Lotrial D may be available in the countries listed below.
Enalapril is reported as an ingredient of Lotrial D in the following countries:
Hydrochlorothiazide is reported as an ingredient of Lotrial D in the following countries:
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Triaminic Expectorant may be available in the countries listed below.
Guaifenesin is reported as an ingredient of Triaminic Expectorant in the following countries:
Pseudoephedrine hydrochloride (a derivative of Pseudoephedrine) is reported as an ingredient of Triaminic Expectorant in the following countries:
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Flusal may be available in the countries listed below.
Omeprazole is reported as an ingredient of Flusal in the following countries:
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Oxicodal may be available in the countries listed below.
Oxcarbazepine is reported as an ingredient of Oxicodal in the following countries:
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Paceum may be available in the countries listed below.
Diazepam is reported as an ingredient of Paceum in the following countries:
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Alendron-Mepha may be available in the countries listed below.
Alendronic Acid sodium trihydrate (a derivative of Alendronic Acid) is reported as an ingredient of Alendron-Mepha in the following countries:
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Co-Lisinopril EG may be available in the countries listed below.
Hydrochlorothiazide is reported as an ingredient of Co-Lisinopril EG in the following countries:
Lisinopril is reported as an ingredient of Co-Lisinopril EG in the following countries:
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Rayonfur may be available in the countries listed below.
Nitrofural is reported as an ingredient of Rayonfur in the following countries:
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Fenitoina Denver Farma may be available in the countries listed below.
Phenytoin sodium salt (a derivative of Phenytoin) is reported as an ingredient of Fenitoina Denver Farma in the following countries:
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Flexicônes may be available in the countries listed below.
Benzocaine is reported as an ingredient of Flexicônes in the following countries:
Neomycin sulfate (a derivative of Neomycin) is reported as an ingredient of Flexicônes in the following countries:
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Terazosina Cinfa may be available in the countries listed below.
Terazosin hydrochloride (a derivative of Terazosin) is reported as an ingredient of Terazosina Cinfa in the following countries:
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Diclonac S may be available in the countries listed below.
Diclofenac sodium salt (a derivative of Diclofenac) is reported as an ingredient of Diclonac S in the following countries:
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Rx only
Each 5 mL of Oral Solution contains:
Diazepam........................................................... 5 mg
Each mL of IntensolTM Oral Solution (Concentrate) contains:
Diazepam............................................................ 5 mg
Alcohol................................................................ 19%
Inactive Ingredients:
The wintergreen-spice flavored 5 mg/5 mL Oral Solution contains bitterness modifier, citric acid, D&C Yellow No. 10, FD&C Red No. 40, flavoring, polyethylene glycol, propylene glycol, sodium citrate, sorbitol, and water.
The 5 mg/mL IntensolTM Oral Solution (Concentrate) contains alcohol, D&C Yellow No. 10, polyethylene glycol, propylene glycol, succinic acid, and water.
Diazepam is a benzodiazepine derivative. Chemically, diazepam is 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one. It is a colorless crystalline compound, insoluble in water and has a molecular weight of 284.74. Its structural formula is as follows:
C16H13CIN2
In animals diazepam appears to act on parts of the limbic system, the thalamus and hypothalamus, and induces calming effects. Diazepam, unlike chlorpromazine and reserpine, has no demonstrable peripheral autonomic blocking action, nor does it produce extrapyramidal side effects; however, animals treated with diazepam do have a transient ataxia at higher doses. Diazepam was found to have transient cardiovascular depressor effects in dogs. Long-term experiments in rats revealed no disturbances of endocrine function.
Oral LD50 of diazepam is 720 mg/kg in mice and 1240 mg/kg in rats. Intraperitoneal administration of 400 mg/kg to a monkey resulted in death on the sixth day.
A series of rat reproduction studies was performed with diazepam in oral doses of 1, 10, 80 and 100 mg/kg. At 100 mg/kg there was a decrease in the number of pregnancies and surviving offspring in these rats. Neonatal survival of rats at doses lower than 100 mg/kg was within normal limits. Several neonates in these rat reproduction studies showed skeletal or other defects. Further studies in rats at doses up to and including 80 mg/kg/day did not reveal teratological effects on the offspring.
In humans, measurable blood levels of diazepam were obtained in maternal and cord blood, indicating placental transfer of the drug.
Diazepam is indicated for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic.
In acute alcohol withdrawal, diazepam may be useful in the symptomatic relief of acute agitation, tremor, impending or acute delirium tremens and hallucinosis.
Diazepam is a useful adjunct for the relief of skeletal muscle spasm due to reflex spasm to local pathology (such as inflammation of the muscles or joints, or secondary to trauma); spasticity caused by upper motor neuron disorders (such as cerebral palsy and paraplegia); athetosis; and stiff-man syndrome.
Oral diazepam may be used adjunctively in convulsive disorders, although it has not proved useful as the sole therapy.
The effectiveness of diazepam in long-term use, that is, more than 4 months, has not been assessed by systematic clinical studies. The physician should periodically reassess the usefulness of the drug for the individual patient.
Diazepam is contraindicated in patients with a known hypersensitivity to this drug and, because of lack of sufficient clinical experience, in children under 6 months of age. It may be used in patients with open angle glaucoma who are receiving appropriate therapy, but is contraindicated in acute narrow angle glaucoma.
Diazepam is not of value in the treatment of psychotic patients and should not be employed in lieu of appropriate treatment. As is true of most preparations containing CNS-acting drugs, patients receiving diazepam should be cautioned against engaging in hazardous occupations requiring complete mental alertness such as operating machinery or driving a motor vehicle.
As with other agents which have anticonvulsant activity, when diazepam is used as an adjunct in treating convulsive disorders, the possibility of an increase in the frequency and/or severity of grand mal seizures may require an increase in the dosage of standard anticonvulsant medication. Abrupt withdrawal of diazepam in such cases may also be associated with a temporary increase in the frequency and/or severity of seizures.
Since diazepam has a central nervous system depressant effect, patients should be advised against the simultaneous ingestion of alcohol and other CNS-depressant drugs during diazepam therapy.
An increased risk of congenital malformations associated with the use of minor tranquilizers (diazepam, meprobamate and chlordiazepoxide) during the first trimester of pregnancy has been suggested in several studies. Because use of these drugs is rarely a matter of urgency, their use during this period 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.
Manifestations of diazepam overdosage include somnolence, confusion, coma and diminished reflexes. Respiration, pulse and blood pressure should be monitored, as in all cases of drug overdosage, although, in general, these effects have been minimal following overdosage. General supportive measures should be employed, along with immediate gastric lavage. Intravenous fluids should be administered and an adequate airway maintained. Hypotension may be combated by the use of norepinephrine or metaraminol. Dialysis is of limited value. As with the management of intentional overdosage 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-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert including CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS should be consulted prior to use.
