Ergomar

Generic Name: Ergotamine Tartrate
Class: Non-selective alpha-Adrenergic Blocking Agents
VA Class: CN105
CAS Number: 379-79-3

• 
  

  Possible serious and/or life-threatening cerebral and/or peripheral ischemia when used concomitantly with potent CYP3A4 inhibitors (see Interactions); concomitant use contraindicated.^{138 139 140}

  
  

Introduction

Naturally occurring ergot alkaloid.^{b 140}

Uses for Ergomar

Vascular Headaches

Prevention or abortion of vascular headaches (e.g., migraine, cluster headaches), when used alone or in fixed combination with caffeine.^{138 139 140} Should not be used for chronic daily management of vascular headaches.^{138 139 140}

Generally not preferred for terminating acute cluster headaches; onset of action is slower than that of other therapies (e.g., sumatriptan, oxygen).^{134 136 141 142}

Has been used for short-term (e.g., up to 3 weeks) prophylaxis of episodic cluster headaches to suppress a series of attacks and reduce duration of cluster period.^{134 136 137 141 142} Prophylactic administration at bedtime may be particularly useful in selected patients with nocturnal cluster attacks.^{134 135 136 139 140 141}

Ineffective in the treatment of muscle contraction headaches.^b

Ergomar Dosage and Administration

General

• Vascular Headaches


• 
  

  Administer as soon as possible after onset of first symptoms of vascular headache.^{138 139 140}

  
  


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  After administering the initial dose, patient should lie down and relax in a quiet, darkened room.^b

  
  


• 
  

  Do not administer within 24 hours of a selective serotonin agonist (e.g., sumatriptan).^{115 116 144 145} (See Specific Drugs under Interactions.)

  
  

Administration

Administer orally or rectally (as fixed-combination preparation containing ergotamine and caffeine).^{139 140}

Administer sublingually (as single-entity preparation).¹³⁸

Sublingual Administration

Place tablets under the tongue and allow to dissolve.¹³⁸

Rectal Administration

If suppositories become softened, chill them in ice-cold water to solidify before removing the foil wrapper.¹³⁹

Dosage

Available as ergotamine tartrate; dosage expressed in terms of the salt.^{138 139 140}

Adults

Vascular Headaches

Oral

Fixed-combination ergotamine and caffeine (e.g., Cafergot) tablets: 2 mg of ergotamine tartrate (2 tablets) initially, followed by 1 mg at 30-minute intervals until attack has abated (maximum 6 mg per attack).¹⁴⁰

For short-term prophylaxis of cluster headaches, 3–4 mg daily (in divided doses) has been administered for up to 3 weeks.^{135 142} May be administered 30–60 minutes prior to an expected attack in patients with consistent attack patterns.^{135 142} In selected patients with nocturnal attacks, 1–2 mg may be given at bedtime on a short-term basis.^{134 137 140 142} Monitor carefully to avoid excessive weekly dosages;¹⁴² give due consideration to recommended maximum weekly dosage (see Prescribing Limits under Dosage and Administration).¹⁴⁰

Sublingual

Ergotamine tartrate (Ergomar) tablets: 2 mg (1 tablet) initially, followed by 2 mg at 30-minute intervals until attack has abated (maximum 6 mg per 24-hour period).¹³⁸

For short-term prophylaxis of cluster headaches, 3–4 mg daily (in divided doses) has been administered for up to 3 weeks.^{135 142} May be administered 30–60 minutes prior to an expected attack in patients with consistent attack patterns.^{135 142} Monitor carefully to avoid excessive weekly dosages;¹⁴² give due consideration to recommended maximum weekly dosage (see Prescribing Limits under Dosage and Administration).¹⁴⁰

Rectal

Fixed-combination ergotamine and caffeine (e.g., Migergot) suppositories: 2 mg of ergotamine tartrate (1 suppository) initially.¹³⁹ If necessary, may give a second 2-mg dose after 1 hour.¹³⁹

In selected patients with cluster headaches at night, 1–2 mg may be given at bedtime on a short-term basis.^{137 139 142} Give due consideration to recommended maximum weekly dosage (see Prescribing Limits under Dosage and Administration).^{139 142}

Prescribing Limits

Adults

Vascular Headaches

Oral

Maximum 6 mg (6 Cafergot tablets) per attack or 10 mg (10 Cafergot tablets) per week.¹⁴⁰

Sublingual

Maximum 6 mg (3 Ergomar tablets) per 24-hour period or 10 mg (5 Ergomar tablets) per week.¹³⁸

Rectal

Maximum 4 mg (2 Migergot suppositories) per attack or 10 mg (5 Migergot suppositories) per week.¹³⁹

Cautions for Ergomar

Contraindications

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  Known or suspected pregnancy.^{138 139 140}

  
  


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  Concomitant therapy with potent CYP3A4 inhibitors.^{124 125 126 127 138 139 140} (See Interactions.)

  
  


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  Peripheral vascular disease, CHD, or hypertension.^{138 139 140}

  
  


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  Impaired hepatic or renal function.^{138 139 140}

  
  


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  Sepsis.^{138 139 140}

  
  


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  Known hypersensitivity to ergot alkaloids or any ingredient in the formulation.^{138 139 140}

  
  

Warnings/Precautions

Warnings

Fibrosis

Possible retroperitoneal and pleuropulmonary fibrosis.^{106 138 139 140}

Possible fibrotic thickening of the aortic, mitral, tricuspid, and/or pulmonary valves with continuous, long-term administration;^{100 101 102 103 104 105 106 107 138 139 140} do not administer on a chronic daily basis.^{138 139 140}

Examine patients regularly for development of fibrotic complications; perform appropriate tests (e.g., ECG, laboratory tests, radiographic examination) if signs or symptoms of these conditions occur.^{100 109 113 114}

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; fetal growth retardation observed in animals.^{138 139 140}

General Precautions

Ergotism

Potential for ergotism, manifested by intense arterial vasoconstriction, producing signs and symptoms of peripheral vascular ischemia; if left untreated, can progress to gangrene.^{138 139 140} Do not exceed recommended dosages.^{138 139 140}

If signs and symptoms of impaired circulation occur, discontinue therapy and keep affected extremities warm.^b

Misuse and Abuse

Solitary rectal or anal ulcer associated with abuse of ergotamine suppositories (e.g., use of higher than recommended dosages or continual use at the recommended dose for many years); usually resolves 4–8 weeks following discontinuance of the drug.¹³⁹

Possible withdrawal symptoms (e.g., rebound headache) upon discontinuance of the drug following indiscriminate use over long periods of time.^{138 139 140}

Use of Fixed Combinations

When used in fixed combination with caffeine, consider the cautions, precautions, and contraindications associated with caffeine.^{139 140}

Specific Populations

Pregnancy

Category X.^{138 139 140} (See Fetal/Neonatal Morbidity and Mortality and also see Contraindications under Cautions.)

Oxytocic effects are maximal in 3rd trimester; contraindicated in labor and delivery.^{138 139 140}

Lactation

Distributed into milk; may cause vomiting, diarrhea, weak pulse, seizures, and unstable BP in nursing infants.^{128 129 138 139 140} Discontinue nursing or the drug.^{138 139 140}

Inhibits prolactin, but no reports of decreased lactation.^{138 139 140}

Pediatric Use

Safety and efficacy not established in children.^{138 139 140}

Hepatic Impairment

Use contraindicated.^{138 139 140}

Renal Impairment

Use contraindicated.^{138 139 140}

Common Adverse Effects

Nausea, vomiting, abdominal pain, numbness and tingling of the fingers and toes, muscle pain in the extremities, weakness in the legs.^{138 139 140 b}

Interactions for Ergomar

Extensively metabolized, principally by CYP3A4.^{138 139 140} Inhibits CYP3A.^{138 139 140}

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A4 inhibitors: Potential pharmacokinetic interaction (increased serum ergotamine concentrations); potentially fatal cerebral ischemia and/or ischemia of the extremities possible.^{123 124 125 126 127 138 139 140} Concomitant use with potent CYP3A4 inhibitors contraindicated.^{123 124 125 126 127 138 139 140}

Less-potent CYP3A4 inhibitors: Similar effects not reported to date; however, consider possibility of serious toxicity during concomitant use.^{138 139 140}

