Isometheptene, Dichloralphenazone, and Acetaminophen (Systemic)
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INN:
Acetaminophen—Paracetamol
VA CLASSIFICATION
Primary: CN103
Secondary: CN105
Commonly used brand name(s): Amidrine; Duradrin; I.D.A; Iso-Acetazone; Isocom; Midchlor; Midrin; Migquin; Migrapap; Migratine; Migrazone; Migrend; Migrex; Mitride.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
†Not commercially available in Canada.
Category:
Vascular headache suppressant (migraine)—
Note: Some headache specialists question the validity of the term ``vascular headache'' because a correlation between dilatation of cerebral blood vessels and symptoms of migraine has not been demonstrated conclusively.
Indications
Accepted
Headache, migraine (treatment) and
Headache, tension-type (treatment)—Isometheptene, dichloralphenazone, and acetaminophen combination is indicated to relieve occasional migraine headaches {03}{04}{06}{20}{21} (with or without aura) and coexisting migraine and tension-type headaches (“mixed” headache syndrome){03}. However, the U.S. FDA has classified this combination as being “possibly” effective in the treatment of migraine headaches. This classification requires the submission of adequate and well-controlled studies in order to provide substantial evidence of effectiveness.{20}{21}
Note: Some headache specialists question the value of this formulation in pure tension-type headaches. However, the distinction between vascular, tension-type, and “mixed” headaches is often difficult or uncertain, and the medication may relieve some headaches characterized as tension-type.{19}
Because frequent use of headache-aborting medications by headache-prone individuals may lead to tolerance and dependence, this medication is not recommended for regular use by patients who experience frequent, especially daily, headaches{02}.
To reduce analgesic use, underlying problems that may contribute to tension-type headaches, such as inflammation or structural abnormalities in the cervical or temporomandibular areas, should be identified and treated{03}{04}. In some patients, application of heat, muscle relaxants, and/or physical therapy may be helpful{02}. Other medications having the potential to cause habituation (e.g., benzodiazepines used as muscle relaxants) should be used as infrequently as possible{02}{03}{04}.
Chronic tension-type headaches and severe migraines that occur more frequently than twice a month may require additional prophylactic treatment to reduce the frequency, severity, and/or duration of the headaches{02}{03}{04}{05}{06}. The prophylactic agents most commonly used for tension-type headaches are tricyclic antidepressants, especially amitriptyline, and/or beta-adrenergic blocking agents, especially propranolol{02}{03}{04}. For migraines, beta-adrenergic blocking agents, calcium channel blocking agents, tricyclic antidepressants, monoamine oxidase inhibitors, methysergide, pizotyline (not commercially available in the U.S.), and sometimes cyproheptadine (especially in children) are used as prophylaxis{03}{04}{05}{06}. The combination of amitriptyline plus propranolol has been found superior to either agent used alone as prophylaxis against “mixed” headaches{07}{08}.
Identification and avoidance of precipitating factors is also important in the overall management of the patient with migraine headaches{04}{06}. Relaxation and/or biofeedback techniques may also be helpful in controlling some types of headache, and may reduce the need for medication{06}.
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Molecular weight—
Isometheptene mucate: 492.7 {09}
Dichloralphenazone: 519.04 {10}
Acetaminophen: 151.16 {10}
Mechanism of action/Effect:
Isometheptene—The mechanism of action has not been established. Isometheptene is an indirect-acting sympathomimetic agent with vasoconstricting activity. {01} {11} It has been proposed that constriction of cerebral blood vessels reduces the pulsation in cerebral arteries that may be responsible for the pain of migraine headaches {03} {06}. However, studies have not consistently shown a significant correlation between dilatation of cerebral blood vessels and pain or other symptoms of migraine headaches, or between a vasoconstrictive action and relief of migraine {18}.
Dichloralphenazone—A complex of chloral hydrate and antipyrine {09} (INN: phenazone) {10}. It is present in this formulation as a mild sedative and relaxant {01}.
Acetaminophen—The mechanism of analgesic action has not been fully determined. Acetaminophen may act predominantly by inhibiting prostaglandin synthesis in the central nervous system (CNS) and, to a lesser extent, through a peripheral action by blocking pain-impulse generation. The peripheral action may also be due to inhibition of prostaglandin synthesis or to inhibition of the synthesis or actions of other substances that sensitize pain receptors to mechanical or chemical stimulation {12}.