Withdrawal symptoms of the barbiturate type have occurred after the discontinuation of benzodiazepines (see DRUG ABUSE AND DEPENDENCE section).
If diazepam is 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 known compounds which may potentiate the action of diazepam such as phenothiazines, narcotics, barbiturates, MAO inhibitors and other antidepressants. The usual precautions are indicated for severely depressed patients or those in whom there is any evidence of latent depression; particularly the recognition that suicidal tendencies may be present and protective measures may be necessary. The usual precautions in treating patients with impaired renal or hepatic function should be observed.
In elderly and debilitated patients, it is recommended that the dosage be limited to the smallest effective amount to preclude the development of ataxia or oversedation (2 mg to 2 1/2 mg once or twice daily, initially, to be increased gradually as needed and tolerated).
The clearance of diazepam and certain other benzodiazepines can be delayed in association with Tagamet (cimetidine) administration. The clinical significance of this is unclear.
To assure the safe and effective use of benzodiazepines, patients should be informed that, since benzodiazepines may produce psychological and physical dependence, it is advisable that they consult with their physician before either increasing the dose or abruptly discontinuing this drug.
Side effects most commonly reported were drowsiness, fatigue and ataxia. Infrequently encountered were confusion, constipation, depression, diplopia, dysarthria, headache, hypotension, incontinence, jaundice, changes in libido, nausea, changes in salivation, skin rash, slurred speech, tremor, urinary retention, vertigo and blurred vision. Paradoxical reactions such as acute hyperexcited states, anxiety, hallucinations, increased muscle spasticity, insomnia, rage, sleep disturbances and stimulation have been reported; should these occur, use of the drug should be discontinued.
Because of isolated reports of neutropenia and jaundice, periodic blood counts and liver function tests are advisable during long-term therapy. Minor changes in EEG patterns, usually low-voltage fast activity, have been observed in patients during and after diazepam therapy and are of no known significance.
Diazepam Oral Solution and IntensolTM Oral Solution (Concentrate) are classified by the Drug Enforcement Administration as a Schedule IV controlled substance.
Withdrawal symptoms, similar in character to those noted with barbiturates and alcohol (e.g., convulsions, tremor, abdominal and muscle cramps, vomiting and sweating), have occurred following abrupt discontinuance of diazepam. The more severe withdrawal symptoms have usually been limited to those patients who received excessive doses over an extended period of time. Generally milder withdrawal symptoms (e.g., dysphoria and insomnia) have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic levels for several months. Consequently, after extended therapy, abrupt discontinuance should generally be avoided and a gradual dosage tapering schedule followed. Addiction-prone individuals (such as drug addicts or alcoholics) should be under careful surveillance when receiving diazepam or other psychotropic agents because of the predisposition of such patients to habituation and dependence.
Dosage should be individualized for maximum beneficial effect. While the usual daily dosages given below will meet the needs of most patients, there will be some who may require higher doses. In such cases dosage should be increased cautiously to avoid adverse effects.
| Adults: | Usual Daily Dosage |
| Management of Anxiety Disorders and Relief of Symptoms of Anxiety. | Depending upon severity of symptoms – 2 mg to 10 mg, 2 to 4 times daily. |
| Symptomatic Relief in Acute Alcohol Withdrawal. | 10 mg, 3 or 4 times during the first 24 hours, reducing to 5 mg, 3 or 4 times daily as needed. |
| Adjunctively for Relief of Skeletal Muscle Spasm. | 2 mg to 10 mg, 3 or 4 times daily. |
| Adjunctively in Convulsive Disorders. | 2 mg to 10 mg, 2 to 4 times daily. |
| Geriatric Patients or in the presence of debilitating disease. | 2 mg to 2 1/2 mg, 1 or 2 times daily initially; increase gradually as needed and tolerated. |
| Children: | |
| Because of varied responses to CNS-acting drugs, initiate therapy with lowest dose and increase as required. Not for use in children under 6 months. | 1 mg to 2 1/2 mg, 3 or 4 times daily initially; increase gradually as needed and tolerated. |
An Intensol is a concentrated oral solution as compared to standard oral liquid medications. It is recommended that an Intensol be mixed with liquid or semi-solid food such as water, juices, soda or soda-like beverages, applesauce and puddings.
Use only the calibrated dropper provided with this product. Draw into the dropper the amount prescribed for a single dose. Then squeeze the dropper contents into a liquid or semi-solid food. Stir the liquid or food gently for a few seconds. The Intensol formulation blends quickly and completely. The entire amount of the mixture, of drug and liquid or drug and food, should be consumed immediately. Do not store for future use.
Diazepam Oral Solution, 5 mg per 5 mL (Orange-colored, wintergreen-spice flavored solution)
NDC 0054-8207-16: Unit dose Patient CupTM filled to deliver 5 mL (Diazepam 5 mg), ten 5 mL Patient CupsTM per shelf pack, 4 shelf packs per shipper.
NDC 0054-3188-63: Bottle of 500 mL.
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]
Dispense in tight, light-resistant container as defined in the USP/NF.
Diazepam IntensolTM Oral Solution (Concentrate), 5 mg per mL
(Clear, yellow solution)
NDC 0054-3185-44: Bottle of 30 mL with calibrated dropper [graduations of 0.2 mL (1 mg), 0.4 mL (2 mg), 0.6 mL (3 mg), 0.8 mL (4 mg), and 1 mL (5 mg) on the dropper].
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]
Discard opened bottle after 90 days.
PROTECT FROM LIGHT.
4048501//05 Revised September 2009
© RLI, 2009
NDC 0054-8207-16: Unit dose Patient CupTM filled to deliver 5 mL (Diazepam 5 mg)
Rx Only
Roxane Laboratories, Inc.
NDC 0054-3188-63: Bottle of 500 mL.
Rx Only
Roxane Laboratories, Inc.
NDC 0054-3185-44: Bottle of 30 mL with calibrated dropper
Rx Only
Roxane Laboratories, Inc.
| DIAZEPAM diazepam solution | ||||||||||||||||||||
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| Marketing Information | |||
| Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
| ANDA | ANDA070928 | 04/03/1987 | |
| DIAZEPAM INTENSOL diazepam intensol solution, concentrate | ||||||||||||||||||||
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| Marketing Information | |||
| Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
| ANDA | ANDA071415 | 04/03/1987 | |
| DIAZEPAM diazepam solution | ||||||||||||||||||||
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| Marketing Information | |||
| Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
| ANDA | ANDA070928 | 06/14/1990 | |
| Labeler - Roxane Laboratories, Inc (058839929) |
| Registrant - Roxane Laboratories, Inc (058839929) |
| Establishment | |||
| Name | Address | ID/FEI | Operations |
| Boehringer Ingelheim Roxane Inc | 128407710 | MANUFACTURE | |
Furosemid Basics may be available in the countries listed below.
