily doses of the OC one hour prior to Byetta administration decreased the mean Cmax of ethinyl estradiol by 15% but the mean Cmax of levonorgestrel was not significantly changed as compared to when the OC was given alone. Byetta did not alter the mean trough concentrations of levonorgestrel after repeated daily dosing of the oral contraceptive for both regimens. However, the mean trough concentration of ethinyl estradiol was increased by 20% when the OC was administered 30 minutes after Byetta administration injection as compared to when the OC was given alone. The effect of Byetta on OC pharmacokinetics is confounded by the possible food effect on OC in this study. Therefore, OC products should be administered at least one hour prior to Byetta injection.
Warfarin
Administration of warfarin (25 mg) 35 minutes after repeated doses of Byetta (5 mcg BID on days 1-2 and 10 mcg BID on days 3-9) in healthy volunteers delayed warfarin Tmax by approximately 2 hours. No clinically relevant effects on Cmax or AUC of S- and R-enantiomers of warfarin were observed. Byetta did not significantly alter the pharmacodynamic properties (e.g., international normalized ratio) of warfarin [see Drug Interactions (7.2)].
Specific Populations
Renal Impairme
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