Specific Drugs

Drug	Interaction	Comment
Antifungals, azole (e.g., itraconazole, ketoconazole)	Inhibition of ergotamine metabolism; increased risk of potentially fatal cerebral ischemia and/or ischemia of the extremities123 124 125 126 127 138 139 140	Concomitant use contraindicated124 125 126 127 138 139 140
Caffeine	Increased plasma ergotamine concentrations143 b
HIV protease inhibitors (e.g., ritonavir, nelfinavir, indinavir)	Inhibition of ergotamine metabolism; increased risk of potentially fatal cerebral ischemia and/or ischemia of the extremities123 124 125 126 127 138 139 140	Concomitant use contraindicated124 125 126 127 138 139 140
Macrolide antibiotics (e.g., erythromycin, clarithromycin, troleandomycin)	Inhibition of ergotamine metabolism; increased risk of potentially fatal cerebral ischemia and/or ischemia of the extremities123 124 125 126 127 138 139 140	Concomitant use contraindicated124 125 126 127 138 139 140
Methysergide (no longer commercially available in US)	Potential for excessive vasoconstriction143	Decrease ergotamine dosage by about 50%; keep frequency of ergotamine administration at a minimumb
Nicotine	Possible vasoconstriction and increased ischemic response138 139 140	Concomitant use not recommended138 139 140
Propranolol	Potentiation of ergotamine’s vasoconstrictive action138 139 140	Use with cautionb
Serotonin (5-HT1) receptor agonists (e.g., sumatriptan)	Additive vasoconstrictor effects115 116 117 118 119 144 145	Use within 24 hours contraindicated115 116 144 145
Sympathomimetic agents	Potential for extreme BP elevations138 139 140	Concomitant use not recommended138 139 140

Ergomar Pharmacokinetics

Absorption

Bioavailability

Absorption is variable following oral administration.^b

Undergoes first-pass metabolism following oral administration.^b

Distribution

Extent

Crosses the blood-brain barrier and is distributed into milk.^b

Elimination

Metabolism

Extensively metabolized in the liver, mainly by CYP3A4.^b

Elimination Route

Metabolites are excreted mainly (90%) in bile;^b only traces of unchanged drug are excreted in urine and feces.¹¹²

Eliminated by dialysis.^b

Half-life

Biphasic; terminal half-life is approximately 21 hours.^b

Stability

Storage

Oral

Tablets

Tight, light-resistant container at 15–30°C.¹⁴⁰

Sublingual

Tablets

20–25°C (may be exposed to 15–30°C).¹³⁸ Protect from light and heat.¹³⁸

Rectal

Suppositories

2–8°C.¹³⁹

ActionsActions

• 
  

  Complex pharmacologic effects, including α-adrenergic blocking activity, direct stimulation of peripheral and cranial vascular smooth muscle, and serotonin antagonist activity.^{138 139 140}

  
  


• 
  

  Mechanism by which ergotamine aborts vascular headaches is probably direct vasoconstriction of dilated carotid artery bed.^b

  
  


• 
  

  Has greater vasoconstrictor activity than other ergot alkaloids but less α-adrenergic blocking activity than dihydroergotamine;^{b 138 139 140} weaker antagonist of serotonin than is methysergide.^b

  
  

Advice to Patients

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  Risk of ergotism; importance of informing clinicians if intermittent claudication; muscle pain; or numbness, coldness, and pallor of the digits occur.^{138 139 140}

  
  


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  Importance of informing clinicians if persistent paresthesia, chest/muscle/abdominal pain, speeding or slowing of heart rate, swelling, or itching occurs.^{b 138 139 140}

  
  


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  Importance of taking ergotamine exactly as prescribed.^{138 139 140}

  
  


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  Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.^{138 139 140}

  
  


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  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.^{138 139 140}

  
  


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  Importance of informing patients of other important precautionary information.^{138 139 140} (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

On February 26, 2007, FDA warned 20 firms that manufacture or distribute unapproved drug preparations containing ergotamine tartrate of the agency’s intention to take enforcement action (e.g., seizure, injunction, other judicial proceeding) against all firms attempting to manufacture or distribute such preparations after April 25, 2007, or August 25, 2007, respectively, without an approved new drug application (NDA).^{130 131 132} Manufacturers’ labelings for most of these unapproved preparations omitted critical drug interaction warnings, and the preparations did not undergo FDA review of safety, efficacy, quality, and labeling.^{131 132} There currently are approved ergotamine-containing preparations on the US market.^{130 131 132}

Ergotamine Tartrate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Sublingual	Tablets	2 mg	Ergomar	Rosedale

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Ergotamine Tartrate Combinations

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	1 mg with Caffeine 100 mg*	Cafergot	Novartis
Rectal	Suppositories	2 mg with Caffeine 100 mg	Migergot	G&W

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Cafergot 1-100MG Tablets (SANDOZ): 30/$49.99 or 90/$139.97

Migergot 2-100MG Suppositories (G & W LABS): 12/$95.99 or 36/$259.98

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions December 2009. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

Only references cited for selected revisions after 1984 are available electronically.

14. Medications: In: Kliegman RM, Behrman RE, Jenson HB, Stanton BF, eds. Nelson textbook of pediatrics. 18th ed. Philadelphia: WB Saunders Company; 2007: 2974.

100. A Redfield MM, Nicholson WJ, Edwards WD. Valve disease associated with ergot alkaloid use: echocardiographic and pathologic correlations. Ann Intern Med. 1992; 117:50-52. [IDIS 298556] [PubMed 1596047]

101. Bana DS, MacNeal PS, LeCompte PM et al. Cardiac murmurs and endocardial fibrosis associated with methysergide therapy. Am Heart J. 1974; 88:640-55. [IDIS 46354] [PubMed 4420941]

102. Misch KA. Development of heart valve lesions during methysergide therapy. Br Med J. 1974; 2:365-6. [IDIS 4307] [PubMed 4835843]

103. Hauck AJ, Edwards WD, Danielson K et al. Mitral and aortic valve disease associated with ergotamine therapy for migraine. Arch Pathol Lab Med. 1990; 114:62-4. [PubMed 2403780]

104. Munroe DS, Allen P, Cox AR. Mitral regurgitation occurring during methysergide (Sansert) therapy. Can Med Assoc J. 1969; 101:62-5. [IDIS 10120] [PubMed 5348490]

105. Mason JW, Billingham ME, Friedman JP. Methysergide-induced heart disease: a case of multivalvular and myocardial fibrosis. Circulation. 1977; 56:889-90. [IDIS 98306] [PubMed 912852]

106. Spierings ELH. Cardiac murmurs indicative of aortic valve disease with chronic and excessive intake of ergotamine. Headache. 1988; 28:278-9. [PubMed 3170186]

107. Graham JR. Cardiac and pulmonary fibrosis during methysergide therapy for headache. Am J Med Sci. 1967; 254:1-12. [IDIS 86] [PubMed 6027684]

108. Khan MA, Herzog CA, St Peter JV et al. The prevalence of cardiac valvular insufficiency assessed by transthoracic echocardiography in obese patients treated with appetite-suppressant drugs. N Engl J Med. 1998; 339:713-8. [IDIS 411507] [PubMed 9731086]

109. Graham JR, Suby HI, LeCompte PR et al. Fibrotic disorders associated with methysergide therapy for headache. N Engl J Med. 1966; 274:359-68. [IDIS 1053] [PubMed 5903120]

110. Slugg PH, Kunkel RS. Complications of methysergide therapy: retroperitoneal fibrosis, mitral regurgitation, edema, and hemolytic anemia. JAMA. 1970; 213:297-8. [IDIS 13760] [PubMed 5467905]

111. Orlando RC, Moyer P, Barnett TB. Methysergide therapy and constrictive pericarditis. Ann Intern Med. 1978; 88:213-4. [IDIS 77377] [PubMed 626452]

112. Ergomar (ergotamine tartrate sublingual tablets) prescribing information (dated 1997 Jun). In: Physicians’ desk reference. 52nd ed. Montvale, NJ: Medical Economics Company Inc; 1998:1518-9.

113. Sansert (methysergide maleate tablets) prescribing information (dated 1995 Jun). In: Physicians’ desk reference. 51st ed. Montvale, NJ: Medical Economics Company Inc; 1997:2424-5.

114. Elkind AH, Friedman AP, Bachman A et al. Silent retroperitoneal fibrosis associated with methysergide therapy. JAMA. 1968; 206:1041-44. [IDIS 7031] [PubMed 5695652]

115. GlaxoSmithKline. Imitrex (sumatriptan succinate) injection prescribing information. Research Triangle Park, NC; 2008 Feb.

116. GlaxoSmithKline. Imitrex (sumatriptan succinate) tablets prescribing information. Research Triangle Park, NC; 2007 Oct.

117. Anon. New medicines: sumatriptan. Intl Pharm J. 1992; 6:55-7.

118. Myerburg RJ, Kessler KM, Mallon SM et al. Life-threatening ventricular arrhythmias in patients with silent myocardial ischemia due to coronary artery spasm. N Engl J Med. 1992; 326:1451-5. [IDIS 296579] [PubMed 1574091]

119. Tfelt-Hansen P, Sperling B, Winter PDO’B. Transient additional effect of sumatriptan on ergotamine-induced constriction of peripheral arteries in man. Clin Pharmacol Ther. 1992; 51:149.