Furosemide is reported as an ingredient of Furosemid Basics in the following countries:
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Marvitrox may be available in the countries listed below.
Azithromycin is reported as an ingredient of Marvitrox in the following countries:
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Gyne-Lotremin may be available in the countries listed below.
Clotrimazole is reported as an ingredient of Gyne-Lotremin in the following countries:
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Fluor Lacer may be available in the countries listed below.
Sodium Fluoride is reported as an ingredient of Fluor Lacer in the following countries:
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Minartine may be available in the countries listed below.
Levocarnitine is reported as an ingredient of Minartine in the following countries:
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Kentacef may be available in the countries listed below.
Cefatrizine comp. with propylene glycole (a derivative of Cefatrizine) is reported as an ingredient of Kentacef in the following countries:
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Prop.INN
0064506-49-6
C27-H30-O6
450
Treatment of peptic ulcer
Acetic acid, [5-[(3-methyl-2-butenyl)oxy]-2-[3-[4-[(3-methyl-2-butenyl)oxy]phenyl]-1-oxo-2-propenyl]phenoxy]-
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Glossary
| IS | Inofficial Synonym |
| JAN | Japanese Accepted Name |
| OS | Official Synonym |
| Prop.INN | Proposed International Nonproprietary Name (World Health Organization) |
Flurodeks may be available in the countries listed below.
Sodium Fluoride is reported as an ingredient of Flurodeks in the following countries:
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Fluconazol Apotex may be available in the countries listed below.
Fluconazole is reported as an ingredient of Fluconazol Apotex in the following countries:
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Diclo-1A Pharma may be available in the countries listed below.
Diclofenac sodium salt (a derivative of Diclofenac) is reported as an ingredient of Diclo-1A Pharma in the following countries:
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Treating pain and discomfort caused by ingrown toenails.
Dr. Scholl's Ingrown Toenail Pain Reliever Gel works by absorbing into the nail to help relieve ingrown toenail pain.
Contact your doctor or health care provider right away if any of these apply to you.
Some medical conditions may interact with Dr. Scholl's Ingrown Toenail Pain Reliever Gel. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:
Some MEDICINES MAY INTERACT with Dr. Scholl's Ingrown Toenail Pain Reliever Gel. Because little, if any, of Dr. Scholl's Ingrown Toenail Pain Reliever Gel is absorbed into the blood, the risk of it interacting with another medicine is low.
Ask your health care provider if Dr. Scholl's Ingrown Toenail Pain Reliever Gel 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.
Use Dr. Scholl's Ingrown Toenail Pain Reliever Gel as directed by your doctor. Check the label on the medicine for exact dosing instructions.
Ask your health care provider any questions you may have about how to use Dr. Scholl's Ingrown Toenail Pain Reliever Gel.
All medicines may cause side effects, but many people have no, or minor, side effects. No COMMON side effects have been reported with Dr. Scholl's Ingrown Toenail Pain Reliever Gel. Seek medical attention right away if any of these SEVERE side effects occur:
Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue).
This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.
See also: Dr. Scholl's Ingrown Toenail Pain Reliever side effects (in more detail)
If OVERDOSE is suspected: Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.
Store Dr. Scholl's Ingrown Toenail Pain Reliever Gel between 59 and 77 degrees F (15 and 25 degrees C), in a tightly closed container. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Dr. Scholl's Ingrown Toenail Pain Reliever Gel out of the reach of children and away from pets.
This information is a summary only. It does not contain all information about Dr. Scholl's Ingrown Toenail Pain Reliever Gel. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.
Brondil may be available in the countries listed below.
Ambroxol is reported as an ingredient of Brondil in the following countries:
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Omeprasec may be available in the countries listed below.
Omeprazole magnesium salt (a derivative of Omeprazole) is reported as an ingredient of Omeprasec in the following countries:
Omeprazole sodium salt (a derivative of Omeprazole) is reported as an ingredient of Omeprasec in the following countries:
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Gestiferrol may be available in the countries listed below.
Ferrous Fumarate is reported as an ingredient of Gestiferrol in the following countries:
Folic Acid is reported as an ingredient of Gestiferrol in the following countries:
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Halocur may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Halofuginone is reported as an ingredient of Halocur in the following countries:
Halofuginone lactate (a derivative of Halofuginone) is reported as an ingredient of Halocur in the following countries:
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Lopéramide Arrow Conseil may be available in the countries listed below.
Loperamide hydrochloride (a derivative of Loperamide) is reported as an ingredient of Lopéramide Arrow Conseil in the following countries:
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Fluconazol Milo may be available in the countries listed below.
Fluconazole is reported as an ingredient of Fluconazol Milo in the following countries:
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Fluoben may be available in the countries listed below.
Flubendazole is reported as an ingredient of Fluoben in the following countries:
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Potasio Gluconate may be available in the countries listed below.
Potassium Gluconate is reported as an ingredient of Potasio Gluconate in the following countries:
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Fluoresceine Oxybuprocaine Faure may be available in the countries listed below.
Fluorescein sodium (a derivative of Fluorescein) is reported as an ingredient of Fluoresceine Oxybuprocaine Faure in the following countries:
Oxybuprocaine hydrochloride (a derivative of Oxybuprocaine) is reported as an ingredient of Fluoresceine Oxybuprocaine Faure in the following countries:
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Bisoprolol-HCT Arcana may be available in the countries listed below.
Bisoprolol fumarate (a derivative of Bisoprolol) is reported as an ingredient of Bisoprolol-HCT Arcana in the following countries:
Hydrochlorothiazide is reported as an ingredient of Bisoprolol-HCT Arcana in the following countries:
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Furosemid-Teva may be available in the countries listed below.
Furosemide is reported as an ingredient of Furosemid-Teva in the following countries:
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Norocarp may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Carprofen is reported as an ingredient of Norocarp in the following countries:
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Myophos may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Sodium Selenite is reported as an ingredient of Myophos in the following countries:
Tocopherol, α- acetate (a derivative of Tocopherol, α-) is reported as an ingredient of Myophos in the following countries:
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The short-term management of obesity combined with a diet and exercise program.
Bontril PDM is an anorectic. Exactly how Bontril PDM works is unknown, although one of its effects is to decrease your appetite.
Contact your doctor or health care provider right away if any of these apply to you.
Some medical conditions may interact with Bontril PDM. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:
Some MEDICINES MAY INTERACT with Bontril PDM. Tell your health care provider if you are taking any other medicines, especially any of the following:
This may not be a complete list of all interactions that may occur. Ask your health care provider if Bontril PDM 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.
Use Bontril PDM as directed by your doctor. Check the label on the medicine for exact dosing instructions.