Absorption:
Acetaminophen—Rapid and almost complete; may be decreased if taken following a high-carbohydrate meal.
Distribution:
In breast milk—Acetaminophen: Peak concentrations of 10 to 15 mcg per mL (66.2 to 99.3 micromoles/L) have been measured 1 to 2 hours following maternal ingestion of a single 650-mg dose.
Biotransformation:
Dichloralphenazone—Hydrolyzed to the active compounds chloral hydrate and antipyrine {09}. Chloral hydrate is metabolized in the liver and erythrocytes to the active metabolite trichloroethanol, which may be further metabolized to inactive metabolites {12}. It is also metabolized in the liver and kidneys to inactive metabolites.
Acetaminophen—Approximately 90 to 95% of a dose is metabolized in the liver, primarily by conjugation with glucuronic acid, sulfuric acid, and cysteine {12}. An intermediate metabolite, which may accumulate in overdosage after the primary metabolic pathways become saturated, is hepatotoxic {12} and possibly nephrotoxic {13}.
Half-life:
Acetaminophen:
1 to 4 hours; does not change with renal failure but may be prolonged in acute overdosage, in some forms of hepatic disease, and in the elderly; may be somewhat shortened in children.
In breast milk: 1.35 to 3.5 hours.
Time to peak concentration:
Acetaminophen—0.5 to 2 hours.
Peak plasma concentration
Acetaminophen—5 to 20 mcg per mL (with doses up to 650 mg).
Time to peak effect
Acetaminophen—1 to 3 hours.
Duration of action:
Acetaminophen—3 to 4 hours.
Elimination:
Acetaminophen—Renal, as metabolites, primarily conjugates; 3% of a dose may be excreted unchanged.
In dialysis—
Hemodialysis: 120 mL per minute (for unmetabolized drug); metabolites are also cleared rapidly.
Hemoperfusion: 200 mL per minute.
Peritoneal dialysis: <10 mL per minute.
Precautions to Consider
Note: The quantity of dichloralphenazone in this combination formulation does not provide full therapeutic doses of its active components chloral hydrate and antipyrine (phenazone). However, the possibility should be considered that precautions applying to chloral hydrate (see Chloral Hydrate [Systemic] ) and to antipyrine may apply to ingestion of an overdose or to overuse of this combination medication.
Cross-sensitivity and/or related problems
Patients sensitive to aspirin are usually not sensitive to acetaminophen; however, acetaminophen has caused mild bronchospastic reactions in some aspirin-sensitive asthmatics (less than 5% of those tested) {14}.
Pregnancy/Reproduction
Fertility—
Chronic toxicity studies in animals have shown that high doses of acetaminophen cause testicular atrophy and inhibition of spermatogenesis; the relevance of this finding to use in humans is not known.
Pregnancy—
Acetaminophen crosses the placenta. However, problems in humans have not been documented.
Breast-feeding
Problems in humans have not been documented. Although peak concentrations of 10 to 15 mcg per mL (66.2 to 99.3 micromoles/L) of acetaminophen have been measured in breast milk 1 to 2 hours following maternal ingestion of a single 650-mg dose, neither acetaminophen nor its metabolites were detected in the urine of the nursing infants. The half-life in breast milk is 1.35 to 3.5 hours.
Pediatrics
No published information is available on the relationship of age to the effects of this combination medication in pediatric patients.
Geriatrics
No published information is available on the relationship of age to the effects of this combination medication in geriatric patients. Geriatric patients are more likely to have peripheral vascular disease, and are therefore more likely to be adversely affected by peripheral vasoconstriction, than are younger adults. However, isometheptene may be safer for elderly patients than the ergot derivatives used to abort acute vascular headaches {07}. Also, elderly patients are more likely to have age-related renal function impairment, which may require caution in patients receiving acetaminophen and isometheptene.
Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Alcohol or
CNS depressants (concurrent use with dichloralphenazone may cause additive sedation)
Alcohol, especially chronic abuse of or
Hepatic enzyme inducers (See Appendix II ) or
Hepatotoxic medications, other (See Appendix II ) (risk of hepatotoxicity with single toxic doses of acetaminophen may be increased in alcoholics or in patients regularly taking other hepatotoxic medications or hepatic enzyme–inducing agents)
(chronic use of barbiturates [except butalbital] or primidone has been reported to decrease the therapeutic effects of acetaminophen, probably because of increased metabolism resulting from induction of hepatic microsomal enzyme activity; the possibility should be considered that similar effects may occur with other hepatic enzyme inducers)
» Monoamine oxidase (MAO) inhibitors (concurrent use with an indirect-acting sympathomimetic such as isometheptene may cause sudden and severe hypertension and hyperpyrexia, which can reach crisis levels)
Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
With diagnostic test results
Glucose, blood, determinations (acetaminophen may cause values to be falsely decreased when measured by the glucose oxidase/peroxidase method but probably not when measured by the hexokinase [glucose-6-phosphate dehydrogenase (G6PD)] method)
5-Hydroxyindoleacetic acid (5-HIAA), serum, determinations (acetaminophen may cause false-positive results with qualitative screening tests using nitrosonaphthol reagent; the quantitative test is unaffected)
Pancreatic function test using bentiromide (administration of acetaminophen prior to the bentiromide test will invalidate test results because acetaminophen is also metabolized to an arylamine and will thus increase the apparent quantity of para-aminobenzoic acid [PABA] recovered; it is recommended that acetaminophen be discontinued at least 3 days prior to administration of bentiromide)
Uric acid, serum, determinations (acetaminophen may cause falsely increased values when the phosphotungstate uric acid test method is used)
With physiology/laboratory test values
Bilirubin, serum and
Lactate dehydrogenase (LDH), serum and
Prothrombin time and
Transaminase, serum (values may be increased indicating acetaminophen-induced hepatotoxicity, especially in alcoholics, patients taking other hepatic enzyme inducers, or patients with pre-existing hepatic disease, when single toxic doses [>8 to 10 grams] are taken)
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).
Risk-benefit should be considered when the following medical problems exist
» Alcoholism, active or
» Hepatic function impairment{20}{21} or
» Viral hepatitis (increased risk of acetaminophen-induced hepatotoxicity)
Any condition in which the vasoconstrictive or other sympathomimetic effects of isometheptene may be hazardous, such as:
Cardiovascular {01} or cerebrovascular insufficiency, including recent myocardial infarction or stroke{20}{21}
» Glaucoma {20}{21} , not optimally controlled
» Hypertension {20}{21} , not optimally controlled
» Organic heart disease {20}{21}
Peripheral vascular disease {20}{21}
» Renal function impairment, severe {20}{21}
Sensitivity to acetaminophen, dichloralphenazone, or to isometheptene, history of{20}{21}
Side/Adverse Effects
Note: The quantity of dichloralphenazone in this combination formulation does not provide full therapeutic doses of its active metabolites chloral hydrate and antipyrine (phenazone). However, the possibility should be considered that ingestion of an overdose or overuse of this combination medication may induce side effects characteristic of chloral hydrate (see Chloral Hydrate [Systemic]) and/or antipyrine.
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Those indicating need for medical attention
Incidence less frequent
Anemia or methemoglobinemia (unusual tiredness or weakness )
Incidence rare
Agranulocytosis (unexplained sore throat and fever)
anemia (unusual tiredness or weakness)
dermatitis, allergic{20}{21} (skin rash, hives, or itching)
hepatitis (yellow eyes or skin)
thrombocytopenia ( unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)—usually asymptomatic
Symptoms of tolerance and/or dependence
—with overuse
Headaches —more frequent, severe, and difficult to treat than previously {03} {04} {05} {06}
Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
Drowsiness
Incidence less frequent or rare
— dose-related
Dizziness{20}{21}
fast or irregular heartbeat
Overdose
For specific information on the agents used in the management of isometheptene, dichloralphenazone, and acetaminophen overdose, see:
• Acetylcysteine (Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).
Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute
Gastrointestinal upset (diarrhea; loss of appetite ; nausea or vomiting; stomach cramps or pain)
increased sweating
Note: Early signs and symptoms of acetaminophen overdose, i.e., gastrointestinal upset and increased sweating often do not occur. However, when they do occur, they usually appear within 6 to 14 hours after ingestion of an overdose and persist for about 24 hours.
Chronic
Hepatotoxicity (pain, tenderness, and/or swelling in upper abdominal area)
Note: The first indications of overdosage may be signs and symptoms of possible liver damage and abnormalities in liver function tests, which may not occur until 2 to 4 days after ingestion of the overdose. Maximal changes in liver function tests usually occur 3 to 5 days after ingestion of the overdose.
Overt hepatic disease or failure may occur 4 to 6 days after ingestion of the overdose. Hepatic encephalopathy (with mental changes, confusion, agitation, or stupor), convulsions, respiratory depression, coma, cerebral edema, coagulation defects, gastrointestinal bleeding, disseminated intravascular coagulation, hypoglycemia, metabolic acidosis, cardiac arrhythmias, and cardiovascular collapse may occur.
Renal tubular necrosis leading to renal failure (signs may include bloody or cloudy urine and sudden decrease in amount of urine) has also been reported in acetaminophen overdose, usually, but not exclusively, in conjunction with acetaminophen-induced hepatotoxicity{15}.
Treatment of overdose
For acetaminophen:
To decrease absorption—Emptying the stomach via induction of emesis or gastric lavage.
Removing activated charcoal (if used) by gastric lavage may be advisable. Although activated charcoal is recommended in cases of mixed drug overdose, it may interfere with absorption of orally administered acetylcysteine (antidote used to protect against acetaminophen-induced hepatotoxicity) and decrease its efficacy.
To enhance elimination—Instituting hemodialysis or hemoperfusion to remove acetaminophen from the circulation may be beneficial if acetylcysteine administration cannot be instituted within 24 hours following ingestion of a massive acetaminophen overdose. However, the efficacy of such treatment in preventing acetaminophen-induced hepatotoxicity is not known.
Specific treatment—Use of acetylcysteine. It is recommended that acetylcysteine administration be instituted as soon as possible after ingestion of an overdose has been reported, without waiting for the results of plasma acetaminophen determinations or other laboratory tests. Acetylcysteine is most effective if treatment is started within 10 to 12 hours after ingestion of the overdose; however, it may be of some benefit if treatment is started within 24 hours. See the package insert or Acetylcysteine (Systemic) monograph for specific dosing guidelines for use of this product.
Monitoring—Determining plasma acetaminophen concentration at least 4 hours following ingestion of the overdose. Determinations performed prior to this time are not reliable for assessing potential hepatotoxicity. Initial plasma concentrations above 150 mcg per mL (mcg/mL [993 micromoles/L]) at 4 hours, 100 mcg/mL (662 micromoles/L) at 6 hours, 70 mcg/mL (463.4 micromoles/L) at 8 hours, 50 mcg/mL (331 micromoles/L) at 10 hours, 20 mcg/mL (132.4 micromoles/L) at 15 hours, 8 mcg/mL (53 micromoles/L) at 20 hours, or 3.5 mcg/mL (23.2 micromoles/L) at 24 hours postingestion indicate possible hepatotoxicity and the need for completing the full course of acetylcysteine treatment. If the initial determination indicates a plasma concentration below those listed at the times indicated, cessation of acetylcysteine therapy can be considered. However, some clinicians advise that more than one determination should be performed to ascertain peak absorption and half-life of acetaminophen prior to considering discontinuation of acetylcysteine.
Monitoring renal and cardiac function and administering appropriate therapy as required.
Performing liver function tests (serum aspartate aminotransferase [AST; SGOT], serum alanine aminotransferase [ALT; SGPT], prothrombin time, and bilirubin) at 24-hour intervals for at least 96 hours postingestion if the plasma acetaminophen concentration indicates potential hepatotoxicity. If no abnormalities are detected within 96 hours, further determinations are not needed.
Supportive care—May include maintaining fluid and electrolyte balance, correcting hypoglycemia, and administering vitamin K 1 (if prothrombin time ratio exceeds 1.5) and fresh frozen plasma or clotting factor concentrate (if prothrombin time ratio exceeds 3.0).
For dichloralphenazone:
To decrease absorption—May include gastric lavage (endotracheal tube with inflated cuff should be in place to prevent aspiration of vomitus).
To enhance elimination—Hemodialysis may be effective in promoting the clearance of the active metabolite trichloroethanol.
Specific treatment—May include providing artificial respiration with oxygen.
Monitoring—Continuous cardiac monitoring is important, especially in patients with predisposing cardiac disease.
Supportive care— May include maintaining normal body temperature, maintaining appropriate fluid and electrolyte therapy and urinary output, and supporting respiration and circulation. Patients in whom intentional overdose is known or suspected should be referred for psychiatric consultation.
For isometheptene:
To decrease absorption—Emptying the stomach by induction of emesis or gastric lavage.
Monitoring—May include monitoring the patient, especially for signs and symptoms of excessive sympathetic stimulation or vasoconstriction, and treating observed symptoms as necessary.
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Isometheptene, Dichloralphenazone, and Acetaminophen (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):
Before using this medication
» Conditions affecting use, especially:
Allergic reaction to acetaminophen or to this combination medication, history of
Pregnancy—Acetaminophen crosses the placenta
Breast-feeding—Acetaminophen is excreted in breast milk
Other medications, especially monoamine oxidase inhibitors
Other medical problems, especially alcoholism (active), glaucoma, hypertension, heart disease, hepatic disease or viral hepatitis, and severe renal function impairment
Proper use of this medication
» Importance of not taking more medication than the amount prescribed; risk of tolerance and dependence with too frequent use; also, acetaminophen may cause liver damage with long-term use or greater than recommended doses
» Most effective when taken as soon as headache appears or at first sign of migraine attack (prodromal stage)
» Lying down in a quiet, dark room after taking initial dose
» Compliance with prophylactic therapy, if prescribed
Proper dosing
» Proper storage
Precautions while using this medication
» Checking with physician if usual dose fails to relieve headaches, or if frequency and/or severity of headaches increases; possibility that tolerance to the medication has developed and/or withdrawal (rebound) or chronic, daily headaches are occurring
» Caution if other medications containing acetaminophen are used
» Caution when driving or doing jobs requiring alertness because of possible drowsiness or dizziness, especially if also taking a CNS depressant.
» Avoiding use of alcohol, which increases the risk of liver toxicity with high doses of acetaminophen, especially in alcoholics; also, alcohol may aggravate or induce headache
Side/adverse effects
Signs of potential side effects, especially allergic dermatitis, blood dyscrasias, hepatotoxicity, and methemoglobinemia
General Dosing Information
Therapy is most effective when initiated at the first symptoms of a headache (during the prodrome, for migraine with aura) {03} {06}.
After the first dose has been administered, it is recommended that the patient lie down and relax in a quiet, darkened room, because this contributes to relief of headaches {04}.
In headache-prone individuals, frequent use of headache relievers may cause tolerance, leading to an increased dosage requirement {03}, and to physical dependence, {03} {04} leading to both medication abuse {04} {06} {16} and chronic (daily or near-daily) headaches. {03} {04} {05} {06} Patients who experience frequent headaches may also be dependent on a variety of other medications, including opioid analgesics, barbiturate-containing analgesic combinations, simple analgesics such as acetaminophen or aspirin, ergotamine, and antianxiety agents or sedatives {04} {06} {16}.
Chronic headaches resulting from overmedication may be difficult to relieve, especially if the patient continues to take headache suppressants {16} and/or analgesics {16} {17}. It is recommended that all such medications be discontinued {04} {16} {17}. In-patient treatment may be necessary during detoxification {17}. Naproxen, alone {03} or together with amitriptyline {16}, may reduce the severity of the headaches. Repetitive intravenous administration of dihydroergotamine (in conjunction with metoclopramide [to control dihydroergotamine-induced nausea and vomiting]) is recommended by some headache specialists to relieve chronic, intractable headaches associated with dependency on headache-aborting medications {17}. Appropriate treatment for symptoms of withdrawal from other substances frequently used or abused by chronic headache patients may also be needed {17}. In addition, appropriate prophylactic treatment should be initiated or adjusted to reduce the frequency and/or severity of future headaches {17}.
Oral Dosage Forms
ISOMETHEPTENE MUCATE, DICHLORALPHENAZONE, AND ACETAMINOPHEN CAPSULES USP
Usual adult dose
Tension-type headache
Oral, 1 or 2 capsules every four hours as needed, up to 8 capsules a day.{20}{21}
Vascular headache suppressant (migraine)
Oral, 2 capsules at the start of the attack (during the prodrome, for migraine with aura), followed by 1 capsule every hour as needed, up to 5 capsules in twelve hours.{20}{21}
Usual pediatric dose
Dosage has not been established.
Strength(s) usually available
U.S.—
65 mg of isometheptene mucate, 100 mg of dichloralphenazone, and 325 mg of acetaminophen (Rx) [Amidrine] [Duradrin (FD&C yellow No. 10)] [I.D.A (FD&C yellow No. 10)] [Iso-Acetazone] [Isocom] [Midchlor (FD&C yellow No. 10)] [Midrin (FD&C yellow No. 6){20}] [Migrapap] [Migquin] [Migratine] [Migrazone] [Migrend] [Migrex] [Mitride][Generic]{21}
Canada—
Not commercially available.
Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F). Store in a well-closed container.
Revised: 12/22/1999
References
- All references used in the development and earlier revisions of this monograph have not yet been incorporated into the computer database and, therefore, are not listed below. Citations for information not yet referenced in the monograph will be provided upon request.
- Prescribing information Midrin, Carnrick (U.S.), in Physician's desk reference 46th ed 1991: 836. rev. 11/88.
- Kunkel RS. Diagnosis and treatment of muscle contraction (tension-type) headaches. Med Clin N Amer 1991; 75: 595-603.
- AMA Drug Evaluations (Subscription). Chicago: American Medical Association; 1990 (summer update): Section 2, 2:1-2:11.
- Couch JR. Headache. In: Rakel RE, ed. Conn's current therapy. Philadelphia: W.B. Saunders; 1991: 830-41.
- Anthony M. The treatment of migraine and other headaches. Curr Opin Neurol Neurosurg 1991; 4: 245-52.
- Diamond S. Migraine headache. Med Clin N Amer 1991; 75: 545-66.
- Baumel B., Eisner LS. Diagnosis and treatment of headache in the elderly. Med Clin N Amer 1991; 75: 661-75.
- Mathew NT. Prophylaxis of migraine and mixed headache. A randomized controlled study. Headache 1991; 21: 105-9.
- Reynolds JEF, ed. Martindale. The extra pharmacopeia 29th ed. London: Pharmaceutical Press; 1985: 15, 273, 799-800.
- Fleeger CA, ed. USAN and the USP dictionary of drug names. Rockville: The U.S. Pharmacopeial Convention, Inc. 1992: 18, 194.
- Gennaro AR, ed. Remington's pharmaceutical sciences 17th ed. Easton: Mack; 1985: 881, 891-2.
- Gilman AG, Rall TW, Nies AS, Taylor P, eds. Goodman and Gilman's the pharmacological basis of therapeutics 8th ed. New York: Pergamon Press; 1990: 357; 364-5; 640-1; 656-7.
- Sandler DP, Smith JC, Weinberg CR et al. Analgesic use and chronic renal disease. N Engl J Med 1989 May 11; 320: 1238-43.
- Szczeklik A. Analgesics, allergy, and asthma. Drugs 1986; 32 (suppl 4): 148-63.
- Reviewer comment; Acetaminophen (Systemic) monograph, 1991 revision.
- Hering R, Steiner TJ. Abrupt outpatient withdrawal of medication in analgesic-abusing migraineurs. Lancet 1991; 337: 1442-3.
- Silberstein SD, Schulman EA, Hopkins M. Repetitive intravenous DHE in the treatment of refractory headache. Headache 1990; 30: 334-9.
- Raskin NH. Pharmacology of migraine. Prog Drug Res 1990; 34: 209-30.
- Panelist comments, draft 1/92 and ballot 5/92.
- Product information: Midrin®, isometheptene mucate, dichloralphenazone, and acetaminophen. Carnrick Laboratories, Inc., Cedar Knolls, NJ, U.S.A., Rev. 5/98, Rec. 11/99.
- Product Information: isometheptene mucate, dichloralphenazone and acetaminophen. Duramed Pharmaceuticals, Inc., Cincinnati, OH, U.S.A., Rev. 4/98, Rec. 11/99.
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