120. Henry P, d’Allens H, French Migraine Network Bordeaux-Lyon-Grenoble. Subcutaneous sumatriptan in the acute treatment of migraine in patients using dihydroergotamine as prophylaxis. Headache. 1993; 33:432-5. [PubMed 8262783]

121. US Headache Consortium. Evidence-based guidelines for migraine headache in the primary care setting. St. Paul, MN; 2001. From the American Academy of Neurology web site. [pharmacologic management of acute attacks]).

123. Clarithromycin (Biaxin) interactions: ergotamine (Ergomar). In: Hansten PD, Horn JR. Hansten and Horn’s drug interactions analysis and management. St. Louis, MO: Facts and Comparisons; 2002:350.

124. Horowitz RS, Dart RC, Gomez HF. Clinical ergotism with lingual ischemia induced by clarithromycin-ergotamine interaction. Arch Intern Med. 1996; 156:456-8. [IDIS 363451] [PubMed 8607732]

125. Dresser GK, Spence JD, Bailey DG. Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacokinet. 2000; 38:41-57. [PubMed 10668858]

126. Ergotamine (Ergostat) interactions: indinavir (Crixivan). In: Hansten PD, Horn JR. Hansten and Horn’s drug interactions analysis and management. St. Louis, MO: Facts and Comparisons; 2002:356.

127. Ergotamine (Ergostat) interactions: ritonavir (Norvir). In: Hansten PD, Horn JR. Hansten and Horn’s drug interactions analysis and management. St. Louis, MO: Facts and Comparisons; 2002:357a.

128. Ergotamine. In: Briggs GG, Freeman RK, Yaffe SJ eds. Drugs in pregnancy and lactation. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2002:497-501/e.

129. American Academy of Pediatrics Committee on Drugs. The transfer of drugs and other chemicals into human milk. Policy statement. Pediatrics. 2001; 108:776-89. [IDIS 468574] [PubMed 11533352]

130. Food and Drug Administration. Ergotamine tartrate. Rockville, MD; 2007 Mar 2. From FDA website.

131. Food and Drug Administration. FDA takes action to halt marketing of unapproved ergotamine–Companies ordered to cease manufacturing and distribution of illegal drugs to treat migraine headaches. FDA News March 1, 2007. From FDA web site.

132. Food and Drug Administration. Warning letters for ergotamine-containing drug products (issued February 26, 2007). From FDA web site.

133. Custer JW, Rau RE, eds. The Harriet Lane Handbook: a manual for pediatric house officers. 18th ed. Philadelphia, PA: Elsevier Mosby: 2009:821.

134. Schreiber CP, Young WB. Cluster headache. In Freitag F, Cady R, eds. Standards of care for headache diagnosis and treatment. Chicago: National Headache Foundation; 2008: 66-74.

135. Agency for Healthcare Research and Quality. Treatment of primary headache: cluster headache. Standards of care for headache diagnosis and treatment. From the National Guideline Clearinghouse website. Accessed 7/31/09.

136. Capobianco DJ, Dodick DW. Diagnosis and treatment of cluster headache. Semin Neurol. 2006; 26:242-59. [PubMed 16628535]

137. May A. Cluster headache: pathogenesis, diagnosis, and management. Lancet. 2005 Sep 3-9; 366:843-55.

138. Rosedale Therapeutics. Ergomar (ergotamine tartrate) sublingual tablets prescribing information. Bristol, TN. 2007 Aug.

139. G and W Laboratories, Inc. Ergotamine tartrate and caffeine suppositories prescribing information. South Plainfield, NJ. 2003 Apr.

140. Novartis. Cafergot (ergotamine tartrate and caffeine) tablets prescribing information. East Hanover, NJ. 2003 Mar.

141. Balasubramaniam R, Klasser GD. Trigeminal autonomic cephalalgias. Part 1: cluster headache. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007; 104:345-58. [PubMed 17618143]

142. Ekbom K, Hardebo JE. Cluster headache: aetiology, diagnosis and management. Drugs. 2002; 62:61-9. [PubMed 11790156]

143. Eadie MJ. Clinically significant drug interactions with agents specific for migraine attacks. CNS Drugs. 2001; 15:105-18. [PubMed 11460889]

144. AstraZeneca. Zomig (zolmitriptan) nasal spray prescribing information. Wilmington, DE; 2008 Oct.

145. Merck & Co., Inc. Maxalt (rizatriptan benzoate) tablets and Maxalt-MLT (rizatriptan benzoate) orally distinegrating tablets prescribing information. Whitehouse Station, NJ; 2008 Feb.

b. AHFS drug information 2009. McEvoy GK, ed. Ergotamine tartrate. Bethesda, MD: American Society of Health-System Pharmacists; 2009:1406-9.

More Ergomar resources

• Ergomar Side Effects (in more detail)
• Ergomar Use in Pregnancy & Breastfeeding
• Ergomar Drug Interactions
• Ergomar Support Group
• 1 Review for Ergomar - Add your own review/rating

• Ergomar Concise Consumer Information (Cerner Multum)


• Ergomar MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Ergomar with other medications

• Migraine

Hycodan

hydrocodone bitartrate and homatropine methylbromide

Dosage Form: Tablets and Syrup CIII

Hycodan Description

Hycodan contains hydrocodone (dihydrocodeinone) bitartrate, a semisynthetic centrally-acting opioid antitussive. Homatropine methylbromide is included in a subtherapeutic amount to discourage deliberate overdosage.

Each Hycodan tablet or teaspoonful (5 mL) contains:

Hydrocodone Bitartrate, USP             5 mg

Homatropine Methylbromide, USP     1.5 mg

Hycodan tablets also contain: calcium phosphate dibasic, colloidal silicon dioxide, lactose, magnesium stearate, starch and stearic acid.

Hycodan syrup also contains: caramel coloring, FD&C Red 40, liquid sugar, methylparaben, propylparaben, sorbitol solution and wild cherry imitation flavor. The hydrocodone component is 4,5α-epoxy-3-methoxy-17-methylmorphinan-6-one tartrate (1:1) hydrate (2:5), a fine white crystal or crystalline powder, which is derived from the opium alkaloid, thebaine, has a molecular weight of (494.50), and may be represented by the following structural formula:

Homatropine methylbromide is 8-Azoniabicyclo [3.2.1]octane,3-[(hydroxyphenyl-acetyl)oxy]-8,8-dimethyl-,bromide, endo-; a white crystal or fine white crystalline powder, with a molecular weight of (370.29).

Hycodan - Clinical Pharmacology

Hydrocodone is a semisynthetic opioid antitussive and analgesic with multiple actions qualitatively similar to those of codeine. The precise mechanism of action of hydrocodone and other opiates is not known; however, hydrocodone is believed to act directly on the cough center. In excessive doses, hydrocodone, like other opium derivatives, will depress respiration. The effects of hydrocodone in therapeutic doses on the cardiovascular system are insignificant. Hydrocodone can produce miosis, euphoria, physical and physiological dependence.

Following a 10 mg oral dose of hydrocodone administered to five adult male subjects, the mean peak concentration was 23.6 ± 5.2 ng/mL. Maximum serum levels were achieved at 1.3 ± 0.3 hours and the half-life was determined to be 3.8 ± 0.3 hours. Hydrocodone exhibits a complex pattern of metabolism including O-demethylation, N-demethylation and 6-keto reduction to the corresponding 6-α- and 6-β-hydroxymetabolites.

Indications and Usage for Hycodan

Hycodan (hydrocodone bitartrate and homatropine methylbromide) is indicated for the symptomatic relief of cough.

Contraindications

Hycodan should not be administered to patients who are hypersensitive to hydrocodone or homatropine methylbromide.

Warnings

Hydrocodone can produce drug dependence of the morphine type and, therefore, has the potential for being abused. Psychic dependence, physical dependence and tolerance may develop upon repeated administration of Hycodan and it should be prescribed and administered with the same degree of caution appropriate to the use of other opioid drugs (see DRUG ABUSE AND DEPENDENCE).

Respiratory Depression

Hycodan produces dose-related respiratory depression by directly acting on brain stem respiratory centers. If respiratory depression occurs, it may be antagonized by the use of naloxone hydrochloride and other supportive measures when indicated.

Head Injury and Increased Intracranial Pressure

The respiratory depression properties of opioids and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or a pre-existing increase in intracranial pressure. Furthermore, opioids produce adverse reactions which may obscure the clinical course of patients with head injuries.

Acute Abdominal Conditions

The administration of Hycodan or other opioids may obscure the diagnosis or clinical course of patients with acute abdominal conditions.

Pediatric Use

In young pediatric patients, as well as adults, the respiratory center is sensitive to the depressant action of opioid cough suppressants in a dose-dependent manner. Benefit to risk ratio should be carefully considered especially in the pediatric population with respiratory embarrassment (e.g., croup).

Precautions

General

Before prescribing medication to suppress or modify cough, it is important to ascertain that the underlying cause of cough is identified, that modification of cough does not increase the risk of clinical or physiological complications, and that appropriate therapy for the primary disease is provided.