Ask your health care provider any questions you may have about how to use Bontril PDM.
When used for long periods of time or at high doses, Bontril PDM may not work as well and may require higher doses to obtain the same effect as when originally taken. This is known as TOLERANCE. Talk with your doctor if Bontril PDM stops working well. Do not take more than prescribed.
When used for longer than a few weeks or at high doses, some people develop a need to continue taking Bontril PDM. This is known as DEPENDENCE or addiction.
If you suddenly stop taking Bontril PDM, you may experience WITHDRAWAL symptoms including extreme fatigue and depression.
All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:
Agitation; blurred vision; constipation; diarrhea; dizziness; dry mouth; flushing; headache; nausea; nervousness; overstimulation; restlessness; trouble sleeping.
Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); changes in sex drive; fast or irregular heartbeat; frequent urination or trouble urinating; hallucinations; seizures; severe headache or dizziness; stomach pain; sweating; tremor; unusual behavior or personality changes.
This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.
See also: Bontril PDM side effects (in more detail)
Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include coma; confusion; diarrhea; nausea; panic attack; rapid breathing; seizures; severe restlessness; stomach cramps; tremor; vomiting.
Store Bontril PDM at room temperature, between 68 and 77 degrees F (20 and 25 degrees C). Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Bontril PDM out of the reach of children and away from pets.
This information is a summary only. It does not contain all information about Bontril PDM. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.
Scholl Corn Removal may be available in the countries listed below.
UK matches:
Salicylic Acid is reported as an ingredient of Scholl Corn Removal in the following countries:
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Glossary
| SPC | Summary of Product Characteristics (UK) |
Relpax® (eletriptan) Tablets contain eletriptan hydrobromide, which is a selective 5-hydroxytryptamine 1B/1D (5-HT1B/1D) receptor agonist. Eletriptan is chemically designated as (R)-3-[(1-Methyl-2-pyrrolidinyl)methyl]-5-[2-(phenylsulfonyl)ethyl]-1H-indole monohydrobromide, and it has the following chemical structure:
The empirical formula is C22H26N2O2S . HBr, representing a molecular weight of 463.40. Eletriptan hydrobromide is a white to light pale colored powder that is readily soluble in water.
Each Relpax Tablet for oral administration contains 24.2 or 48.5 mg of eletriptan hydrobromide equivalent to 20 mg or 40 mg of eletriptan, respectively. Each tablet also contains the inactive ingredients microcrystalline cellulose NF, lactose NF, croscarmellose sodium NF, magnesium stearate NF, titanium dioxide USP, hypromellose, triacetin USP and FD&C Yellow No. 6 aluminum lake.
Eletriptan binds with high affinity to 5-HT1B, 5-HT1D and 5-HT1F receptors, has modest affinity for 5-HT1A, 5-HT1E, 5-HT2B and 5-HT7 receptors, and little or no affinity for 5-HT2A, 5-HT2C, 5-HT3, 5-HT4, 5-HT5A and 5-HT6 receptors. Eletriptan has no significant affinity or pharmacological activity at adrenergic alpha1, alpha2, or beta; dopaminergic D1 or D2; muscarinic; or opioid receptors.
Two theories have been proposed to explain the efficacy of 5-HT receptor agonists in migraine. One theory suggests that activation of 5-HT1 receptors located on intracranial blood vessels, including those on the arteriovenous anastomoses, leads to vasoconstriction, which is correlated with the relief of migraine headache. The other hypothesis suggests that activation of 5-HT1 receptors on sensory nerve endings in the trigeminal system results in the inhibition of pro-inflammatory neuropeptide release.
In the anesthetized dog, eletriptan has been shown to reduce carotid arterial blood flow, with only a small increase in arterial blood pressure at high doses. While the effect on blood flow was selective for the carotid arterial bed, decreases in coronary artery diameter were observed. Eletriptan has also been shown to inhibit trigeminal nerve activity in the rat.
Eletriptan is well absorbed after oral administration with peak plasma levels occurring approximately 1.5 hours after dosing to healthy subjects. In patients with moderate to severe migraine the median Tmax is 2.0 hours. The mean absolute bioavailability of eletriptan is approximately 50%. The oral pharmacokinetics are slightly more than dose-proportional over the clinical dose range. The AUC and Cmax of eletriptan are increased by approximately 20 to 30% following oral administration with a high fat meal.
The volume of distribution of eletriptan following IV administration is 138L. Plasma protein binding is moderate and approximately 85%.
The N-demethylated metabolite of eletriptan is the only known active metabolite. This metabolite causes vasoconstriction similar to eletriptan in animal models. Though the half-life of the metabolite is estimated to be about 13 hours, the plasma concentration of the N-demethylated metabolite is 10–20% of parent drug and is unlikely to contribute significantly to the overall effect of the parent compound.
In vitro studies indicate that eletriptan is primarily metabolized by cytochrome P-450 enzyme CYP3A4 (see WARNINGS, DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY: Drug Interactions).
The terminal elimination half-life of eletriptan is approximately 4 hours. Mean renal clearance (CLR) following oral administration is approximately 3.9 L/h. Non-renal clearance accounts for about 90% of the total clearance.
The pharmacokinetics of eletriptan are generally unaffected by age.
Eletriptan has been given to only 50 patients over the age of 65. Blood pressure was increased to a greater extent in elderly subjects than in young subjects. The pharmacokinetic disposition of eletriptan in the elderly is similar to that seen in younger adults (see PRECAUTIONS).
There is a statistically significant increased half-life (from about 4.4 hours to 5.7 hours) between elderly (65 to 93 years of age) and younger adult subjects (18 to 45 years of age) (see PRECAUTIONS).
The pharmacokinetics of eletriptan are unaffected by gender.
A comparison of pharmacokinetic studies run in western countries with those run in Japan has indicated an approximate 35% reduction in the exposure of eletriptan in Japanese male volunteers compared to western males. Population pharmacokinetic analysis of two clinical studies indicates no evidence of pharmacokinetic differences between Caucasians and non-Caucasian patients.
In a study of 16 healthy females, the pharmacokinetics of eletriptan remained consistent throughout the phases of the menstrual cycle.
There was no significant change in clearance observed in subjects with mild, moderate or severe renal impairment, though blood pressure elevations were observed in this population (see WARNINGS).
The effects of severe hepatic impairment on eletriptan metabolism have not been evaluated. Subjects with mild or moderate hepatic impairment demonstrated an increase in both AUC (34%) and half-life. The Cmax was increased by 18% (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
In vitro studies have shown that eletriptan is metabolized by the CYP3A4 enzyme. A clinical study demonstrated about a 3-fold increase in Cmax and about a 6-fold increase in the AUC of eletriptan when combined with ketoconazole. The half-life increased from 5 hours to 8 hours and the Tmax increased from 2.8 hours to 5.4 hours. Another clinical study demonstrated about a 2-fold increase in Cmax and about a 4-fold increase in AUC when erythromycin was co-administered with eletriptan. It has also been shown that co-administration of verapamil and eletriptan yields about a 2-fold increase in Cmax and about a 3-fold increase in AUC of eletriptan, and that co-administration of fluconazole and eletriptan yields about a 1.4-fold increase in Cmax and about a 2-fold increase in AUC of eletriptan.
Eletriptan should not be used within at least 72 hours of treatment with the following potent CYP3A4 inhibitors: ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir and nelfinavir. Eletriptan should not be used within 72 hours with drugs that have demonstrated potent CYP3A4 inhibition and have this potent effect described in the CONTRAINDICATIONS, WARNINGS or PRECAUTIONS sections of their labeling (see WARNINGS and DOSAGE AND ADMINISTRATION).
The Cmax and AUC of eletriptan were increased by 10 and 33%, respectively, in the presence of propranolol. No interactive increases in blood pressure were observed. No dosage adjustment appears to be needed for patients taking propranolol (see PRECAUTIONS).
The effect of eletriptan on enzymes other than cytochrome P-450 has not been investigated. In vitro human liver microsome studies suggest that eletriptan has little potential to inhibit CYP1A2, 2C9, 2E1 and 3A4 at concentrations up to 100µM. While eletriptan has an effect on CYP2D6 at high concentration, this effect should not interfere with metabolism of other drugs when eletriptan is used at recommended doses. There is no in vitro or in vivo evidence that clinical doses of eletriptan will induce drug metabolizing enzymes. Therefore, eletriptan is unlikely to cause clinically important drug interactions mediated by these enzymes.
The efficacy of Relpax in the acute treatment of migraines was evaluated in eight randomized, double-blind placebo-controlled studies. All eight studies used 40 mg. Seven studies evaluated an 80 mg dose and two studies included a 20 mg dose.
In all eight studies, randomized patients treated their headaches as outpatients. Seven studies enrolled adults and one study enrolled adolescents (age 11 to 17). Patients treated in the seven adult studies were predominantly female (85%) and Caucasian (94%) with a mean age of 40 years (range 18 to 78). In all studies, patients were instructed to treat a moderate to severe headache. Headache response, defined as a reduction in headache severity from moderate or severe pain to mild or no pain, was assessed up to 2 hours after dosing. Associated symptoms such as nausea, vomiting, photophobia and phonophobia were also assessed.
Maintenance of response was assessed for up to 24 hours post dose. In the adult studies, a second dose of Relpax Tablets or other medication was allowed 2 to 24 hours after the initial treatment for both persistent and recurrent headaches. The incidence and time to use of these additional treatments were also recorded.
In the seven adult studies, the percentage of patients achieving headache response 2 hours after treatment was significantly greater among patients receiving Relpax Tablets at all doses compared to those who received placebo. The two-hour response rates from these controlled clinical studies are summarized in Table 1.
| Placebo | Relpax 20 mg | Relpax 40 mg | Relpax 80 mg | |
|---|---|---|---|---|
| NA - Not Applicable | ||||
| ||||
| Study 1 | 23.8% (n=126) | 54.3%* (n=129) | 65.0%* (n=117) | 77.1%* (n=118) |
| Study 2 | 19.0% (n=232) | NA | 61.6%* (n=430) | 64.6%* (n=446) |
| Study 3 | 21.7% (n=276) | 47.3%* (n=273) | 61.9%* (n=281) | 58.6%* (n=290) |
| Study 4 | 39.5% (n=86) | NA | 62.3%* (n=175) | 70.0%* (n=170) |
| Study 5 | 20.6% (n=102) | NA | 53.9%* (n=206) | 67.9%* (n=209) |
| Study 6 | 31.3% (n=80) | NA | 63.9%* (n=169) | 66.9%* (n=160) |
| Study 7 | 29.5% (n=122) | NA | 57.5%* (n=492) | NA |
Comparisons of the performance of different drugs based upon results obtained in different clinical trials are never reliable. Because studies are generally conducted at different times, with different samples of patients, by different investigators, employing different criteria and/or different interpretations of the same criteria, under different conditions (dose, dosing regimen, etc.), quantitative estimates of treatment response and the timing of response may be expected to vary considerably from study to study.
The estimated probability of achieving an initial headache response within 2 hours following treatment is depicted in Figure 1.
*Figure 1 shows the Kaplan-Meier plot of probability over time of obtaining headache response (no or mild pain) following treatment with eletriptan. The plot is based on 7 placebo-controlled, outpatient trials in adults providing evidence of efficacy (Studies 1 through 7). Patients not achieving headache response or taking additional treatment prior to 2 hours were censored at 2 hours.
For patients with migraine-associated photophobia, phonophobia, and nausea at baseline, there was a decreased incidence of these symptoms following administration of Relpax as compared to placebo.
Two to 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain relief in the form of a second dose of study treatment or other medication. The estimated probability of taking a second dose or other medications for migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 2.
*This Kaplan-Meier plot is based on data obtained in 7 placebo-controlled trials in adults (Studies 1 through 7). Patients were instructed to take a second dose of study medication as follows: a) in the event of no response at 2 hours (studies 2 and 4–7) or at 4 hours (study 3); b) in the event of headache recurrence within 24 hours (studies 2–7). Patients not using additional treatments were censored at 24 hours. The plot includes both patients who had headache response at 2 hours and those who had no response to the initial dose. It should be noted that the protocols did not allow remedication within 2 hours post dose.
The efficacy of Relpax was unaffected by the duration of attack; gender or age of the patient; relationship to menses; or concomitant use of estrogen replacement therapy/oral contraceptives or frequently used migraine prophylactic drugs.
In a single study in adolescents (n=274), there were no statistically significant differences between treatment groups. The headache response rate at 2 hours was 57% for both Relpax 40 mg Tablets and placebo.
Relpax is indicated for the acute treatment of migraine with or without aura in adults.
Relpax is not intended for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine (see CONTRAINDICATIONS). Safety and effectiveness of Relpax Tablets have not been established for cluster headache, which is present in an older, predominantly male population.
Relpax Tablets should not be given to patients with ischemic heart disease (e.g., angina pectoris, history of myocardial infarction, or documented silent ischemia) or to patients who have symptoms, or findings consistent with ischemic heart disease, coronary artery vasospasm, including Prinzmetal's variant angina, or other significant underlying cardiovascular disease (see WARNINGS).
Relpax Tablets should not be given to patients with cerebrovascular syndromes including (but not limited to) strokes of any type as well as transient ischemic attacks (see WARNINGS).
Relpax Tablets should not be given to patients with peripheral vascular disease including (but not limited to) ischemic bowel disease (see WARNINGS).