Special Risk Patients

Hycodan (hydrocodone bitartrate and homatropine methylbromide) should be given with caution to certain patients such as the elderly or debilitated, and those with severe impairment of hepatic or renal functions, hypothyroidism, Addison's disease, prostatic hypertrophy or urethral stricture, asthma, and narrow-angle glaucoma.

Information for Patients

Hydrocodone may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. The patient using Hycodan should be cautioned accordingly.

Drug Interactions

Patients receiving opioids, antihistamines, antipsychotics, antianxiety agents or other CNS depressants (including alcohol) concomitantly with Hycodan may exhibit an additive CNS depression. When combined therapy is contemplated, the dose of one or both agents should be reduced. The use of MAO inhibitors or tricyclic antidepressants with hydrocodone preparations may increase the effect of either the antidepressant or hydrocodone.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies of Hycodan in animals to evaluate the carcinogenic and mutagenic potential and the effect on fertility have not been conducted.

Pregnancy

Teratogenic Effects: Pregnancy Category C

Animal reproduction studies have not been conducted with Hycodan. It is also not known whether Hycodan can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Hycodan should be given to a pregnant woman only if clearly needed.

Nonteratogenic Effects

Babies born to mothers who have been taking opioids regularly prior to delivery will be physically dependent. The withdrawal signs include irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting and fever. The intensity of the syndrome does not always correlate with the duration of maternal opioid use or dose.

Labor and Delivery

As with all opioids, administration of Hycodan to the mother shortly before delivery may result in some degree of respiratory depression in the newborn, especially if higher doses are used.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Hycodan, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness of Hycodan in pediatric patients under six have not been established.

Adverse Reactions

Central Nervous System

Sedation, drowsiness, mental clouding, lethargy, impairment of mental and physical performance, anxiety, fear, dysphoria, dizziness, psychic dependence, mood changes.

Gastrointestinal System

Nausea and vomiting may occur; they are more frequent in ambulatory than in recumbent patients. Prolonged administration of Hycodan may produce constipation.

Genitourinary System

Ureteral spasm, spasm of vesicle sphincters and urinary retention have been reported with opiates.

Respiratory Depression

Hycodan may produce dose-related respiratory depression by acting directly on brain stem respiratory centers (see OVERDOSAGE).

Dermatological

Skin rash, pruritus.

Drug Abuse and Dependence

Hycodan (hydrocodone bitartrate and homatropine methylbromide) is a Schedule III opioid. Psychic dependence, physical dependence and tolerance may develop upon repeated administration of opioids; therefore, Hycodan should be prescribed and administered with caution. However, psychic dependence is unlikely to develop when Hycodan is used for a short time for the treatment of cough. Physical dependence, the condition in which continued administration of the drug is required to prevent the appearance of a withdrawal syndrome, assumes clinically significant proportions only after several weeks of continued oral opioid use, although some mild degree of physical dependence may develop after a few days of opioid therapy.

Overdosage

Signs and Symptoms

Serious overdosage with hydrocodone is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. In severe overdosage, apnea, circulatory collapse, cardiac arrest and death may occur. The ingestion of very large amounts of Hycodan may, in addition, result in acute homatropine intoxication.

Treatment

Primary attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and the institution of assisted or controlled ventilation. The opioid antagonist naloxone hydrochloride is a specific antidote for respiratory depression which may result from overdosage or unusual sensitivity to opioids including hydrocodone. Therefore, an appropriate dose of naloxone hydrochloride should be administered, preferably by the intravenous route, simultaneously with efforts at respiratory resuscitation. For further information, see full prescribing information for naloxone hydrochloride. An antagonist should not be administered in the absence of clinically significant respiratory depression. Oxygen, intravenous fluids, vasopressors and other supportive measures should be employed as indicated. Gastric emptying may be useful in removing unabsorbed drug.

Hycodan Dosage and Administration

Adults

One (1) tablet or one (1) teaspoonful (5 mL) of the syrup every 4 to 6 hours as needed; do not exceed six (6) tablets or six (6) teaspoonfuls in 24 hours.

Children 6 to 12 Years of Age

One-half (1/2) tablet or one-half (1/2) teaspoonful (2.5 mL) of the syrup every 4 to 6 hours as needed; do not exceed three (3) tablets or three (3) teaspoonfuls in 24 hours.

How is Hycodan Supplied

Hycodan is supplied as a white, biconvex tablet, one face bisected and debossed with “Hycodan”, and the other face plain, available in:

Bottles of 100        NDC 63481-042-70

Bottles of 500        NDC 63481-042-85

Store tablets at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled Room Temperature.]

Dispense in a tight, light-resistant container, as defined in the USP, with a child-resistant closure (as required).

Hycodan is also available as a clear red colored, wild cherry flavored syrup in:

Bottles of one pint     NDC 63481-234-16

Store syrup at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled Room Temperature.]

Oral prescription where permitted by state law.

Manufactured for:

Endo Pharmaceuticals Inc.

Chadds Ford, Pennsylvania 19317

Hycodan® is a Registered Trademark of Endo Pharmaceuticals Inc.

Copyright © Endo Pharmaceuticals Inc. 2003

Printed in U.S.A.

412042/May, 2003

Hycodan  hydrocodone bitartrate and homatropine methylbromide  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 63481-042 Route of Administration ORAL DEA Schedule CIII

INGREDIENTS Name (Active Moiety) Type Strength Hydrocodone Bitartrate (hydrocodone) Active 5 MILLIGRAM  In 1 TABLET Homatropine Methylbromide (Homatropine) Active 1.5 MILLIGRAM  In 1 TABLET calcium phosphate dibasic Inactive   colloidal silicon dioxide Inactive   lactose Inactive   magnesium stearate Inactive   starch Inactive   stearic acid Inactive

Product Characteristics Color WHITE (WHITE) Score 2 pieces Shape ROUND (ROUND) Size 8mm Flavor Imprint Code Hycodan Contains          Coating false Symbol false

Packaging # NDC Package Description Multilevel Packaging 1 63481-042-70 100 TABLET In 1 BOTTLE None 2 63481-042-85 500 TABLET In 1 BOTTLE None

Hycodan  hydrocodone bitartrate and homatropine methylbromide  syrup

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 63481-234 Route of Administration ORAL DEA Schedule CIII

INGREDIENTS Name (Active Moiety) Type Strength Hydrocodone Bitartrate (hydrocodone) Active 5 MILLIGRAM  In 5 MILLILITER Homatropine Methylbromide (Homatropine) Active 1.5 MILLIGRAM  In 5 MILLILITER caramel coloring Inactive   FD&C Red 40 Inactive   sugar Inactive   methylparaben Inactive   propylparaben Inactive   sorbitol solution Inactive   wild cherry imitation flavor Inactive

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 63481-234-16 1 [pt_us] (PINT) In 1 BOTTLE None

Revised: 06/2006Endo Pharmaceuticals Inc.

More Hycodan resources

• Hycodan Side Effects (in more detail)
• Hycodan Dosage
• Hycodan Use in Pregnancy & Breastfeeding
• Drug Images
• Hycodan Drug Interactions
• Hycodan Support Group
• 23 Reviews for Hycodan - Add your own review/rating

• Hycodan MedFacts Consumer Leaflet (Wolters Kluwer)


• Hycodan Concise Consumer Information (Cerner Multum)


• Hydromet Syrup MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Hycodan with other medications

• Cough

Monteban

Dosage Form: FOR ANIMAL USE ONLY
Monteban® 45 Narasin

ELANCO *

AF0510-50B

For Use in Broiler

Chicken Feeds Only

Monteban® 45

Narasin

Net Weight: 50 lbs (22.68 kg)

Type A Medicated Article

Do Not Feed Undiluted.

Active Drug Ingredient

Narasin .................................................................................. 45 g per lb

For the prevention of coccidiosis caused by Eimeria necatrix, E. tenella, E. acervulina, E. brunetti, E. mivati, and E. maxima.

Important: Must be thoroughly mixed in feeds before use.

Mixing Directions – Thoroughly mix the following amounts of Monteban to provide 54 through 72 grams of narasin in one ton of feed. The dosage should be adjusted to meet the severity of the coccidial challenge, which varies with environmental and management conditions.

It is recommended that a preblend of Monteban in 15-20 lbs of feed be made before incorporating into the total amount of finished feed.

Narasin	Monteban
(Grams/Ton)	(Lbs/Ton of Type C Feed)
	Lbs
54	1.20
59	1.31
63	1.40
68	1.51
72	1.60

Feeding Directions– Feed continuously as the sole ration.

CAUTION: Do not allow adult turkeys, horses or other equines access to narasin formulations. Ingestion of narasin by these species has been fatal.

NOT FOR HUMAN USE

WARNING: When mixing and handling Monteban, use protective clothing, impervious gloves and a dust mask. Operators should wash thoroughly with soap and water after handling. If accidental eye contact occurs, immediately rinse thoroughly with water.

Store in a cool, dry place.