Because Relpax Tablets may increase blood pressure, it should not be given to patients with uncontrolled hypertension (see WARNINGS).
Relpax Tablets should not be administered to patients with hemiplegic or basilar migraine.
Relpax Tablets should not be used within 24 hours of treatment with another 5-HT1 agonist, an ergotamine-containing or ergot-type medication such as dihydroergotamine (DHE) or methysergide.
Relpax Tablets should not be used in patients with known hypersensitivity to eletriptan or any of its inactive ingredients.
Relpax Tablets should not be given to patients with severe hepatic impairment.
Relpax Tablets should only be used where a clear diagnosis of migraine has been established.
Eletriptan should not be used within at least 72 hours of treatment with the following potent CYP3A4 inhibitors: ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, and nelfinavir. Eletriptan should not be used within 72 hours with drugs that have demonstrated potent CYP3A4 inhibition and have this potent effect described in the CONTRAINDICATIONS, WARNINGS or PRECAUTIONS sections of their labeling (see CLINICAL PHARMACOLOGY: Drug Interactions and DOSAGE AND ADMINISTRATION).
In a coronary angiographic study of rapidly infused intravenous eletriptan to concentrations exceeding those achieved with 80 mg oral eletriptan in the presence of potent CYP3A4 inhibitors, a small dose-related decrease in coronary artery diameter similar to that seen with a 6 mg subcutaneous dose of sumatriptan was observed.
Because of the potential of 5-HT1 agonists to cause coronary vasospasm, eletriptan should not be given to patients with documented ischemic or vasospastic coronary artery disease (CAD) (see CONTRAINDICATIONS). It is strongly recommended that eletriptan not be given to patients in whom unrecognized CAD is predicted by the presence of risk factors (e.g., hypertension, hypercholesterolemia, smoker, obesity, diabetes, strong family history of CAD, female with surgical or physiological menopause, or male over 40 years of age) unless a cardiovascular evaluation provides satisfactory clinical evidence that the patient is reasonably free of coronary artery and ischemic myocardial disease or other significant underlying cardiovascular disease. The sensitivity of cardiac diagnostic procedures to detect cardiovascular disease or predisposition to coronary artery vasospasm is modest, at best. If, during the cardiovascular evaluation, the patient's medical history, electrocardiographic, or other investigations reveal findings indicative of, or consistent with coronary artery vasospasm or myocardial ischemia, eletriptan should not be administered (see CONTRAINDICATIONS).
For patients with risk factors predictive of CAD, who are determined to have a satisfactory cardiovascular evaluation, it is strongly recommended that administration of the first dose of eletriptan take place in the setting of a physician's office or similar medically staffed and equipped facility unless the patient has previously received eletriptan. Because cardiac ischemia can occur in the absence of clinical symptoms, consideration should be given to obtaining on the first occasion of use an electrocardiogram (ECG) during the interval immediately following administration of Relpax Tablets, in these patients with risk factors.
It is recommended that patients who are intermittent long-term users of 5-HT1 agonists including Relpax Tablets, and who have or acquire risk factors predictive of CAD, as described above, undergo periodic cardiovascular evaluation as they continue to use Relpax Tablets.
The systematic approach described above is intended to reduce the likelihood that patients with unrecognized cardiovascular disease will be inadvertently exposed to eletriptan.
Serious adverse cardiac events, including acute myocardial infarction, life-threatening disturbances of cardiac rhythm, and death have been reported within a few hours following the administration of 5-HT1 agonists including Relpax. Considering the extent of use of 5-HT1 agonists in patients with migraine, the incidence of these events is extremely low.
Premarketing experience with eletriptan among the 7,143 unique individuals who received eletriptan during premarketing clinical trials: In a clinical pharmacology study, in subjects undergoing diagnostic coronary angiography, a subject with a history of angina, hypertension and hypercholesterolemia, receiving intravenous eletriptan (Cmax of 127 ng/mL equivalent to 60 mg oral eletriptan), reported chest tightness and experienced angiographically documented coronary vasospasm with no ECG changes of ischemia.
There was also one report of atrial fibrillation in a patient with a past history of atrial fibrillation.
Postmarketing experience with eletriptan: Serious cardiovascular events, some resulting in death, have been reported in association with the use of Relpax. In very rare cases, these events have occurred in the absence of known cardiovascular diseases. The uncontrolled nature of postmarketing surveillance, however, makes it impossible to determine definitively if the cases were actually caused by eletriptan or to reliably assess causation in individual cases.
Cerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with 5-HT1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. It should be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, and transient ischemic attack).
5-HT1 agonists may cause vasospastic reactions other than coronary artery vasospasm. Both peripheral vascular ischemia and colonic ischemia with abdominal pain and bloody diarrhea have been reported with 5-HT1 agonists.
The development of a potentially life-threatening serotonin syndrome may occur with triptans, including Relpax treatment, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). If concomitant treatment with Relpax and an SSRI (e.g., fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram) or SNRI (e.g., venlafaxine, duloxetine) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). (See PRECAUTIONS—DRUG INTERACTIONS).
Significant elevation in blood pressure, including hypertensive crisis, has been reported on rare occasions in patients receiving 5-HT1 agonists with and without a history of hypertension. In clinical pharmacology studies, oral eletriptan (at doses of 60 mg or more) was shown to cause small, transient dose-related increases in blood pressure, predominantly diastolic, consistent with its mechanism of action and with other 5-HT1B/1D agonists. The effect was more pronounced in renally impaired and elderly subjects. A single patient with hepatic cirrhosis received eletriptan 80 mg and experienced a blood pressure of 220/96 mm Hg five hours after dosing. The treatment-related event persisted for seven hours.
Eletriptan is contraindicated in patients with uncontrolled hypertension (see CONTRAINDICATIONS).
An 18% increase in mean pulmonary artery pressure was seen following dosing with another 5-HT1 agonist in a study evaluating subjects undergoing cardiac catheterization.
As with other 5-HT1 agonists, sensations of tightness, pain, pressure and heaviness have been reported after treatment with eletriptan in the precordium, throat, and jaw. Events that are localized to the chest, throat, neck and jaw have not been associated with arrhythmias or ischemic ECG changes in clinical trials; in a clinical pharmacology study of subjects undergoing diagnostic coronary angiography, one subject with a history of angina, hypertension and hypercholesterolemia, receiving intravenous eletriptan, reported chest tightness and experienced angiographically documented coronary vasospasm with no ECG changes of ischemia. Because 5-HT1 agonists may cause coronary artery vasospasm, patients who experience signs or symptoms suggestive of angina following dosing should be evaluated for the presence of CAD or a predisposition to Prinzmetal's variant angina before receiving additional doses of medication, and should be monitored electrocardiographically if dosing is resumed and similar symptoms recur. Similarly, patients who experience other symptoms or signs suggestive of decreased arterial flow, such as ischemic bowel syndrome or Raynaud's syndrome following the use of any 5-HT1 agonist are candidates for further evaluation (see CONTRAINDICATIONS and WARNINGS).
Excessive use of any anti-migraine medicinal product can lead to daily chronic headaches. Overuse of all triptans has been reported primarily in patients with chronic daily headache.
The effects of severe hepatic impairment on eletriptan metabolism was not evaluated. Subjects with mild or moderate hepatic impairment demonstrated an increase in both AUC (34%) and half-life. The Cmax was increased by 18%. Eletriptan should not be used in patients with severe hepatic impairment. No dose adjustment is necessary in mild to moderate impairment (see DOSAGE AND ADMINISTRATION).
In rats treated with a single intravenous (3 mg/kg) dose of radio-labeled eletriptan, elimination of radioactivity from the retina was prolonged, suggesting that eletriptan and/or its metabolites may bind to the melanin of the eye. Because there could be accumulation in melanin-rich tissues over time, this raises the possibility that eletriptan could cause toxicity in these tissues after extended use. Although no systematic monitoring of ophthalmologic function was undertaken in clinical trials, and no specific recommendations for ophthalmologic monitoring are offered, prescribers should be aware of the possibility of long-term ophthalmologic effects.
Transient corneal opacities were seen in dogs receiving oral eletriptan at 5 mg/kg and above. They were observed during the first week of treatment, but were not present thereafter despite continued treatment. Exposure at the no-effect dose level of 2.5 mg/kg was approximately equal to that achieved in humans at the maximum recommended daily dose.
See PATIENT INFORMATION at the end of this labeling for the text of the separate leaflet provided for patients.
Patients should be cautioned about the risk of serotonin syndrome with the use of Relpax or other triptans, especially during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs).
No specific laboratory tests are recommended.
Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine [DHE] or methysergide) and eletriptan within 24 hours of each other is not recommended (see CONTRAINDICATIONS).
Eletriptan is metabolized primarily by CYP3A4 (see WARNINGS regarding use with potent CYP3A4 inhibitors).
Eletriptan is not a substrate for monoamine oxidase (MAO) enzymes; therefore, there is no expectation of an interaction between eletriptan and MAO inhibitors.
The Cmax and AUC of eletriptan were increased by 10 and 33% respectively in the presence of propranolol. No interactive increases in blood pressure were observed. No dosage adjustment appears to be needed for patients taking propranolol (see CLINICAL PHARMACOLOGY).
Cases of life-threatening serotonin syndrome have been reported during combined use of selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) and triptans (See WARNINGS).
Concomitant use of other 5-HT1 agonists within 24 hours of Relpax treatment is not recommended (see CONTRAINDICATIONS).
Relpax Tablets are not known to interfere with commonly employed clinical laboratory tests.
Lifetime carcinogenicity studies, 104 weeks in duration, were carried out in mice and rats by administering eletriptan in the diet. In rats, the incidence of testicular interstitial cell adenomas was increased at the high dose of 75 mg/kg/day. The estimated exposure (AUC) to parent drug at that dose was approximately 6 times that achieved in humans receiving the maximum recommended daily dose (MRDD) of 80 mg, and at the no-effect dose of 15 mg/kg/day it was approximately 2 times the human exposure at the MRDD. In mice, the incidence of hepatocellular adenomas was increased at the high dose of 400 mg/kg/day. The exposure to parent drug (AUC) at that dose was approximately 18 times that achieved in humans receiving the MRDD, and the AUC at the no-effect dose of 90 mg/kg/day was approximately 7 times the human exposure at the MRDD.
Eletriptan was not mutagenic in bacterial or mammalian cell assays in vitro, testing negative in the Ames reverse mutation test and the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) mutation test in Chinese hamster ovary cells. It was not clastogenic in two in vivo mouse micronucleus assays. Results were equivocal in in vitro human lymphocyte clastogenicity tests, in which the incidence of polyploidy was increased in the absence of metabolic activation (-S9 conditions), but not in the presence of metabolic activation.
In a rat fertility and early embryonic development study, doses tested were 50, 100 and 200 mg/kg/day, resulting in systemic exposures to parent drug in rats, based on AUC, that were 4, 8 and 16 times MRDD, respectively, in males and 7, 14 and 28 times MRDD, respectively, in females. There was a prolongation of the estrous cycle at the 200 mg/kg/day dose due to an increase in duration of estrus, based on vaginal smears. There were also dose-related, statistically significant decreases in mean numbers of corpora lutea per dam at all 3 doses, resulting in decreases in mean numbers of implants and viable fetuses per dam. This suggests a partial inhibition of ovulation by eletriptan. There was no effect on fertility of males and no other effect on fertility of females.
In reproductive toxicity studies in rats and rabbits, oral administration of eletriptan was associated with developmental toxicity (decreased fetal and pup weights and an increased incidence of fetal structural abnormalities). Effects on fetal and pup weights were observed at doses that were, on a mg/m2 basis, 6 to 12 times greater than the clinical maximum recommended daily dose (MRDD) of 80 mg. The increase in structural alterations occurred in the rat and rabbit at doses that, on a mg/m2 basis, were 12 times greater than (rat) and approximately equal to (rabbit) the MRDD.
When pregnant rats were administered eletriptan during the period of organogenesis at doses of 10, 30 or 100 mg/kg/day, fetal weights were decreased and the incidences of vertebral and sternebral variations were increased at 100 mg/kg/day (approximately 12 times the MRDD on a mg/m2 basis). The 100 mg/kg dose was also maternally toxic, as evidenced by decreased maternal body weight gain during gestation. The no-effect dose for developmental toxicity in rats exposed during organogenesis was 30 mg/kg, which is approximately 4 times the MRDD on a mg/m2 basis.
When doses of 5, 10 or 50 mg/kg/day were given to New Zealand White rabbits throughout organogenesis, fetal weights were decreased at 50 mg/kg, which is approximately 12 times the MRDD on a mg/m2 basis. The incidences of fused sternebrae and vena cava deviations were increased in all treated groups. Maternal toxicity was not produced at any dose. A no-effect dose for developmental toxicity in rabbits exposed during organogenesis was not established, and the 5 mg/kg dose is approximately equal to the MRDD on a mg/m2 basis.
There are no adequate and well-controlled studies in pregnant women; therefore, eletriptan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Eletriptan is excreted in human breast milk. In one study of 8 women given a single dose of 80 mg, the mean total amount of eletriptan in breast milk over 24 hours in this group was approximately 0.02% of the administered dose. The ratio of eletriptan mean concentration in breast milk to plasma was 1:4, but there was great variability. The resulting eletriptan concentration-time profile was similar to that seen in the plasma over 24 hours, with very low concentrations of drug (mean 1.7 ng/mL) still present in the milk 18–24 hours post dose. The N-desmethyl active metabolite was not measured in the breast milk. Caution should be exercised when Relpax is administered to nursing women.