Not to be used after the date printed at top of bag.

*Elanco®, Monteban® and the diagonal color bar are trademarks of Eli Lilly and Company.

TAKE TIME

OBSERVE LABEL DIRECTIONS

Restricted Drug (California) - Use Only a s Directed - NADA # 118-980, Approved by FDA

Elanco Animal Health

A Division of Eli Lilly and Company

Indianapolis, IN 46285, U.S.A.

To report adverse effects, access medical information, or obtain additional product information, call 1-800-428-4441.

BG7070DEAMB (V01-02-2007)

Monteban  narasin  granule

Product Information Product Type OTC TYPE A MEDICATED ARTICLE ANIMAL DRUG NDC Product Code (Source) 0986-0510 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength NARASIN (NARASIN) NARASIN 45 g  in 0.45 kg

Inactive Ingredients Ingredient Name Strength RICE BRAN   LIGHT MINERAL OIL

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0986-0510-*1 22.68 kg In 1 BAG None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NADA	NADA118980	06/01/2009

Labeler - Elanco Animal Health Co (807447169)

Establishment
Name	Address	ID/FEI	Operations
Clinton Laboratories		039138631	MANUFACTURE, ANALYSIS

Revised: 07/2008Elanco Animal Health Co

Quibron T/SR

theophylline, anhydrous

Dosage Form: Tablets

ACCUDOSE® Tablets

SUSTAINED-RELEASE BRONCHODILATOR

Description

Theophylline is structurally classified as a methylxanthine. It occurs as a white, odorless, crystalline powder with a bitter taste. Anhydrous theophylline has the chemical name 1HPurine- 2,6-dione,3,7-dihydro-1,3-dimethyl-, and is represented by the following structural formula:

The molecular formula of anhydrous theophylline is C7H8N4O2 with a molecular weight of 180.17.

Quibron®-T/SR is available as tablets intended for oral administration, containing 300 mg of anhydrous theophylline per tablet. Quibron®-T/SR is an oral bronchodilator in a sustained-release formulation in the ACCUDOSE® Tablet design. With functional trisects and bisects, Quibron®-T/SR Tablets can be accurately divided into 100-, 150-, and 200- mg segments to provide a variety of dosing increments, as required.

QUIBRON®-T/SR TABLETS

	One-third tablet	= 100 mg
	One-half tablet	= 150 mg
	Two-thirds tablet	= 200 mg
	One tablet	= 300 mg

Inactive Ingredient: magnesium stearate.

Clinical Pharmacology

Mechanism of Action:

Theophylline has two distinct actions in the airways of patients with reversible obstruction; smooth muscle relaxation (i.e., bronchodilation) and suppression of the response of the airways to stimuli (i.e., non-bronchodilator prophylactic effects). While the mechanisms of action of theophylline are not known with certainty, studies in animals suggest that bronchodilatation is mediated by the inhibition of two isozymes of phosphodiesterase (PDE III and, to a lesser extent, PDE IV) while non-bronchodilator prophylactic actions are probably mediated through one or more different molecular mechanisms, that do not involve inhibition of PDE III or antagonism of adenosine receptors. Some of the adverse effects associated with theophylline appear to be mediated by inhibition of PDE III (e.g., hypotension, tachycardia, headache, and emesis) and adenosine receptor antagonism (e.g., alterations in cerebral blood flow).

Theophylline increases the force of contraction of diaphragmatic muscles. This action appears to be due to enhancement of calcium uptake through an adenosine-mediated channel.

Serum Concentration-Effect Relationship:

Bronchodilation occurs over the serum theophylline concentration range of 5-20 mcg/mL. Clinically important improvement in symptom control has been found in most studies to require peak serum theophylline concentrations > 10 mcg/mL, but patients with mild disease may benefit from lower concentrations. At serum theophylline concentrations > 20 mcg/mL, both the frequency and severity of adverse reactions increase. In general, maintaining peak serum theophylline concentrations between 10 and 15 mcg/mL will achieve most of the drug’s potential therapeutic benefit while minimizing the risk of serious adverse events.

Pharmacokinetics:

Overview Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. Theophylline does not undergo any appreciable pre-systemic elimination, distributes freely into fat-free tissues and is extensively metabolized in the liver.

The pharmacokinetics of theophylline vary widely among similar patients and cannot be predicted by age, sex, body weight or other demographic characteristics. In addition, certain concurrent illnesses and alterations in normal physiology (see Table I) and co-administration of other drugs (see Table II) can significantly alter the pharmacokinetic characteristics of theophylline. Within-subject variability in metabolism has also been reported in some studies, especially in acutely ill patients. It is, therefore, recommended that serum theophylline concentrations be measured frequently in acutely ill patients (e.g., at 24-hr intervals) and periodically in patients receiving long-term therapy, e.g., at 6-12 month intervals. More frequent measurements should be made in the presence of any condition that may significantly alter theophylline clearance (see PRECAUTIONS, Laboratory Tests).

Table I. Mean and range of total body clearance and half-life of theophylline related to age and altered physiological states.¶

Population characteristics	Total body clearance* mean (range)†† (mL/kg/min)	Half-life mean (range)†† (hr)
Age
Premature neonates
postnatal age 3-15 days	0.29 (0.09–0.49)	30 (17–43)
postnatal age 25-57 days	0.64 (0.04–1.2)	20 (9.4–30.6)
Term infants
postnatal age 1-2 days	NR†	25.7 (25-26.5)
postnatal age 3-30 weeks	NR†	11 (6-29)
Children
1-4 years	1.7 (0.5-2.9)	3.4 (1.2-5.6)
4-12 years	1.6 (0.8-2.4)	NR†
13-15 years	0.9 (0.48-1.3)	NR†
6-17 years	1.4 (0.2-2.6)	3.7 (1.5-5.9)
Adults (16-60 years)
otherwise healthy
non-smoking asthmatic	0.65 (0.27-1.03)	8.7 (6.1-12.8)
Elderly (>60 years)
non-smokers with normal cardiac, liver, and renal function	0.41 (0.21-0.61)	9.8 (1.6-18)
Concurrent illness or altered physiological state
Acute pulmonary edema	0.33** (0.07-2.45)	19** (3.1-82)
COPD->60 years, stable
non-smoker >1 year	0.54 (0.44-0.64)	11 (9.4-12.6)
COPD with cor pulmonale	0.48 (0.08-0.88)	NR†
Cystic fibrosis (14-28 years)	1.25 (0.31-2.2)	6.0 (1.8-10.2)
Fever associated with acute viral respiratory
illness (children 9-15 years)	NR†	7.0 (1.0-13
Liver disease - cirrhosis	0.31** (0.1-0.7)	32** (10-56)
acute hepatitis	0.35 (0.25-0.45)	19.2 (16.6-21.8)
cholestasis	0.65 (0.25-1.45)	14.4 (5.7-31.8)
Pregnancy -    1st trimester	NR†	8.5 (3.1-13.9)
2nd trimester	NR†	8.8 (3.8-13.8)
3rd trimester	NR†	13.0 (8.4-17.6)
Sepsis with multi-organ failure	0.47 (0.19-1.9)	18.8 (6.3-24.1)
Thyroid disease -   hypothyroid	0.38 (0.13-0.57)	11.6 (8.2-25)
hyperthyroid	0.8 (0.68-0.97)	4.5 (3.7-5.6)

¶ For various North American patient populations from literature reports. Different rates of elimination and consequent dosage requirements have been observed among other peoples.

* Clearance represents the volume of blood completely cleared of theophylline by the liver in one minute. Values listed were generally determined at serum theophylline concentrations <20 mcg/mL; clearance may decrease and half-life may increase at higher serum concentrations due to non-linear pharmacokinetics.

†† Reported range or estimated range (mean ± 2 SD) where actual range not reported.

† NR = not reported or not reported in a comparable format.

** Median

Note: In addition to the factors listed above, theophylline clearance is increased and half-life decreased by low carbohydrate/high protein diets, parenteral nutrition, and daily consumption of charcoal-broiled beef. A high carbohydrate/low protein diet can decrease the clearance and prolong the half-life of theophylline.

Absorption Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. After a single immediate-release theophylline dose of 5 mg/kg in adults, a mean peak serum concentration of about 10 mcg/mL (range 5-15 mcg/mL) can be expected 1-2 hr after the dose. Co-administration of theophylline with food or antacids does not cause clinically significant changes in the absorption of theophylline from immediate-release dosage forms.

In cigarette smokers (1 to 2 packs/day) the mean half-life is 4 to 5 hours, much shorter than in nonsmokers. The increase in clearance associated with smoking is presumably due to stimulation of the hepatic metabolic pathway by components of cigarette smoke. The duration of this effect after cessation of smoking is unknown but may require 6 months to 2 years before the rate approaches that of a nonsmoker.

In a single-dose study of Quibron®-T/SR (theophylline, anhydrous), a 300-mg dose in 12 fasted normal male subjects gave a mean peak plasma level of 5.26 ± 1.04 (S.D.) µg/mL at 6.25 ± 1.10 (S.D.) hours.

In a multi-dose, steady state study of 16 adult patients with a mean age of 39.0 years, the patients were dose-titrated to a therapeutically effective level without toxicity. Doses were administered once every 12 hours and ranged from 7.8 mg/kg/24 hours to 18.6 mg/kg/24 hours with a mean dose of 10.0 ± 2.8 (S.D.) mg/kg/24 hours. No food-fasting conditions were imposed in the study. A mean Cmax of 13.9 ± 3.2 (S.D.) µg/mL, a mean Cmin of 7.7± 2.0 (S.D.) µg/mL, and a mean percent fluctuation [(Cmax - Cmin)/Cmin x 100] of 87.1 ± 49.6 (S.D.) resulted from the study.

In a multi-dose, steady state study of 15 patients with a mean age of 14.4 years, the patients were dose-titrated to a therapeutically effective level without toxicity. Doses were administered once every 12 hours and ranged from 9.1 mg/kg/24 hours to 22.6 mg/kg/24 hours with a mean dose of 13.3 ± 3.9 (S.D.) mg/kg/24 hours. No food-fasting conditions were imposed in the study. A mean Cmax of 13.8 ± 3.9 (S.D.) µg/mL, a mean Cmin of 8.0 ± 2.5 (S.D.) µg/mL, and a mean percent fluctuation [(Cmax - Cmin)/Cmin x 100] of 85.4 ± 57.7 (S.D.) resulted from the study.

In a multiple-dose bioavailability study in 16 normal volunteers, when tested against an immediate-release reference tablet, Quibron®-T/SR was found to be 98% bioavailable.

Distribution Once theophylline enters the systemic circulation, about 40% is bound to plasma protein, primarily albumin. Unbound theophylline distributes throughout body water, but distributes poorly into body fat. The apparent volume of distribution of theophylline is approximately 0.45 L/kg (range 0.3-0.7 L/kg) based on ideal body weight. Theophylline passes freely across the placenta, into breast milk and into the cerebrospinal fluid (CSF). Saliva theophylline concentrations approximate unbound serum concentrations, but are not reliable for routine or therapeutic monitoring unless special techniques are used. An increase in the volume of distribution of theophylline, primarily due to reduction in plasma protein binding, occurs in premature neonates, patients with hepatic cirrhosis, uncorrected acidemia, the elderly and in women during the third trimester of pregnancy. In such cases, the patient may show signs of toxicity at total (bound + unbound) serum concentrations of theophylline in the therapeutic range (10-20 mcg/mL) due to elevated concentrations of the pharmacologically active unbound drug.

Similarly, a patient with decreased theophylline binding may have a sub-therapeutic total drug concentration while the pharmacologically active unbound concentration is in the therapeutic range. If only total serum theophylline concentration is measured, this may lead to an unnecessary and potentially dangerous dose increase. In patients with reduced protein binding, measurement of unbound serum theophylline concentration provides a more reliable means of dosage adjustment than measurement of total serum theophylline concentration. Generally, concentrations of unbound theophylline should be maintained in the range of 6-12 mcg/mL.

Metabolism Following oral dosing, theophylline does not undergo any measurable first-pass elimination. In adults and children beyond one year of age, approximately 90% of the dose is metabolized in the liver. Biotransformation takes place through demethylation to 1-methylxanthine and 3-methylxanthine and hydroxylation to 1,3-dimethyluric acid. 1- methylxanthine is further hydroxylated, by xanthine oxidase, to 1-methyluric acid. About 6% of a theophylline dose is N-methylated to caffeine. Theophylline demethylation to 3- methylxanthine is catalyzed by cytochrome P-450 1A2, while cytochromes P-450 2E1 and P-450 3A3 catalyze the hydroxylation to 1,3-dimethyluric acid. Demethylation to 1- methylxanthine appears to be catalyzed either by cytochrome P-450 1A2 or a closely related cytochrome. In neonates, the N-demethylation pathway is absent while the function of the hydroxylation pathway is markedly deficient. The activity of these pathways slowly increases to maximal levels by one year of age.

Caffeine and 3-methylxanthine are the only theophylline metabolites with pharmacologic activity. 3-methylxanthine has approximately one tenth the pharmacologic activity of theophylline and serum concentrations in adults with normal renal function are < 1 mcg/mL. In patients with end-stage renal disease, 3-methylxanthine may accumulate to concentrations that approximate the unmetabolized theophylline concentration. Caffeine concentrations are usually undetectable in adults regardless of renal function. In neonates, caffeine may accumulate to concentrations that approximate the unmetabolized theophylline concentration and thus, exert a pharmacologic effect.

Both the N-demethylation and hydroxylation pathways of theophylline biotransformation are capacity-limited. Due to the wide intersubject variability of the rate of theophylline metabolism, non-linearity of elimination may begin in some patients at serum theophylline concentrations < 10 mcg/mL. Since this non-linearity results in more than proportional changes in serum theophylline concentrations with changes in dose, it is advisable to make increases or decreases in dose in small increments in order to achieve desired changes in serum theophylline concentrations (see DOSAGE AND ADMINISTRATION, Table VI). Accurate prediction of dose-dependency of theophylline metabolism in patients a priori is not possible, but patients with very high initial clearance rates (i.e., low steady state serum theophylline concentrations at above average doses) have the greatest likelihood of experiencing large changes in serum theophylline concentration in response to dosage changes.

Excretion In neonates, approximately 50% of the theophylline dose is excreted unchanged in the urine. Beyond the first three months of life, approximately 10% of the theophylline dose is excreted unchanged in the urine. The remainder is excreted in the urine mainly as 1,3-dimethyluric acid (35-40%), 1-methyluric acid (20-25%) and 3- methylxanthine (15-20%). Since little theophylline is excreted unchanged in the urine and since active metabolites of theophylline (i.e., caffeine, 3-methylxanthine) do not accumulate to clinically significant levels even in the face of end-stage renal disease, no dosage adjustment for renal insufficiency is necessary in adults and children >3 months of age. In contrast, the large fraction of the theophylline dose excreted in the urine as unchanged theophylline and caffeine in neonates requires careful attention to dose reduction and frequent monitoring of serum theophylline concentrations in neonates with reduced renal function (See WARNINGS).

Serum Concentrations at Steady State After multiple doses of immediate-release theophylline, steady state is reached in 30-65 hours (average 40 hours) in adults. At steady state, on a dosage regimen with 6-hour intervals, the expected mean trough concentration is approximately 60% of the mean peak concentration, assuming a mean theophylline half-life of 8 hours. The difference between peak and trough concentrations is larger in patients with more rapid theophylline clearance. In patients with high theophylline clearance and half-lives of about 4-5 hours, such as children age 1 to 9 years, the trough serum theophylline concentration may be only 30% of peak with a 6-hour dosing interval. In these patients a slow release formulation would allow a longer dosing interval (8-12 hours) with a smaller peak/trough difference.

Special Populations (See Table I for mean clearance and half-life values)

Geriatric The clearance of theophylline is decreased by an average of 30% in healthy elderly adults (>60 yrs) compared to healthy young adults. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in elderly patients (see WARNINGS).

Pediatrics The clearance of theophylline is very low in neonates (see WARNINGS). Theophylline clearance reaches maximal values by one year of age, remains relatively constant until about 9 years of age and then slowly decreases by approximately 50% to adult values at about age 16. Renal excretion of unchanged theophylline in neonates amounts to about 50% of the dose, compared to about 10% in children older than three months and in adults. Careful attention to dosage selection and monitoring of serum theophylline concentrations are required in pediatric patients (see WARNINGS and DOSAGE AND ADMINISTRATION).

Gender Gender differences in theophylline clearance are relatively small and unlikely to be of clinical significance. Significant reduction in theophylline clearance, however, has been reported in women on the 20th day of the menstrual cycle and during the third trimester of pregnancy.

Race Pharmacokinetic differences in theophylline clearance due to race have not been studied.

Renal Insufficiency Only a small fraction, e.g., about 10%, of the administered theophylline dose is excreted unchanged in the urine of children greater than three months of age and adults. Since little theophylline is excreted unchanged in the urine and since active metabolites of theophylline (i.e., caffeine, 3-methylxanthine) do not accumulate to clinically significant levels even in the face of end-stage renal disease, no dosage adjustment for renal insufficiency is necessary in adults and children >3 months of age. In contrast, approximately 50% of the administered theophylline dose is excreted unchanged in the urine in neonates. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in neonates with decreased renal function (see WARNINGS).

Hepatic Insufficiency Theophylline clearance is decreased by 50% or more in patients with hepatic insufficiency (e.g., cirrhosis, acute hepatitis, cholestasis). Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with reduced hepatic function (see WARNINGS).

Congestive Heart Failure (CHF) Theophylline clearance is decreased by 50% or more in patients with CHF. The extent of reduction in theophylline clearance in patients with CHF appears to be directly correlated to the severity of the cardiac disease. Since theophylline clearance is independent of liver blood flow, the reduction in clearance appears to be due to impaired hepatocyte function rather than reduced perfusion. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with CHF (see WARNINGS).

Smokers Tobacco and marijuana smoking appears to increase the clearance of theophylline by induction of metabolic pathways. Theophylline clearance has been shown to increase by approximately 50% in young adult tobacco smokers and by approximately 80% in elderly tobacco smokers compared to non-smoking subjects. Passive smoke exposure has also been shown to increase theophylline clearance by up to 50%. Abstinence from tobacco smoking for one week causes a reduction of approximately 40% in theophylline clearance. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients who stop smoking (see WARNINGS). Use of nicotine gum has been shown to have no effect on theophylline clearance.

Fever Fever, regardless of its underlying cause, can decrease the clearance of theophylline. The magnitude and duration of the fever appear to be directly correlated to the degree of decrease of theophylline clearance. Precise data are lacking, but a temperature of 39°C (102°F) for at least 24 hours is probably required to produce a clinically significant increase in serum theophylline concentrations. Children with rapid rates of theophylline clearance (i.e., those who require a dose that is substantially larger than average [e.g., >22 mg/kg/day] to achieve a therapeutic peak serum theophylline concentration when afebrile) may be at greater risk of toxic effects from decreased clearance during sustained fever. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with sustained fever (see WARNINGS).

Miscellaneous Other factors associated with decreased theophylline clearance include the third trimester of pregnancy, sepsis with multiple organ failure, and hypothyroidism. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with any of these conditions (see WARNINGS). Other factors associated with increased theophylline clearance include hyperthyroidism and cystic fibrosis.

Clinical Studies:

In patients with chronic asthma, including patients with severe asthma requiring inhaled corticosteroids or alternate-day oral corticosteroids, many clinical studies have shown that theophylline decreases the frequency and severity of symptoms, including nocturnal exacerbations, and decreases the “as needed” use of inhaled beta-2 agonists. Theophylline has also been shown to reduce the need for short courses of daily oral prednisone to relieve exacerbations of airway obstruction that are unresponsive to bronchodilators in asthmatics.

In patients with chronic obstructive pulmonary disease (COPD), clinical studies have shown that theophylline decreases dyspnea, air trapping, the work of breathing, and improves contractility of diaphragmatic muscles with little or no improvement in pulmonary function measurements.

Indications and Usage

Theophylline is indicated for the treatment of the symptoms and reversible airflow obstruction associated with chronic asthma and other chronic lung diseases, e.g., emphysema and chronic bronchitis

Contraindications

QUIBRON®-T/SR ACCUDOSE® Tablets are contraindicated in patients with a history of hypersensitivity to theophylline or other components in the product.

Warnings

Concurrent Illness:

Theophylline should be used with extreme caution in patients with the following clinical conditions due to the increased risk of exacerbation of the concurrent condition:

   Active peptic ulcer disease

   Seizure disorders

   Cardiac arrhythmias (not including bradyarrhythmias)

Conditions That Reduce Theophylline Clearance:

There are several readily identifiable causes of reduced theophylline clearance. If the total daily dose is not appropriately reduced in the presence of these risk factors, severe and potentially fatal theophylline toxicity can occur. Careful consideration must be given to the benefits and risks of theophylline use and the need for more intensive monitoring of serum theophylline concentrations in patients with the following risk factors:

Age

Neonates (term and premature)

Children <1 year

Elderly (>60 years)

Concurrent Diseases

Acute pulmonary edema

Congestive heart failure

Cor-pulmonale

Fever; ≥102° for 24 hours or more; or lesser temperature elevations for longer periods

Hypothyroidism

Liver disease; cirrhosis, acute hepatitis

Reduced renal function in infants <3 months of age

Sepsis with multi-organ failure

Shock

Cessation of Smoking

Drug Interactions Adding a drug that inhibits theophylline metabolism (e.g., cimetidine, erythromycin, tacrine) or stopping a concurrently administered drug that enhances theophylline metabolism (e.g., carbamazepine, rifampin). (see PRECAUTIONS, Drug Interactions, Table II).

When Signs or Symptoms of Theophylline Toxicity Are Present:

Whenever a patient receiving theophylline develops nausea or vomiting, particularly repetitive vomiting, or other signs or symptoms consistent with theophylline toxicity (even if another cause may be suspected), additional doses of theophylline should be withheld and a serum theophylline concentration measured immediately. Patients should be instructed not to continue any dosage that causes adverse effects and to withhold subsequent doses until the symptoms have resolved, at which time the clinician may instruct the patient to resume the drug at a lower dosage (see DOSAGE AND ADMINISTRATION, Dosing Guidelines, Table VI).

Dosage Increases:

Increases in the dose of theophylline should not be made in response to an acute exacerbation of symptoms of chronic lung disease since theophylline provides little added benefit to inhaled beta2-selective agonists and systemically administered corticosteroids in this circumstance and increases the risk of adverse effects. A peak steady-state serum theophylline concentration should be measured before increasing the dose in response to persistent chronic symptoms to ascertain whether an increase in dose is safe. Before increasing the theophylline dose on the basis of a low serum concentration, the clinician should consider whether the blood sample was obtained at an appropriate time in relationship to the dose and whether the patient has adhered to the prescribed regimen (see PRECAUTIONS, Laboratory Tests).

As the rate of theophylline clearance may be dose-dependent (i.e., steady-state serum concentrations may increase disproportionately to the increase in dose), an increase in dose based upon a sub-therapeutic serum concentration measurement should be conservative. In general, limiting dose increases to about 25% of the previous total daily dose will reduce the risk of unintended excessive increases in serum theophylline concentration (see DOSAGE AND ADMINISTRATION, Table VI).

Precautions

General:

Careful consideration of the various interacting drugs and physiologic conditions that can alter theophylline clearance and require dosage adjustment should occur prior to initiation of theophylline therapy, prior to increases in theophylline dose, and during follow up (see WARNINGS). The dose of theophylline selected for initiation of therapy should be low and, if tolerated, increased slowly over a period of a week or longer with the final dose guided by monitoring serum theophylline concentrations and the patient’s clinical response (see DOSAGE AND ADMINISTRATION, Table V).

Monitoring Serum Theophylline Concentrations:

Serum theophylline concentration measurements are readily available and should be used to determine whether the dosage is appropriate. Specifically, the serum theophylline concentration should be measured as follows:

1. 
   

   When initiating therapy to guide final dosage adjustment after titration.

   
   


2. 
   

   Before making a dose increase to determine whether the serum concentration is sub-therapeutic in a patient who continues to be symptomatic.

   
   


3. 
   

   Whenever signs or symptoms of theophylline toxicity are present.

   
   


4. 
   

   Whenever there is a new illness, worsening of a chronic illness or a change in the patient’s treatment regimen that may alter theophylline clearance (e.g., fever >102°F sustained for ≥24 hours, hepatitis, or drugs listed in Table II are added or discontinued).

   
   

To guide a dose increase, the blood sample should be obtained at the time of the expected peak serum theophylline concentration; 5-6 hours after a dose at steady-state, drawn more than 6 hours after the dose. For most patients, steady-state will be reached after 3 days of dosing when no doses have been missed, no extra doses have been added, and none of the doses have been taken at unequal intervals. A trough concentration (i.e., at the end of the dosing interval) provides no additional useful information and may lead to an inappropriate dose increase since the peak serum theophylline concentration can be two or more times greater than the trough concentration with an immediate-release formulation. If the serum sample is drawn more than two hours after the dose, the results must be interpreted with caution since the concentration may not be reflective of the peak concentration. In contrast, when signs or symptoms of theophylline toxicity are present, the serum sample should be obtained as soon as possible, analyzed immediately, and the result reported to the clinician without delay. In patients in whom decreased serum protein binding is suspected (e.g., cirrhosis, women during the third trimester of pregnancy), the concentration of unbound theophylline should be measured and the dosage adjusted to achieve an unbound concentration of 6-12 mcg/mL.

Saliva concentrations of theophylline cannot be used reliably to adjust dosage without special techniques.

Effects on Laboratory Tests:

As a result of its pharmacological effects, theophylline at serum concentrations within the 10-20 mcg/mL range modestly increases plasma glucose (from a mean of 88 mg% to 98 mg%), uric acid (from a mean of 4 mg/dL to 6 mg/dL), free fatty acids (from a mean of 451 µeq/l to 800 µeq/l, total cholesterol (from a mean of 140 vs 160 mg/dL), HDL (from a mean of 36 to 50 mg/dL), HDL/LDL ratio (from a mean of 0.5 to 0.7), and urinary free cortisol excretion (from a mean of 44 to 63 mcg/24 hr). Theophylline at serum concentrations within the 10-20 mcg/mL range may also transiently decrease serum concentrations of triiodothyronine (144 before, 131 after one week and 142 ng/dL after 4 weeks of theophylline). The clinical importance of these changes should be weighed against the potential therapeutic benefit of theophylline in individual patients.

Information for Patients:

QUIBRON®-T/SR Tablets should not be chewed or crushed.

The patient (or parent/care giver) should be instructed to seek medical advice whenever nausea, vomiting, persistent headache, insomnia or rapid heart beat occurs during treatment with theophylline, even if another cause is suspected. The patient (or parent/care giver) should be instructed to contact their clinician if they develop a new illness, especially if accompanied by a persistent fever, if they experience worsening of a chronic illness, if they start or stop smoking cigarettes or marijuana, or if another clinician adds a new medication or discontinues a previously prescribed medication. Patients should be instructed to inform all clinicians involved in their care that they are taking theophylline, especially when a medication is being added or deleted from their treatment. Patients should be instructed to not alter the dose, timing of the dose, or frequency of administration without first consulting their clinician. If a dose is missed, the patient should be instructed to take the next dose at the usually scheduled time and to not attempt to make up for the missed dose.

Drug Interactions:

Drug-Drug Interactions Theophylline interacts with a wide variety of drugs. The interaction may be pharmacodynamic, i.e., alterations in the therapeutic response to theophylline or another drug or occurrence of adverse effects without a change in serum theophylline concentration. More frequently, however, the interaction is pharmacokinetic, i.e., the rate of theophylline clearance is altered by another drug resulting in increased or decreased serum theophylline concentrations. Theophylline only rarely alters the pharmacokinetics of other drugs.

The drugs listed in Table II have the potential to produce clinically significant pharmacodynamic or pharmacokinetic interactions with theophylline. The information in the “Effect” column of Table II assumes that the interacting drug is being added to a steady-state theophylline regimen. If theophylline is being initiated in a patient who is already taking a drug that inhibits theophylline clearance (e.g., cimetidine, erythromycin), the dose of theophylline required to achieve a therapeutic serum theophylline concentration will be smaller. Conversely, if theophylline is being initiated in a patient who is already taking a drug that enhances theophylline clearance (e.g., rifampin), the dose of theophylline required to achieve a therapeutic serum theophylline concentration will be larger. Discontinuation of a concomitant drug that increases theophylline clearance will result in accumulation of theophylline to potentially toxic levels, unless the theophylline dose is appropriately reduced. Discontinuation of a concomitant drug that inhibits theophylline clearance will result in decreased serum theophylline concentrations, unless the theophylline dose is appropriately increased.

The drugs listed in Table III have either been documented not to interact with theophylline or do not produce a clinically significant interaction (i.e.,<15% change in theophylline clearance).

The listing of drugs in Tables II and III are current as of January 2, 1996. New interactions are continuously being reported for theophylline, especially with new chemical entities. The clinician should not assume that a drug does not interact with theophylline if it is not listed in Table II. Before addition of a newly available drug in a patient receiving theophylline, the package insert of the new drug and/or the medical literature should be consulted to determine if an interaction between the new drug and theophylline has been reported.

Table II. Clinically significant drug interactions with theophylline*.

Drug	Type of Interaction	Effect**
Adenosine	Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol	A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase
Allopurinol	Decreases theophylline clearance at allopurinol doses ≥600 mg/day.	25% increase
Aminoglutethimide	Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine	Similar to aminoglutethimide.	30% decrease
Cimetidine	Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% increase
Diazepam	Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram	Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effects	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin	Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen	Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine.	Similar to cimetidine.
Halothane	Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A	Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increases theophylline clearance.	20% decrease
Ketamine	Pharmacologic	May lower theophylline seizure threshold.
Lithium	Theophylline increases renal lithium clearance.	Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% decrease
Pancuronium	Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.	Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline	Decreases theophylline clearance.	30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.	25% decrease after two weeks of concurrent PB.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity.Theophylline decreases phenytoin absorption.	Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.	40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction.	100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.	20-40% decrease
Sulfinpyrazone	Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.	20% decrease
Tacrine	Similar to cimetidine, also increases renal clearance of theophylline.	90% increase
Thiabendazole	Decreases theophylline clearance.	190% increase
Ticlopidine	Decreases theophylline clearance.	60% increase
Troleandomycin	Similar to erythromycin.	33-100% increase depending on troleandomycin dose.
Verapamil	Similar to disulfiram.	20% increase

* Refer to PRECAUTIONS, Drug Interactions for further information regarding table.

** Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.

Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*

albuterol,	lomefloxacin
systemic and inhaled	mebendazole
amoxicillin	medroxyprogesterone
ampicillin,	methylprednisolone
with or without sulbactam	metronidazole
atenolol	metoprolol
azithromycin	nadolol
caffeine,	nifedipine
dietary ingestion	nizatidine
cefaclor	norfloxacin
co-trimoxazole	ofloxacin
(trimethoprim and	omeprazole
sulfamethoxazole)	prednisone, prednisolone
diltiazem	ranitidine
dirithromycin	rifabutin
enflurane	roxithromycin
famotidine	sorbitol
felodipine	(purgative doses do not
finasteride	inhibit theophylline
hydrocortisone	absorption)
isoflurane	sucralfate
isoniazid	terbutaline, systemic
isradipine	terfenadine
influenza vaccine	tetracycline
ketoconazole	tocainide

* Refer to PRECAUTIONS, Drug Interactions for information regarding table.

Drug-Food Interactions Quibron®-T/SR has not been adequately studied to determine whether its bioavailability is altered when it is given with food.

Available data suggests that drug administration at the time of food ingestion may influence the absorption characteristics if some or all theophylline controlled-release products, resulting in serum values different from those found after administration in the fasting state.

A drug-food effect, if any, would likely have its greatest clinical significance when high theophylline serum levels are being maintained and/or when large single doses (>13 mg/kg or 900 mg) of a controlled-release theophylline product are given. The influence of type and amount of food on performance of controlled-release theophylline products is under study at this time.

The Effect of Other Drugs on Theophylline Serum Concentration Measurements:

Most serum theophylline assays in clinical use are immunoassays which are specific for theophylline. Other xanthines such as caffeine, dyphylline, and pentoxifylline are not detected by these assays. Some drugs (e.g.,cefazolin, cephalothin), however, may interfere with certain HPLC techniques. Caffeine and xanthine metabolites in neonates or patients with renal dysfunction may cause the reading from some dry reagent office methods to be higher than the actual serum theophylline concentration.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

Long term carcinogenicity studies have been carried out in mice (oral doses 30-150 mg/kg) and rats (oral doses 5-75 mg/kg). Results are pending.

Theophylline has been studied in Ames salmonella, in vivo and in vitro cytogenetics, micronucleus and Chinese hamster ovary test systems and has not been shown to be genotoxic.

In a 14 week continuous breeding study, theophylline, administered to mating pairs of B6C3F1 mice at oral doses of 120, 270 and 500 mg/kg (approximately 1.0- 3.0 times the human dose on a mg/m2 basis) impaired fertility, as evidenced by decreases in the number of live pups per litter, decreases in the mean number of litters per fertile pair, and increases in the gestation period at the high dose as well as decreases in the proportion of pups born alive at the mid and high dose. In 13 week toxicity studies, theophylline was administered to F344 rats and B6C3F1 mice at oral doses of 40-300 mg/kg (approximately 2.0 times the human dose on a mg/m2 basis). At the high dose, systemic toxicity was observed in both species including decreases in testicular weight.

Pregnancy:

CATEGORY C:

There are no adequate and well-controlled studies in pregnant women. Additionally, there are no teratogenicity studies in non-rodents (e.g., rabbits). Theophylline was not shown to be teratogenic in CD-1 mice at oral doses up to 400 mg/kg, approximately 2.0 times the human dose on a mg/m2 basis or in CD-1 rats at oral doses up to 260 mg/kg, approximately 3.0 times the recommended human dose on a mg/m2 basis. At a dose of 220 mg/kg, embryotoxicity was observed in rats in the absence of maternal toxicity.

Nursing Mothers:

Theophylline is excreted into breast milk

AV Heart Block Medications

Drugs associated with AV Heart Block

The following drugs and medications are in some way related to, or used in the treatment of AV Heart Block. This service should be used as a supplement to, and NOT a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners.

Drug List:

Adrenaclick-Auto-Injector

Adrenalin

Adrenalin-Chloride

Asthmahaler-Aerosol

Atreza

Atropen

Epipen-Auto-Injector

Epipen-2-Pak

Epipen-Auto-Injector

Epipen-Jr-Auto-Injector

Epipen-Jr-2-Pak

Epipen-Jr-Auto-Injector

Isuprel

Isuprel-Mistometer

Medihaler-Epi

Medihaler-Iso

Primatene-Mist-Aerosol

Sal-Tropine

Twinject-Auto-Injector

Twinject-Auto-Injector

Twinject-Auto-Injector-Two-Pack