Safety and effectiveness of Relpax Tablets in pediatric patients have not been established; therefore, Relpax is not recommended for use in patients under 18 years of age.
The efficacy of Relpax Tablets (40 mg) in patients 11–17 was not established in a randomized, placebo-controlled trial of 274 adolescent migraineurs (see CLINICAL STUDIES). Adverse events observed were similar in nature to those reported in clinical trials in adults. Postmarketing experience with other triptans includes a limited number of reports that describe pediatric patients who have experienced clinically serious adverse events that are similar in nature to those reported rarely in adults. Long-term safety of eletriptan was studied in 76 adolescent patients who received treatment for up to one year. A similar profile of adverse events to that of adults was observed. The long-term safety of eletriptan in pediatric patients has not been established.
Eletriptan has been given to only 50 patients over the age of 65. Blood pressure was increased to a greater extent in elderly subjects than in young subjects. The pharmacokinetic disposition of eletriptan in the elderly is similar to that seen in younger adults (see CLINICAL PHARMACOLOGY). In clinical trials, there were no apparent differences in efficacy or the incidence of adverse events between patients under 65 years of age and those 65 and above (n=50).
There is a statistically significantly increased half-life (from about 4.4 hours to 5.7 hours) between elderly (65 to 93 years of age) and younger adult subjects (18 to 45 years of age) (see CLINICAL PHARMACOLOGY).
Serious cardiac events, including some that have been fatal, have occurred following the use of 5-HT1 agonists including Relpax. These events are extremely rare and most have been reported in patients with risk factors predictive of CAD. Events reported have included coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, ventricular tachycardia, and ventricular fibrillation (see CONTRAINDICATIONS, WARNINGS and PRECAUTIONS).
Among 4,597 patients who treated the first migraine headache with Relpax in short-term placebo-controlled trials, the most common adverse events reported with treatment with Relpax were asthenia, nausea, dizziness, and somnolence. These events appear to be dose-related.
In long-term open-label studies where patients were allowed to treat multiple migraine attacks for up to 1 year, 128 (8.3%) out of 1,544 patients discontinued treatment due to adverse events.
Table 2 lists adverse events that occurred in the subset of 5,125 migraineurs who received eletriptan doses of 20 mg, 40 mg and 80 mg or placebo in worldwide placebo-controlled clinical trials. The events cited reflect experience gained under closely monitored conditions of clinical trials in a highly selected patient population. In actual clinical practice or in other clinical trials, those frequency estimates may not apply, as the conditions of use, reporting behavior, and the kinds of patients treated may differ.
Only adverse events that were more frequent in a Relpax treatment group compared to the placebo group with an incidence greater than or equal to 2% are included in Table 2.
| Adverse Event Type | Placebo (n=988) | Relpax 20 mg (n=431) | Relpax 40 mg (n=1774) | Relpax 80 mg (n=1932) |
|---|---|---|---|---|
| ATYPICAL SENSATIONS | ||||
| Paresthesia | 2% | 3% | 3% | 4% |
| Flushing/feeling of warmth | 2% | 2% | 2% | 2% |
| PAIN AND PRESSURE SENSATIONS | ||||
| Chest – tightness/pain/pressure | 1% | 1% | 2% | 4% |
| Abdominal – pain/discomfort/stomach pain/cramps/pressure | 1% | 1% | 2% | 2% |
| DIGESTIVE | ||||
| Dry mouth | 2% | 2% | 3% | 4% |
| Dyspepsia | 1% | 1% | 2% | 2% |
| Dysphagia – throat tightness/difficulty swallowing | 0.2% | 1% | 2% | 2% |
| Nausea | 5% | 4% | 5% | 8% |
| NEUROLOGICAL | ||||
| Dizziness | 3% | 3% | 6% | 7% |
| Somnolence | 4% | 3% | 6% | 7% |
| Headache | 3% | 4% | 3% | 4% |
| OTHER | ||||
| Asthenia | 3% | 4% | 5% | 10% |
Relpax is generally well tolerated. Across all doses, most adverse reactions were mild and transient. The frequency of adverse events in clinical trials did not increase when up to 2 doses of Relpax were taken within 24 hours. The incidence of adverse events in controlled clinical trials was not affected by gender, age, or race of the patients. Adverse event frequencies were also unchanged by concomitant use of drugs commonly taken for migraine prophylaxis (e.g., SSRIs, beta blockers, calcium channel blockers, tricyclic antidepressants), estrogen replacement therapy and oral contraceptives.
In the paragraphs that follow, the frequencies of less commonly reported adverse clinical events are presented. Because the reports include events observed in open studies, the role of Relpax Tablets in their causation cannot be reliably determined. Furthermore, variability associated with adverse event reporting, the terminology used to describe adverse events, etc., limit the value of the quantitative frequency estimates provided. Event frequencies are calculated as the number of patients reporting an event divided by the total number of patients (N=4,719) exposed to Relpax. All reported events are included except those already listed in Table 2, those too general to be informative, and those not reasonably associated with the use of the drug. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are those occurring in at least 1/100 patients, infrequent adverse events are those occurring in 1/100 to 1/1000 patients and rare adverse events are those occurring in fewer than 1/1000 patients.
General: Frequent were back pain, chills and pain. Infrequent were face edema and malaise. Rare were abdomen enlarged, abscess, accidental injury, allergic reaction, fever, flu syndrome, halitosis, hernia, hypothermia, lab test abnormal, moniliasis, rheumatoid arthritis and shock.
Cardiovascular: Frequent was palpitation. Infrequent were hypertension, migraine, peripheral vascular disorder and tachycardia. Rare were angina pectoris, arrhythmia, atrial fibrillation, AV block, bradycardia, hypotension, syncope, thrombophlebitis, cerebrovascular disorder, vasospasm and ventricular arrhythmia.
Digestive: Infrequent were anorexia, constipation, diarrhea, eructation, esophagitis, flatulence, gastritis, gastrointestinal disorder, glossitis, increased salivation and liver function tests abnormal. Rare were gingivitis, hematemesis, increased appetite, rectal disorder, stomatitis, tongue disorder, tongue edema and tooth disorder.
Endocrine: Rare were goiter, thyroid adenoma and thyroiditis.
Hemic and Lymphatic: Rare were anemia, cyanosis, leukopenia, lymphadenopathy, monocytosis and purpura.
Metabolic: Infrequent were creatine phosphokinase increased, edema, peripheral edema and thirst. Rare were alkaline phosphatase increased, bilirubinemia, hyperglycemia, weight gain and weight loss.
Musculoskeletal:
