Epinastine Hydrochloride

Class: Antiallergic Agents
Chemical Name: 3-Amino-9,13b-dihydro-1H-dibenz[c,f]imidazo[1,5-a]azepine
Molecular Formula: C₁₆H₁₅N₃
CAS Number: 80012-43-7
Brands: Elestat

Introduction

Relatively selective histamine H₁-receptor antagonist¹ with mast-cell stabilizing properties.²

Uses for Epinastine Hydrochloride

Allergic Conjunctivitis

Prevention of ocular itching associated with allergic conjunctivitis.¹

Epinastine Hydrochloride Dosage and Administration

Administration

Ophthalmic Administration

Apply topically to the eye as an ophthalmic solution.¹ Not for injection or oral use.¹

Dosage

Available as epinastine hydrochloride; dosage expressed in terms of the salt.¹

Pediatric Patients

Allergic Conjunctivitis

Ophthalmic

Children ≥3 years of age: 1 drop of a 0.05% solution in each eye twice daily for up to 8 weeks.¹

Continue therapy throughout period of exposure (i.e., until pollen season is over or until exposure to offending allergen is terminated), even in absence of symptoms.¹

Adults

Allergic Conjunctivitis

Ophthalmic

1 drop of a 0.05% solution in each eye twice daily for up to 8 weeks.¹

Continue therapy throughout period of exposure (i.e., until pollen season is over or until exposure to offending allergen is terminated), even in absence of symptoms.¹

Cautions for Epinastine Hydrochloride

Contraindications

• 
  

  Known hypersensitivity to epinastine or any ingredient in the formulation.¹

  
  

Warnings/Precautions

Specific Populations

Pregnancy

Category C.¹

Lactation

Distributed into milk in rats; not known whether distributed into human milk.¹ Use with caution.¹

Pediatric Use

Safety and efficacy not established in children <3 years of age.¹

Geriatric Use

No overall differences in safety and efficacy relative to younger adults.^{1 11}

Common Adverse Effects

Ocular discomfort (e.g., burning, folliculosis, hyperemia, pruritus), infection (e.g., cold symptoms, upper respiratory infections).¹

Interactions for Epinastine Hydrochloride

No formal drug interaction studies to date.¹¹

Epinastine Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Limited systemic exposure following topical application to the eye.¹ No increase in systemic absorption following multiple dosing.¹

Peak plasma concentrations attained approximately 2 hours after ophthalmic administration.¹

Onset

Rapid onset (within 3–5 minutes).¹

Duration

8 hours.¹

Distribution

Extent

Does not penetrate blood-brain barrier.¹

Distributed into milk in rats; not known whether distributed into human milk.¹

Plasma Protein Binding

64%.¹

Elimination

Metabolism

Less than 10% is metabolized.¹

Elimination Route

55 or 30% of IV dose excreted unchanged in urine or feces, respectively.¹

Half-life

Approximately 12 hours.¹

Stability

Storage

Ophthalmic

Solution

Tightly closed bottle at 15–25°C.¹

ActionsActions

• 
  

  Inhibits the release of mediators (e.g., histamine) from cells involved in hypersensitivity reactions (e.g., mast cells).^{1 2}

  
  


• 
  

  Exhibits mast-cell stabilizing properties.²

  
  


• 
  

  Exhibits some affinity for histamine H₂, α₁- and α₂-adrenergic, and 5-HT₂ receptors.¹

  
  

Advice to Patients

• 
  

  Importance of learning and adhering to proper administration techniques to avoid contamination of the solution with common bacteria that can cause ocular infections.^{1 9} Serious damage to the eye and subsequent loss of vision may result from using contaminated ophthalmic solutions.^{1 9}

  
  


• 
  

  Importance of delaying insertion of contact lenses for at least 10 minutes after epinastine instillation, since benzalkonium chloride preservative may be absorbed by soft lenses; importance of not wearing contact lenses in the presence of ocular redness.^{1 9}

  
  


• 
  

  Not indicated for contact lens-related ocular irritation.^{1 9}

  
  


• 
  

  Importance of reporting any worsening of symptoms or new-onset ocular pain/discomfort.⁹

  
  


• 
  

  Importance of women informing clinician if they are or plan to become pregnant or plan to breast-feed.⁹

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.¹

  
  


• 
  

  Importance of informing patients of other important precautionary information. (See Cautions.)

  
  

Preparations

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

Epinastine Hydrochloride

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Ophthalmic	Solution	0.05% (of epinastine hydrochloride)	Elestat (with benzalkonium chloride)	Allergan

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.

Elestat 0.05% Solution (ALLERGAN): 5/$121.25 or 15/$332.76

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 July 2005. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Allergan. Elestat (epinastine hydrochloride) ophthalmic solution 0.05% prescribing information. Irvine, CA; 2003 Oct. 2

2. Food and Drug Administration Center for Drug Evaluation and Research. Clinical Pharmacology and Biopharmaceutics review: epinastine. Executive Summary. December 19, 2002.

3. Abelson MB, Gomes P, Crampton HJ et al. Efficacy and tolerability of ophthalmic epinastine assessed using the conjunctival antigen challenge model in patients with a history of allergic conjunctivitis. Clin Ther. 2004; 26:35-47. [IDIS 511841] [PubMed 14996516]

4. Whitcup SM, Bradford R, Lue J et al. Efficacy and tolerability of ophthalmic epinastine: a randomized, double-masked, parallel-group, active- and vehicle-controlled environmental trial in patients with seasonal allergic conjunctivitis. Clin Ther. 2004; 26:29-34. [IDIS 511840] [PubMed 14996515]

5. Ciprandi G, Buscaglia S, Cerqueti PM et al. Drug treatment of allergic conjunctivitis: a review of the evidence. Drugs. 1992; 43:154-76. [IDIS 360840] [PubMed 1372215]

6. Morrow GL, Abbott RL. Conjunctivitis. Am Fam Physician. 1998; 57:735-46. [IDIS 418448] [PubMed 9490996]

7. Titi MJ. A critical look at ocular allergy drugs. Am Fam Physician. 1996; 53:2637-42. [IDIS 367250] [PubMed 8644576]

8. Galindez OA, Kaufman HE. Coping with the itchy-burnies: the management of allergic conjunctivitis. Ophthalmology. 1996; 103:1335-6. [IDIS 373485] [PubMed 8841290]

9. Food and Drug Administration. Elestat consumer information. 2003 Dec 04. From FDA website.

10. Tasaka K. Epinastine: An update of its pharmacology, metabolism, clinical efficacy and tolerability in the treatment of allergic diseases. Drugs Today. 2000; 36:735-57. [PubMed 12845334]

11. Allergan. Irvine, CA: Personal communication.

More Epinastine Hydrochloride resources

• Epinastine Hydrochloride Side Effects (in more detail)
• Epinastine Hydrochloride Dosage
• Epinastine Hydrochloride Use in Pregnancy & Breastfeeding
• Epinastine Hydrochloride Support Group
• 3 Reviews for Epinastine Hydrochloride - Add your own review/rating

• Elestat Prescribing Information (FDA)


• Elestat Advanced Consumer (Micromedex) - Includes Dosage Information


• Elestat MedFacts Consumer Leaflet (Wolters Kluwer)


• Elestat Consumer Overview

Compare Epinastine Hydrochloride with other medications

• Conjunctivitis, Allergic

Gemfibrozil

Class: Fibric Acid Derivatives
VA Class: CV350
Chemical Name: 5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanoic acid
Molecular Formula: C₁₅H₂₂O₃
CAS Number: 25812-30-0
Brands: Lopid

Introduction

Antilipemic agent; fibric acid derivative.²

Uses for Gemfibrozil

Prevention of Cardiovascular Events

Adjunct to dietary therapy to reduce the risk of developing CHD in patients with type IIb hyperlipoproteinemia without clinical evidence of CHD (primary prevention) who have an inadequate response to dietary management, weight loss, exercise, and drugs known to reduce LDL-cholesterol and increase HDL-cholesterol (e.g., bile acid sequestrants, niacin) and who have low HDL-cholesterol concentrations in addition to elevated LDL-cholesterol and triglycerides.^{1 67 68 104 105 110 127}

Because of potential toxicity, including malignancy, gallbladder disease, abdominal pain leading to appendectomy and other abdominal surgeries, and an increased incidence of noncardiovascular and all-cause mortality associated with the chemically and pharmacologically similar drug, clofibrate (no longer commercially available in the US), the potential benefit of gemfibrozil in treating patients with type IIa hyperlipoproteinemia and elevations of LDL-cholesterol only is unlikely to outweigh the risks of such therapy.¹

Manufacturer states that gemfibrozil is not indicated for use in the management of patients with low HDL-cholesterol as their only lipid abnormality (isolated low HDL-cholesterol).¹

Reduction of recurrent coronary events†, including death from coronary causes, MI, and stroke in men with clinical evidence of CHD who have low HDL-cholesterol and moderately elevated LDL-cholesterol concentrations.¹³⁷

Dyslipidemias

Adjunct to dietary therapy in the management of severe hypertriglyceridemia in patients at risk of developing pancreatitis (typically those with serum triglyceride concentrations >2000 mg/dL and elevated concentrations of VLDL-cholesterol and fasting chylomicrons) who do not respond adequately to dietary management.¹

Also may be used in patients with triglyceride concentrations of 1000–2000 mg/dL who have a history of pancreatitis or of recurrent abdominal pain typical of pancreatitis;¹ however, efficacy in patients with type IV hyperlipoproteinemia and triglyceride concentrations >1000 mg/dL who exhibit type V patterns subsequent to dietary or alcoholic indiscretion has not been adequately studied.¹

Manufacturer states that gemfibrozil is not indicated for use in patients with type I hyperlipoproteinemia who have elevated triglyceride and chylomicron concentrations but normal VLDL-cholesterol concentrations.¹

Effective in a very limited number of patients with type III hyperlipoproteinemia†^{17 18 37 38 43 45 49} to decrease elevated triglyceride and cholesterol concentrations associated with this disorder.

Gemfibrozil Dosage and Administration

General

• 
  

  Patients should be placed on a standard lipid-lowering diet before initiation of gemfibrozil therapy and should remain on this diet during treatment with the drug.¹

  
  

Administration

Oral Administration

Administer orally twice daily, 30 minutes before the morning and evening meals.¹

Dosage

Adults

Prevention of Cardiovascular Events

Oral

600 mg twice daily.^{1 16 17 18 21 22 24 25 26 27 30 31 91 104 106}

Monitor lipoprotein concentrations periodically.¹ Discontinue therapy in patients who fail to achieve an adequate response after 3 months of therapy.¹

Dyslipidemias

Oral

600 mg twice daily.^{1 16 17 18 21 22 24 25 26 27 30 31 91 104 106}

Monitor lipoprotein concentrations periodically.¹ Discontinue therapy in patients who fail to achieve an adequate response after 3 months of therapy.¹

Cautions for Gemfibrozil

Contraindications

• 
  

  Hepatic impairment, including primary biliary cirrhosis; severe renal impairment; or preexisting gallbladder disease.¹

  
  


• 
  

  Known hypersensitivity to gemfibrozil or any ingredient in the formulation.¹

  
  

Warnings/Precautions

Warnings

Cholelithiasis

May increase cholesterol excretion in bile,^{1 34 61} resulting in cholelithiasis.^{1 26 34} Cholecystitis and cholelithiasis reported.¹ Discontinue therapy if gallbladder studies indicate the presence of gallstones.¹

Musculoskeletal Effects

Use may be associated with myositis.¹ Myalgia, myopathy, myasthenia, painful extremities, arthralgia, synovitis, and rhabdomyolysis reported.¹ Myopathy, rhabdomyolysis, and other complications also reported in patients receiving gemfibrozil concomitantly with certain other antilipemic agents.¹

Monitor creatine kinase (CK, creatine phosphokinase, CPK) concentrations in patients reporting adverse musculoskeletal effects.^{1 108 116} Discontinue therapy if myositis is suspected or diagnosed.¹

Effect on Morbidity and Mortality

Effect on cardiovascular mortality not established.¹ Because gemfibrozil is chemically, pharmacologically, and clinically similar to other fibric acid derivatives, some adverse effects of clofibrate (no longer commercially available in the US) such as increased incidence of cholelithiasis, cholecystitis requiring surgery, postcholecystectomy complications, malignancy, pancreatitis, appendectomy, gallbladder disease, and increased overall mortality may also apply to gemfibrozil,¹ and the usual precautions associated with fibrate therapy should be observed.¹

Cataracts

Possible subcapsular bilateral and unilateral cataracts.¹

Sensitivity Reactions

Hypersensitivity Reactions

Angioedema, laryngeal edema, urticaria, rash, dermatitis, and pruritus reported.¹

Major Toxicities

Hematologic Effects

Mild decreases in hemoglobin,^{1 2} hematocrit,^{1 2 38} and leukocyte counts^{1 2} reported; these counts usually normalize during long-term therapy.¹ Severe anemia, leukopenia, thrombocytopenia, and bone marrow hypoplasia have occurred rarely; eosinophilia also reported.¹

Monitor blood cell counts periodically during the first 12 months of therapy.¹

General Precautions

Hepatic Effects

Possible elevations in serum concentrations of aminotransferase (transaminase) (i.e., AST, ALT),^{1 2 24 25 47} LDH,^{1 2} bilirubin,¹ and alkaline phosphatase.^{1 2 15 25 47} Serum aminotransferase concentrations usually return slowly to pretreatment values following discontinuance of gemfibrozil.¹ Cholestatic jaundice reported.¹

Perform liver function tests periodically.¹ Discontinue therapy if abnormalities persist.¹

Carcinogenicity

Carcinogenicity (e.g., hepatic, Leydig cell tumors) demonstrated in animals.¹

Specific Populations

Pregnancy

Category C.¹

Lactation

Not known if gemfibrozil is distributed into milk.^{1 102} Discontinue nursing or the drug.¹

Pediatric Use

Safety and efficacy not established.¹

Renal Impairment

Possible exacerbation of renal insufficiency in patients with baseline S_cr >2 mg/dL.¹ Consider use of alternative antilipemic therapy against the risks and benefits of a lower dose of gemfibrozil.¹

Common Adverse Effects

GI disturbances (e.g., dyspepsia, abdominal pain, diarrhea, nausea, vomiting, constipation, acute appendicitis, gallbladder surgery), adverse CNS effects (headache, hypesthesia, paresthesias, dizziness, somnolence, peripheral neuritis, depression), fatigue, eczema, vertigo, taste perversion, blurred vision, decreased libido, impotence.¹

Interactions for Gemfibrozil

Specific Drugs

Drug	Interaction	Comments
β-Adrenergic blocking agents	Possible increase in serum triglyceride and decreases in HDL-cholesterol concentrations30 74
Anticoagulants, oral (e.g., warfarin)	Potentiation of anticoagulant effects1 102 124	Use with caution.1 Reduce anticoagulant dosage to maintain PT at desired level to prevent bleeding complications; monitor PT frequently until stabilized1
Estrogens	Potential increase in serum triglyceride concentrations73
HMG-CoA reductase inhibitors (Statins)	Increased risk of adverse musculoskeletal effects (e.g., myopathy, rhabdomyolysis)1
Methyldopa	Possible decrease in HDL- and LDL-cholesterol concentrations74
Repaglinide	Increased repaglinide concentrations and half-life, resulting in enhanced and prolonged blood glucose-lowering effects.138 139 Potential for severe hypoglycemia.138	Patients currently receiving gemfibrozil should not initiate therapy with repaglinide, and vice versa.138 139 Monitor blood glucose and reduce repaglinide dosage as required if drugs already used concomitantly.138 Patients receiving gemfibrozil concomitantly with repaglinide should not receive itraconazole.138
Thiazide diuretics	Possible increase in total cholesterol and triglyceride concentrations.74

Gemfibrozil Pharmacokinetics

Absorption

Bioavailability

Rapidly and completely absorbed from the GI tract.^{1 2 7 76}

Peak plasma concentrations occur within 1–2 hours.^{1 2 7 9} Plasma concentrations do not appear to correlate with therapeutic response.^{29 102}

Food

Rate and extent of absorption increased when administered 30 minutes before meals.¹

Distribution

Extent

Highest tissue concentrations observed in the liver and kidneys in animals.²

Gemfibrozil crosses the placenta;² not known if it is distributed into milk.^{1 102}

Plasma Protein Binding

About 95%.²

Elimination

Metabolism

Appears to be metabolized in the liver to 4 major metabolites produced via 3 metabolic pathways.^{2 7 102} A phenol derivative (metabolite I)^{2 7} is pharmacologically active.¹⁰²

Elimination Route

Excreted in urine (70%) in the form of metabolites and in feces (approximately 6%).¹

Half-life

1.3–1.5 hours.^{1 7 9 10}

Stability

Storage

Oral

Tablets

20–25°C.¹ Protect from light and humidity.¹

Actions and SpectrumActions

• 
  

  Decreases serum concentrations of triglycerides,^{1 15 16 17 18 19 21 22 23 24 26 27 28 29 30 32 33 37 38 45 48 76 91 104} VLDL-cholesterol,^{1 15 17 18 19 25 33 37 38 45 48 76} and, to a lesser extent, LDL-cholesterol.^{1 15 33 37 38 45 76} Increases HDL-cholesterol.^{1 15 16 19 21 22 24 25 26 31 32 33 36 38 45 88 91} Causes a variable reduction in serum total cholesterol,^{1 15 16 17 18 19 21 24 25 26 27 28 29 30 31 32 33 37 38 48 68 105 106} because the decrease in serum cholesterol is a net result of a decrease in VLDL-cholesterol,^{18 19 21 25 26 28 32 33 38 45} an increase in HDL-cholesterol,^{37 68} and an increase^{15 21 30 33 37 45 91} or decrease in LDL-cholesterol.^{21 24 26 32 37 38 45}

  
  


• 
  

  Generally increases LDL-cholesterol in patients with type IV or V hyperlipoproteinemia and decreases LDL-cholesterol in type IIa or IIb disorder.^{21 25 28 45 91}

  
  


• 
  

  Inhibits lipolysis of fat in adipose tissue^{1 54 56 75 76 91} and decreases hepatic uptake of plasma free fatty acids^{1 54 75 76} (i.e., free fatty acid turnover is decreased),^{51 54 75} thereby reducing hepatic triglyceride production^{1 54 75 76} (triglyceride turnover rate is decreased).^{51 75} Also inhibits production^{1 15 54 75 91} and increases clearance^{1 75 102} of VLDL carrier apolipoprotein B (VLDL-apo B), leading to a decrease in VLDL production,^{1 15 45 54 75} enhanced clearance of VLDL,¹⁵ and, subsequently, a decrease in serum triglyceride concentrations.^{2 54 91}

  
  

Advice to Patients

• 
  

  Importance of patients informing clinicians of any unexplained muscle pain, tenderness, or weakness.¹

  
  


• 
  

  Importance of adhering to nondrug therapies and measures, including dietary management, weight control, physical activity, and management of potentially contributory disease (e.g., diabetes mellitus).^{1 64 67 70 133 136}

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.¹

  
  


• 
  

  Importance of informing patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

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

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

Gemfibrozil

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	600 mg*	Gemfibrozil Tablets	Mylan, Sandoz, Teva, Watson
			Lopid (with parabens; scored)	Pfizer

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.

Gemfibrozil 600MG Tablets (CAMBER PHARMACEUTICALS): 60/$22.99 or 90/$29.98

Lopid 600MG Tablets (PFIZER U.S.): 60/$163.98 or 180/$470.99

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 July 2006. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Parke-Davis. Lopid (gemfibrozil) tablets prescribing information. New York, NY; 2003 Oct.

2. Parke-Davis. Lopid (gemfibrozil) compendium of pharmacological and clinical studies. Morris Plains, NJ; 1982 Feb.

3. The United States pharmacopeia, 21st rev, and The national formulary, 16th ed. Rockville, MD: The United States Pharmacopeial Convention, Inc; 1985: 457.

4. Hodges RM. Gemfibrozil—a new lipid lowering agent. Proc R Soc Med. 1976; 69(Suppl 2):1-2. [PubMed 798192]

5. Creger PL, Moersch GW, Neuklis WA. Structure/activity relationship of gemfibrozil (CI-719) and related compounds. Proc R Soc Med. 1976; 69(Suppl 2):3-5. [PubMed 1019152]

6. Rodney G, Uhlendorf P, Maxwell RE. The hypolipidaemic effect of gemfibrozil (CI-719) in laboratory animals. Proc R Soc Med. 1976; 69(Suppl 2):6-10. [PubMed 828263]

7. Okerholm RA, Keeley FJ, Peterson FE et al. The metabolism of gemfibrozil. Proc R Soc Med. 1976; 69(Suppl 2):11-4. [PubMed 828261]

8. Kurtz SM, Fitzgerald JE, Fisken RA et al. Toxicological studies on gemfibrozil. Proc R Soc Med. 1976; 69(Suppl 2):15-23. [PubMed 828262]

9. Smith TC. Toleration and bioavailability of gemfibrozil in healthy men. Proc R Soc Med. 1976; 69(Suppl 2):24-7. [PubMed 798193]

10. Randinitis EJ, Kinkel AW, Nelson C et al. Gas chromatographic determination of gemfibrozil and its metabolites in plasma and urine. J Chromatogr. 1984; 307:210-5. [PubMed 6586728]

11. Gray RH, de la Iglesia FA. Quantitative microscopy comparison of peroxisome proliferation by the lipid-regulating agent gemfibrozil in several species. Hepatology. 1984; 4:520-30. [PubMed 6586630]

12. de la Iglesia FA, Lewis JE, Buchanan RA et al. Light and electron microscopy of liver in hyperlipoproteinemic patients under long-term gemfibrozil treatment. Atherosclerosis. 1982; 43:19-37. [PubMed 6807326]

13. Maxwell RE, Nawrocki JW, Uhlendorf PD. Some comparative effects of gemfibrozil, clofibrate, benzafibrate, cholestyramine, and compactin on sterol metabolism in rats. Atherosclerosis. 1983; 48:195-203. [PubMed 6579963]

14. Kahonen MT, Ylikahri RH. Effect of clofibrate and gemfibrozil on the activities of mitochondrial carnitine acyltransferases in rat liver. Dose-response relations. Atherosclerosis. 1979; 32:47-56. [PubMed 465113]

15. Kesaniemi YA, Grundy SM. Influence of gemfibrozil and clofibrate on metabolism of cholesterol and plasma triglycerides in man. JAMA. 1984; 251:2241-6. [IDIS 184352] [PubMed 6368883]

16. Kaukola S, Manninen V, Malkonen M et al. Gemfibrozil in the treatment of dyslipidaemias in middle-aged survivors of myocardial infarction. Acta Med Scand. 1981; 209:69-73. [IDIS 130843] [PubMed 7010929]

17. Konttinen A, Kuisma I, Ralli R et al. The effect of gemfibrozil on serum lipids in diabetic patients. Ann Clin Res. 1979; 11:240-5. [PubMed 398183]

18. Hoogwerf BJ, Bantle JP, Kuba K et al. Treatment of type III hyperlipoproteinemia with four different treatment regimens. Atherosclerosis. 1984; 51:251-9. [PubMed 6588975]

19. Nye ER, Sutherland NHF, Temples WA. The treatment of hyperlipoproteinemia with gemfibrozil compared with placebo and clofibrate. N Z Med J. 1980; 92:345-9. [IDIS 127495] [PubMed 6935550]

20. Nash DT. Gemfibrozil in combination with other drugs for severe hyperlipidemia: preliminary study comprising four cases. Postgrad Med. 1983; 73:75-82. [IDIS 168636] [PubMed 6572892]

21. Pickering JE. Clinical results with gemfibrozil. Am J Cardiol. 1983; 52:39-40B.

22. Torstila I, Kaukola S, Manninen V et al. Plasma prekallikrein, kallikrein inhibitors, kininogen and lipids during gemfibrozil treatment in type II dyslipidaemia. Acta Med Scand Suppl. 1982; 668:123-9. [IDIS 168767] [PubMed 6188330]

23. Manninen V. Clinical results with gemfibrozil and background to the Helsinki Heart Study. Am J Cardiol. 1983; 52:35-8B.

24. Manninen V, Malkonen M, Eisalo A et al. Gemfibrozil in the treatment of dyslipidaemia: a 5-year follow-up study. Acta Med Scand (Suppl). 1982: 668:82-7. (IDIS 168759)

25. Samuel P. Effects of gemfibrozil on serum lipids. Am J Med. 1983; 74(Suppl 5A):23-7. [IDIS 171223] [PubMed 6573843]

26. Fenderson RW, Deutsch S, Menachemi E et al. Effect of gemfibrozil on serum lipids in man. Angiology. 1982; 33:581-93. [PubMed 6751166]

27. Nash DT. Hyperlipoproteinemia, atherosclerosis and gemfibrozil. Angiology. 1982; 33:594-602. [PubMed 6957155]

28. Lewis JE. Long-term use of gemfibrozil (Lopid) in the treatment of dyslipidemia. Angiology. 1982; 33:603-12. [PubMed 6957156]

29. Jain AK, Ryan JR, LaCorte WSJ et al. Clinical evaluation of gemfibrozil, a new antilipemic agent. Clin Pharmacol Ther. 1981; 29:254-5.

30. Vega GL, Grundy SM. Gemfibrozil therapy in primary hypertriglyceridemia associated with coronary heart disease: effects on metabolism of low-density lipoproteins. JAMA. 1985; 253:2398-403. [IDIS 198753] [PubMed 3856692]

31. Borresen AL, Berg K, Dahlen G et al. The effect of gemfibrozil on human serum apolipoproteins and on serum reserve cholesterol binding capacity (SRCBC). Artery. 1981; 9:77. [PubMed 7018466]

32. Dahlen D, Gillnas T, Borresen AL et al. Effect of gemfibrozil on serum lipid levels. Artery. 1980; 7:224-31. [PubMed 7008748]

33. Schwandt P, Weisweiler P, Neureuther G. Serum lipoprotein lipids after gemfibrozil treatment. Artery. 1979; 5:117-24. [PubMed 231950]

34. Hall MJ, Nelson LM, Russell RI et al. Gemfibrozil—the effect of biliary cholesterol saturation of a new lipid-lowering agent and its comparison with clofibrate. Atherosclerosis. 1981; 39:511-6. [PubMed 6942844]

35. Baird IM, Lewis B, Hill JM. Preliminary observations on the effect of gemfibrozil on the excretion of faecal bile acids. Proc R Soc Med. 1976; 69(Suppl 2):112-4. [PubMed 1019150]

36. Glueck C. Influence of gemfibrozil on high-density lipoproteins. Am J Cardiol. 1983; 52:31-4B.

37. Olsson AG, Rossner S, Walldius G et al. Effect of gemfibrozil on lipoprotein concentrations in different types of hyperlipoproteinaemia. Proc R Soc Med. 1976; 69(Suppl 2):28-31. [PubMed 190607]

38. Vessby B, Lithell J, Boberg J et al. Gemfibrozil as a lipid lowering compound in hyperlipoproteinaemia. A placebo-controlled cross-over trial. Proc R Soc Med. 1976; 69(Suppl 2):32-7. [PubMed 798194]

39. Tuomilehto J, Salonen J, Kuusisto P et al. A clofibrate controlled trial of gemfibrozil in the treatment of hyperlipidaemias. Proc R Soc Med. 1976; 69(Suppl 2):38-40.

40. Beaumont JL, Dachet C. Binding of plasma lipoproteins of chlorophenoxyisobutyric, tibric and nicotinic acids and their esters. Proc R Soc Med. 1976; 69(Suppl 2):41-3. [PubMed 1019153]

41. Eisalo A, Manninen V. Gemfibrozil and clofibrate in the treatment of hyperlipidaemias: a comparative trial. Proc R Soc Med. 1976; 69(Suppl 2):47-8. [PubMed 798197]

42. Eisalo A, Manninen V, Malkonen M et al. Hypolipidaemic action of gemfibrozil in adult nephrotics. Proc R Soc Med. 1976; 69(Suppl 2):47-8. [PubMed 798197]

43. Eisalo A, Manninen V. A long-term trial of gemfibrozil in the treatment of hyperlipidaemias. Proc R Soc Med. 1976; 69(Suppl 2):49-52. [PubMed 798198]

44. Huunan-Seppala A, Manninen V, Burton R et al. Extrinsic factors affecting the response to gemfibrozil. Proc R Soc Med. 1976; 69(Suppl 2):53-7. [PubMed 1019154]

45. Nikkila EA, Ylikahri R, Huttunen JK. Gemfibrozil: effect on serum lipids, lipoproteins, post-heparin plasma lipase activities and glucose tolerance in primary hypertriglyceridaemia. Proc R Soc Med. 1976; 69(Suppl 2):58-63. [PubMed 190608]

46. de Salcedo I, Gorringe JAL, Luiz Salva J et al. Gemfibrozil in a group of diabetics. Proc R Soc Med. 1976; 69(Suppl 2):64-70.

47. Lageder H, Irsigler K. Evaluation of increasing doses of gemfibrozil in hyperlipoproteinaemia. Proc R Soc Med. 1976; 69(Suppl 2):71-5. [PubMed 798199]

48. Janus ED, Costa D, Ononogbu IC et al. The evaluation of lipoprotein changes during gemfibrozil treatment. Proc R Soc Med. 1976; 69(Suppl 2):76-7. [PubMed 1019156]

49. Honorato J, Masso RM, Purroy A. The use of gemfibrozil in the treatment of primary hyperlipoproteinaemia. Preliminary report. Proc R Soc Med. 1976; 69(Suppl 2):78-9. [PubMed 798200]

50. de la Iglesia FA, Pinn SM, Lucas J et al. Quantitative stereology of peroxisomes in hepatocytes from hyperlipoproteinemic patients receiving gemfibrozil. Micron. 1981; 12:97-8.

51. Bremner WF, Third JLHC, Clark B et al. CI-719 in hyperlipoproteinaemia: interim data. Proc R Soc Med. 1976; 69(Suppl 2):83-7. [PubMed 798201]

52. Howard AN, Ghosh P. Gemfibrozil treatment: a comparison with clofibrate. Proc R Soc Med. 1976; 69(Suppl 2):88-9. [PubMed 190609]

53. Wilkening J, Schwandt P. Summary of present data from a clinical trial of CI-719. Proc R Soc Med. 1976; 69(Suppl 2):90-3. [PubMed 1019158]

54. Kissebah AH, Adams PA, Wynn V. Lipokinetic studies with gemfibrozil (CI-719). Proc R Soc Med. 1976; 69(Suppl 2):94-7. [PubMed 190610]

55. Elkeles RS, Ashwell M, Priest R et al. The effect of CI-719 on lipolysis in rat adipose tissue. Proc R Soc Med. 1976; 69(Suppl 2):98-100. [PubMed 1019159]

56. C.dtdon LA. Effect of gemfibrozil in vitro on fat-mobilizing lipolysis in human adipose tissue. Proc R Soc Med. 1976; 69(Suppl 2):101-3.

57. Kallai-Sanfacon MA, Cayen MN, Dubuc J et al. Effect of AY-25, 712 and other lipid-lowering agents on liver catalase and liver carnitine acetyltransferase in rats (41658). Proc Soc Exp Biol Med. 1983; 173:367-71. [PubMed 6867010]

58. O’Brien JR, Etherington MD, Shuttleworth RD et al. A pilot study of the effect of gemfibrozil on some haematological parameters. Thrombosis Res. 1982; 26:275-9.

59. Rasi VPO, Torstila I. Effect of gemfibrozil upon platelet function and blood coagulation. preliminary report. Proc R Soc Med. 1976; 69(Suppl 2):109-11. [PubMed 1019149]

60. Wynn V, chairman. Gemfibrozil: a new lipid lowering agent: open forum. Proc R Soc Med. 1976; 69(Suppl 2):115-20.

61. Leiss O, von Bergmann K, Gnasso A et al. Effect of gemfibrozil on biliary lipid metabolism in normolipemic subjects. Metabolism. 1985; 34:74-82. [PubMed 3855325]

62. Fitzgerald JE, Sanyer JL, Schardein JL et al. Carcinogen bioassay and mutagenicity studies with the hypolipidemic agent gemfibrozil. J Natl Cancer Inst. 1981; 67:1105-14. [PubMed 7029098]

63. Nash DT. Gemfibrozil—a new lipid lowering agent. J Med. 1980; 11:107-16. [PubMed 6931871]

64. National Institutes of Health Office of Medical Applications of Research. Consensus conference: treatment of hypertriglyceridemia. JAMA. 1984; 251:1196-1200. [PubMed 6582287]

65. Levy RI. Current status of the cholesterol controversy. Am J Med. 1983; 74(Suppl 5A):1-4. [PubMed 6342382]

66. Kuo PT. Hyperlipoproteinemia and atherosclerosis: dietary intervention. Am J Med. 1983; 74(Suppl 5A):15-8. [PubMed 6846377]

67. Hunninghake DB. Pharmacologic therapy for the hyperlipidemic patient. Am J Med. 1983; 74(Suppl 5A):19-22. [IDIS 171222] [PubMed 6846378]

68. Anon. Gemfibrozil for hyperlipidemia. Med Lett Drugs Ther. 1982; 24:59-60. [PubMed 6953310]

69. Probstfield JL, Gotto AM Jr. Disorders of lipids and lipoproteins. In: Stein JH, ed. Internal medicine. Boston: Little Brown and Company; 1983:1888-93.

70. National Institutes of Health Office of Medical Applications of Research. Consensus Conference: lowering blood cholesterol to prevent heart disease. JAMA. 1985; 253:2080-6. [PubMed 3974099]

71. Gordon T, Castelli WP, Hjortland MC et al. High density lipoprotein as a protective factor against coronary heart disease: the Framingham study. Am J Med. 1977; 62:707-14. [PubMed 193398]

72. Glueck CJ. Relationship of lipid disorders to coronary heart disease. Am J Med. 1983; 74(Suppl 5A):10-4. [PubMed 6846376]

73. American Heart Association Committee to Design a Dietary Treatment of Hyperlipoproteinemia. Recommendations for treatment of hyperlipidemia in adults: a joint statement of the Nutrition Committee and the Council on Arteriosclerosis. Circulation. 1984; 69:1065-90A. [PubMed 6713610]

74. Weinberger MH. Antihypertensive therapy and lipids: evidence, mechanisms, and implications. Arch Intern Med. 1985; 145:1102-5. [IDIS 200606] [PubMed 2860883]

75. Kissebah AH, Alfarsi S, Adams PW et al. Transport kinetics of plasma free fatty acids, very low density lipoprotein triglycerides and apoprotein in patients with endogenous hypertriglyceridemia: effects of 2,2-dimethyl,5(2,5-xylyloxy)valic acid therapy. Atherosclerosis. 1976; 24:199-218. [PubMed 182185]

76. Brown MS, Goldstein JL. Drugs used in the treatment of hyperlipoproteinemias. In: Gilman AG, Goodman LS, Rall TW et al, eds. Goodman and Gilman’s the pharmacological basis of therapeutics. 7th ed. New York: The Macmillan Company; 1985:827-45.

77. National Heart, Lung, and Blood Institute Lipid Metabolism—Atherogenesis Branch. The lipid research clinics coronary primary prevention trial results: part I. Reduction in incidence of coronary heart disease. JAMA. 1984; 251:351-64. [IDIS 180094] [PubMed 6361299]

78. National Heart, Lung, and Blood Institute Lipid Metabolism—Atherogenesis Branch. The lipid research clinics coronary primary prevention trial results: part II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA. 1984; 251:365-74. [IDIS 180095] [PubMed 6361300]

79. Hansten PD. Drug interactions. 5th ed. Philadelphia: Lea & Febiger; 1985:76.

80. Manninen V, Malkonen M. Effect of gemfibrozil on the blood levels of the high density lipoprotein subfractions HDL₂ and HDL₃. Res Clin Forums. 1982; 4:77-83.

81. W.H.O. cooperative trial on primary prevention of ischaemic heart disease using clofibrate to lower serum cholesterol: mortality follow-up. Report from the Committee of Principal Investigators. Lancet. 1980; 2:379-85.

82. A co-operative trial in the primary prevention of ischaemic heart disease using clofibrate. Report from the Committee of Principal Investigators. Br Heart J. 1978; 40:1069-118. [IDIS 118395] [PubMed 361054]

83. WHO cooperative trial on primary prevention of ischaemic heart disease with clofibrate to lower serum cholesterol: final mortality follow-up. Report from the Committee of Principal Investigators. Lancet. 1984; 2:600-4. [IDIS 190015] [PubMed 6147641]

84. The Coronary Drug Project Research Group. Clofibrate and niacin in coronary heart disease. JAMA. 1975; 231:360-81. [IDIS 49334] [PubMed 1088963]

85. The Coronary Drug Project Research Group. Gallbladder disease as a side effect of drugs influencing lipid metabolism: experience in the Coronary Drug Project. N Engl J Med. 1977; 296:1185-90. [IDIS 71278] [PubMed 323705]

86. Oliver MF. Cholesterol, coronaries, clofibrate and death. N Engl J Med. 1978; 299:1360-2. [PubMed 362204]

87. Green KG. Interpretation of clofibrate trial. Lancet. 1984; 2:1095-6. [PubMed 6150164]

88. Glueck CJ. Nonpharmacologic and pharmacologic alteration of high-density lipoprotein cholesterol: therapeutic approaches to prevention of atherosclerosis. Am Heart J. 1985; 110:1107-15. [IDIS 208439] [PubMed 2865887]

89. American Medical Association Council on Scientific Affairs. Dietary and pharmacologic therapy for the lipid risk factors. JAMA. 1983; 250:1873-9. [IDIS 176576] [PubMed 6620484]

90. Anon. Lipid-lowering drugs. Med Lett Drugs Ther. 1985; 27:74-6. [PubMed 3860714]

91. Saku K, Gartside PS, Hynd BA et al. Mechanism of action of gemfibrozil on lipoprotein metabolism. J Clin Invest. 1985; 75:1702-12. [IDIS 199851] [PubMed 3923042]

92. Grundy SM. Consensus statement: role of therapy with “statins” in patients with hypertriglyceridemia. Am J Cardiol. 1998; 81:1-6B. [IDIS 403201] [PubMed 9462596]

93. Mahley RW. Atherogenic lipoproteins and coronary artery disease: concepts derived from recent advances in cellular and molecular biology. Circulation. 1985; 72:943-8. [PubMed 4042302]

94. Reviewers’ comments (personal observations); 1985 Dec.

95. Cheung MC, Albers JJ, Wahl PW et al. High density lipoproteins during hypolipidemic therapy: a comparative study of four drugs. Atherosclerosis. 1980; 35:215-28. [PubMed 7362696]

96. Hazzard WR, Wahl PW, Gagne C et al. Plasma and lipoprotein lipid responses to four hypolipid drugs. Lipids. 1984; 19:73-9. [PubMed 6708754]

97. Pierides AM, Alvarez-Ude F, Kerr DN. Clofibrate-induced muscle damage in patients with chronic renal failure. Lancet. 1975; 2:1279-82. [PubMed 54800]

98. Bridgman JF, Rosen SM, Thorp JM. Complications during clofibrate treatment on nephrotic-syndrome hyperlipoproteinaemia. Lancet. 1972; 2:506-9. [PubMed 4115569]

99. Levy RI, Brensike JF, Epstein SE et al. The influence of changes in lipid values induced by cholestyramine and diet on progression of coronary artery disease: results of the NHLBI Type II Coronary Intervention Study. Circulation. 1984; 69:325-37. [IDIS 180723] [PubMed 6360415]

100. Gosselin RE, Smith RP, Hodge HC. Clinical toxicology of commercial products. 5th ed. Baltimore: Williams & Wilkins; 1984:I-10.

101. Brensike JF, Levy RI, Kelsey SF et al. Effects of therapy with cholestyramine on progression of coronary arteriosclerosis: results of the NHLBI Type II Coronary Intervention Study. Circulation. 1984; 69:313-24. [IDIS 180722] [PubMed 6360414]

102. Rhodes DF (Parke-Davis, Morris Plains, NJ): Personal communication; 1986 Jan 21.

103. Hoeg JM, Gregg RE, Brewer HB. An approach to the management of hyperlipoproteinemia. JAMA. 1986; 255:512-21. [IDIS 209539] [PubMed 3510334]

104. Frick MH, Elo O, Haapa K et al. Helsinki Heart Study: primary prevention trial with gemfibrozil in middle-aged men with dyslipidemia: safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med. 1987; 317:1237-45. [IDIS 235055] [PubMed 3313041]

105. Rifkind BM. Gemfibrozil, lipids, and coronary risk. N Engl

Metopirone

Dosage Form: capsule, gelatin coated
Metopirone

Metopirone®

metyrapone USP

Capsules

Diagnostic Test of Pituitary

Adrenocorticotropic Function

Rx only

Prescribing Information

DESCRIPTION

Metopirone, metyrapone USP, is an inhibitor of endogenous adrenal corticosteroid synthesis, available as 250-mg capsules for oral administration. Its chemical name is 2-methyl-1, 2-di-3-pyridyl-1-propanone, and its structural formula is

Metyrapone USP is a white to light amber, fine, crystalline powder, having a characteristic odor. It is sparingly soluble in water, and soluble in methanol and in chloroform. It forms water-soluble salts with acids. Its molecular weight is 226.28.

Inactive Ingredients.       Polyethylene glycol, glycerine, gelatin, sodium ethyl hydroxybenzoate, sodium propyl hydroxybenzoate, ethyl vanillin, 4-methoxyacetophenone, titanium dioxide, brown ink.

CLINICAL PHARMACOLOGY

Pharmacodynamics

The pharmacological effect of Metopirone is to reduce cortisol and corticosterone production by inhibiting the 11-β-hydroxylation reaction in the adrenal cortex. Removal of the strong inhibitory feedback mechanism exerted by cortisol results in an increase in adrenocorticotropic hormone (ACTH) production by the pituitary. With continued blockade of the enzymatic steps leading to production of cortisol and corticosterone, there is a marked increase in adrenocortical secretion of their immediate precursors, 11-desoxycortisol and desoxycorticosterone, which are weak suppressors of ACTH release, and a corresponding elevation of these steroids in the plasma and of their metabolites in the urine. These metabolites are readily determined by measuring urinary 17-hydroxycorticosteroids (17-OHCS) or 17-ketogenic steroids (17-KGS). Because of these actions, Metopirone is used as a diagnostic test, with urinary 17-OHCS measured as an index of pituitary ACTH responsiveness. Metopirone may also suppress biosynthesis of aldosterone, resulting in a mild natriuresis.

Pharmacokinetics

The response to Metopirone does not occur immediately. Following oral administration, peak steroid excretion occurs during the subsequent 24-hour period.

Absorption

Metopirone is absorbed rapidly and well when administered orally as prescribed. Peak plasma concentrations are usually reached 1 hour after administration. After administration of 750 mg, mean peak plasma concentrations are 3.7 µg/mL, falling to 0.5 µg/mL 4 hours after administration. Following a single 2000-mg dose, mean peak plasma concentrations of metyrapone in plasma are 7.3 µg/mL.

Metabolism

The major biotransformation is reduction of the ketone to metyrapol, an active alcohol metabolite. Eight hours after a single oral dose, the ratio of metyrapone to metyrapol in the plasma is 1:1.5. Metyrapone and metyrapol are both conjugated with glucuronide.

Excretion

Metyrapone is rapidly eliminated from the plasma. The mean ± SD terminal elimination half-life is 1.9 ± 0.7 hours. Metyrapol takes about twice as long as metyrapone to be eliminated from the plasma. After administration of 4.5 g metyrapone (750 mg every 4 hours), an average of 5.3% of the dose was excreted in the urine in the form of metyrapone (9.2% free and 90.8% as glucuronide) and 38.5% in the form of metyrapol (8.1% free and 91.9% as glucuronide) within 72 hours after the first dose was given.

INDICATIONS AND USAGE

Metopirone is a diagnostic drug for testing hypothalamic-pituitary ACTH function.

CONTRAINDICATIONS

Metopirone is contraindicated in patients with adrenal cortical insufficiency, or hypersensitivity to Metopirone or to any of its excipients.

WARNINGS

Metopirone may induce acute adrenal insufficiency in patients with reduced adrenal secretory capacity.

PRECAUTIONS

General

Ability of adrenals to respond to exogenous ACTH should be demonstrated before Metopirone is employed as a test. In the presence of hypo- or hyperthyroidism, response to the Metopirone test may be subnormal.

Since Metopirone may cause dizziness and sedation, patients should exercise caution when driving or operating machinery.

Laboratory Tests

See INTERPRETATION.

Drug Interactions

Drugs affecting pituitary or adrenocortical function, including all corticosteroid therapy, must be discontinued prior to and during testing with Metopirone.

The metabolism of Metopirone is accelerated by phenytoin; therefore, results of the test may be inaccurate in patients taking phenytoin within two weeks before. A subnormal response may occur in patients on estrogen therapy.

Metopirone inhibits the glucuronidation of acetaminophen and could possibly potentiate acetaminophen toxicity.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity and reproduction studies in animals have not been conducted.

Metopirone was not mutagenic with or without metabolic activation in three strains of bacteria.

Pregnancy Category C

A subnormal response to Metopirone may occur in pregnant women. Animal reproduction studies have not been conducted with Metopirone. The Metopirone test was administered to 20 pregnant women in their second and third trimester of pregnancy and evidence was found that the fetal pituitary responded to the enzymatic block. It is not known if Metopirone can affect reproduction capacity. Metopirone should be given to a pregnant woman only if clearly needed.

Animal reproduction studies adequate to evaluate teratogenicity and postnatal development have not been conducted with Metopirone.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Metopirone is administered to a nursing woman.

Pediatric Use

See DOSAGE AND ADMINISTRATION.

Geriatric Use

Clinical studies of Metopirone did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

ADVERSE REACTIONS

Cardiovascular System: Hypotension

Gastrointestinal System: Nausea, vomiting, abdominal discomfort or pain.

Central Nervous System: Headache, dizziness, sedation.

Dermatologic System: Allergic rash.

Hematologic System: Rarely, decreased white blood cell count or bone marrow depression.

OVERDOSAGE

Acute Toxicity

One case has been recorded in which a 6-year-old girl died after two doses of Metopirone, 2 g.

Oral LD50 in animals (mg/kg): rats, 521; maximum tolerated intravenous dose in one dog, 300.

Signs and Symptoms

The clinical picture of poisoning with Metopirone is characterized by gastrointestinal symptoms and by signs of acute adrenocortical insufficiency.

Cardiovascular System: Cardiac arrhythmias, hypotension, dehydration.

Nervous System and Muscles: Anxiety, confusion, weakness, impairment of consciousness.

Gastrointestinal System: Nausea, vomiting, epigastric pain, diarrhea.

Laboratory Findings: Hyponatremia, hypochloremia, hyperkalemia.

Combined Poisoning

In patients under treatment with insulin or oral antidiabetics, the signs and symptoms of acute poisoning with Metopirone may be aggravated or modified.

Treatment

There is no specific antidote. Besides general measures to eliminate the drug and reduce its absorption, a large dose of hydrocortisone should be administered at once, together with saline and glucose infusions.

Surveillance: For a few days blood pressure and fluid and electrolyte balance should be monitored.

DOSAGE AND ADMINISTRATION

Single-Dose Short Test

This test, usually given on an outpatient basis, determines plasma 11-desoxycortisol and/or ACTH levels after a single dose of Metopirone. The patient is given 30 mg/kg (maximum 3 g Metopirone) at midnight with yogurt or milk. The same dose is recommended in children. The blood sample for the assay is taken early the following morning (7:30-8:00 a.m.). The plasma should be frozen as soon as possible. The patient is then given a prophylactic dose of 50 mg cortisone acetate.

Interpretation

Normal values will depend on the method used to determine ACTH and 11-desoxycortisol levels. An intact ACTH reserve is generally indicated by an increase in plasma ACTH to at least 44 pmol/L (200 ng/L) or by an increase in 11-desoxycortisol to over 0.2 µmol/L (70 µg/L). Patients with suspected adrenocortical insufficiency should be hospitalized overnight as a precautionary measure.

Multiple-Dose Test

Day 1: Control period - Collect 24-hour urine for measurement of 17-OHCS or 17-KGS.

Day 2: ACTH test to determine the ability of adrenals to respond - Standard ACTH test such as infusion of 50 units ACTH over 8 hours and measurement of 24-hour urinary steroids. If results indicate adequate response, the Metopirone test may proceed.

Day 3-4: Rest period.

Day 5: Administration of Metopirone: Recommended with milk or snack.

Adults: 750 mg orally, every 4 hours for 6 doses. A single dose is approximately equivalent to 15 mg/kg.

Children: 15 mg/kg orally every 4 hours for 6 doses. A minimal single dose of 250 mg is recommended.

Day 6: After administration of Metopirone - Determination of 24-hour urinary steroids for effect.

Interpretation

ACTH Test

The normal 24-hour urinary excretion of 17-OHCS ranges from 3 to 12 mg. Following continuous intravenous infusion of 50 units ACTH over a period of 8 hours, 17-OHCS excretion increases to 15 to 45 mg per 24 hours.

Metopirone

Normal response: In patients with a normally functioning pituitary, administration of Metopirone is followed by a two- to four-fold increase of 17-OHCS excretion or doubling of 17-KGS excretion.

Subnormal response: Subnormal response in patients without adrenal insufficiency is indicative of some degree of impairment of pituitary function, either panhypopituitarism or partial hypopituitarism (limited pituitary reserve).

1. Panhypopituitarism is readily diagnosed by the classical clinical and chemical evidences of hypogonadism, hypothyroidism, and hypoadrenocorticism. These patients usually have subnormal basal urinary steroid levels. Depending upon the duration of the disease and degree of adrenal atrophy, they may fail to respond to exogenous ACTH in the normal manner. Administration of Metopirone is not essential in the diagnosis, but if given, it will not induce an appreciable increase in urinary steroids.

2. Partial hypopituitarism or limited pituitary reserve is the more difficult diagnosis as these patients do not present the classical signs and symptoms of hypopituitarism. Measurements of target organ functions often are normal under basal conditions. The response to exogenous ACTH is usually normal, producing the expected rise of urinary steroids (17-OHCS or 17-KGS).

The response, however, to Metopirone is subnormal; that is, no significant increase in 17-OHCS or 17-KGS excretion occurs.

This failure to respond to metyrapone may be interpreted as evidence of impaired pituitary-adrenal reserve. In view of the normal response to exogenous ACTH, the failure to respond to metyrapone is inferred to be related to a defect in the CNS-pituitary mechanisms which normally regulate ACTH secretions. Presumably the ACTH secreting mechanisms of these individuals are already working at their maximal rates to meet everyday conditions and possess limited “reserve” capacities to secrete additional ACTH either in response to stress or to decreased cortisol levels occurring as a result of metyrapone administration.

Subnormal response in patients with Cushing’s syndrome is suggestive of either autonomous adrenal tumors that suppress the ACTH-releasing capacity of the pituitary or nonendocrine ACTH-secreting tumors.

Excessive response: An excessive excretion of 17-OHCS or 17-KGS after administration of Metopirone is suggestive of Cushing’s syndrome associated with adrenal hyperplasia. These patients have an elevated excretion of urinary corticosteroids under basal conditions and will often, but not invariably, show a “supernormal” response to ACTH and also to Metopirone, excreting more than 35 mg per 24 hours of either 17-OHCS or 17-KGS.

HOW SUPPLIED

Capsules 250 mg -- soft gelatin, white to yellowish-white, oblong, opaque, imprinted CIBA on one side and LN on the other side in brown ink.

Bottles of 18………………………………………………………………NDC 0078-0455-17

Do not store above 30ºC (86ºF).

Protect from moisture and heat.

Dispense in tight container (USP).

T2010-103

REV: NOVEMBER 2010

Manufactured by:

R.P. Scherer GmbH

Eberbach/Baden, Germany

Distributed by:

Novartis Pharmaceuticals Corporation

East Hanover, New Jersey 07936

© Novartis

PRINCIPAL DISPLAY PANEL

Package Label – 250 mg

Rx Only             NDC 0078-0455-17

Metopirone® (metyrapone USP)

18 capsules

Metopirone  metyrapone  capsule, gelatin coated

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0078-0455 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength METYRAPONE (METYRAPONE) METYRAPONE 250 mg

Inactive Ingredients Ingredient Name Strength ETHYL VANILLIN   GELATIN   GLYCERIN   POLYETHYLENE GLYCOLS   PROPYLPARABEN SODIUM   TITANIUM DIOXIDE

Product Characteristics Color WHITE (yellowish white) Score no score Shape CAPSULE Size 19mm Flavor Imprint Code CIBA;LN Contains

Packaging # NDC Package Description Multilevel Packaging 1 0078-0455-17 18 CAPSULE In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA012911	01/25/1962	11/30/2012

Labeler - Novartis Pharmaceuticals Corporation (002147023)

Revised: 11/2010Novartis Pharmaceuticals Corporation

Zydol 50mg Soluble Tablets

Zydol 50 mg Soluble Tablets

Tramadol hydrochloride

Read all of this leaflet carefully before you start taking this medicine.

• Keep this leaflet. You may need to read it again.


• If you have any further questions, ask your doctor or your pharmacist.


• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.


• If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or your pharmacist.

In this leaflet:

• 1. What Zydol Soluble Tablets is and what it is used for


• 2. Before you take Zydol Soluble Tablets


• 3. How to take Zydol Soluble Tablets


• 4. Possible side effects


• 5. How to store Zydol Soluble Tablets


• 6. Further information

WHAT Zydol Soluble Tablets IS AND WHAT IT IS USED FOR

Tramadol - the active substance in Zydol Soluble Tablets - is a painkiller belonging to the class of opioids that acts on the central nervous system. It relieves pain by acting on specific nerve cells of the spinal cord and brain. Zydol Soluble Tablets is used for the treatment of moderate to severe pain.

BEFORE YOU TAKE Zydol Soluble Tablets

Do not take Zydol Soluble Tablets,

• if you are allergic (hypersensitive) to tramadol or any of the other ingredients of Zydol Soluble Tablets;


• in acute poisoning with alcohol, sleeping pills, pain relievers or other psychotropic medicines (medicines that affect mood and emotions);


• if you are also taking MAO inhibitors (certain medicines used for treatment of depression) or have taken them in the last 14 days before treatment with Zydol Soluble Tablets (see “Taking other medicines”);


• if you are an epileptic and your fits are not adequately controlled by treatment;


• as a substitute in drug withdrawal.

Take special care with Zydol Soluble Tablets,

• if you think that you are addicted to other pain relievers (opioids);


• if you suffer from consciousness disorders (if you feel that you are going to faint);


• if you are in a state of shock (cold sweat may be a sign of this);


• if you suffer from increased pressure in the brain (possibly after a head injury or brain disease);


• if you have difficulty in breathing;


• if you have a tendency towards epilepsy or fits because the risk of a fit may increase;


• if you suffer from a liver or kidney disease;

In such cases please consult your doctor before taking the medicine. Epileptic fits have been reported in patients taking tramadol at the recommended dose level. The risk may be increased when doses of tramadol exceed the recommended upper daily dose limit (400 mg).

Please note that Zydol Soluble Tablets may lead to physical and psychological addiction. When Zydol Soluble Tablets is taken for a long time, its effect may decrease, so that higher doses have to be taken (tolerance development). In patients with a tendency to abuse medicines or who are dependent on medicines, treatment with Zydol Soluble Tablets should only be carried out for short periods and under strict medical supervision.

Please also inform your doctor if one of these problems occurs during Zydol Soluble Tablets treatment or if they applied to you in the past.

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

Zydol Soluble Tablets should not be taken together with MAO inhibitors (certain medicines for the treatment of depression).

The pain-relieving effect of Zydol Soluble Tablets may be reduced and the length of time it acts may be shortened, if you take medicines which contain

• carbamazepine (for epileptic fits);


• pentazocine, nalbuphine or buprenorphine (pain killers);


• ondansetron (prevents nausea).

Your doctor will tell you whether you should take Zydol Soluble Tablets, and what dose.

The risk of side effects increases,

• if you take tranquillizers, sleeping pills, other pain relievers such as morphine and codeine (also as cough medicine), and alcohol while you are taking Zydol Soluble Tablets. You may feel drowsier or feel that you might faint. If this happens tell your doctor.


• if you are taking medicines which may cause convulsions (fits), such as certain antidepressants. The risk having a fit may increase if you take Zydol Soluble Tablets at the same time. Your doctor will tell you whether Zydol Soluble Tablets is suitable for you.


• if you are taking selective serotonin reuptake inhibitors (often referred to as SSRIs) or MAO inhibitors (for the treatment of depression). Zydol Soluble Tablets may interact with these medicines and you may experience symptoms such as confusion, restlessness, fever, sweating, uncoordinated movement of limbs or eyes, uncontrollable jerking of muscles, or diarrhoea.


• if you take coumarin anticoagulants (medicines for blood thinning), e.g. warfarin, together with Zydol Soluble Tablets. The effect of these medicines on blood clotting may be affected and bleeding may occur.

Taking Zydol Soluble Tablets with food and drink

Do not drink alcohol during treatment with Zydol Soluble Tablets as its effect may be intensified. Food does not influence the effect of Zydol Soluble Tablets.

Pregnancy and breast-feeding

Ask your doctor or pharmacist for advice before taking any medicine. There is very little information regarding the safety of tramadol in human pregnancy. Therefore you should not use Zydol Soluble Tablets if you are pregnant.

Chronic use during pregnancy may lead to withdrawal symptoms in newborns.

Generally, the use of tramadol is not recommended during breast-feeding. Small amounts of tramadol are excreted into breast milk. On a single dose it is usually not necessary to interrupt breast-feeding. Please ask your doctor for advice.

Driving and using machines

Zydol Soluble Tablets may cause drowsiness, dizziness and blurred vision and therefore may impair your reactions. If you feel that your reactions are affected, do not drive a car or other vehicle, do not use electric tools or operate machinery, and do not work without a firm hold!

HOW TO TAKE Zydol Soluble Tablets

Always take Zydol Soluble Tablets exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure. The dosage should be adjusted to the intensity of your pain and your individual pain sensitivity. In general the lowest pain-relieving dose should be taken.

Unless otherwise prescribed by your doctor, the usual dose is:

Adults and adolescents from the age of 12 years

One or two Zydol 50 mg tablets (equivalent to 50 mg – 100 mg tramadol hydrochloride). Your doctor may prescribe a different, more appropriate dosage of Zydol Soluble Tablets if necessary. Do not take more than 8 Zydol Soluble Tablets (equivalent to 400 mg tramadol hydrochloride) daily, except if your doctor has instructed you to do so.

Children

Zydol Soluble Tablets is not suitable for children below the age of 12 years.

Elderly patients

In elderly patients (above 75 years) the excretion of tramadol may be delayed. If this applies to you, your doctor may recommend prolonging the dosage interval.

Severe liver or kidney disease (insufficiency)/dialysis patients

Patients with severe liver and/or kidney insufficiency should not take Zydol Soluble Tablets. If in your case the insufficiency is mild or moderate, your doctor may recommend prolonging the dosage interval.

How and when should you take Zydol Soluble Tablets?

Zydol Soluble Tablets are for oral use.

Always dissolve the Zydol Soluble Tablets in about 50 ml of water (about half a cup full) and drink the solution straight away. You may take the tablets on an empty stomach or with meals.

How long should you take Zydol Soluble Tablets?

You should not take Zydol Soluble Tablets for longer than necessary. If you need to be treated for a longer period, your doctor will check at regular short intervals (if necessary with breaks in treatment) whether you should continue to take Zydol Soluble Tablets and at what dose.

If you have the impression that the effect of Zydol Soluble Tablets is too strong or too weak, talk to your doctor or pharmacist.

If you take more Zydol Soluble Tablets than you should

If you have taken an additional dose by mistake, this will generally have no negative effects. You should take your next dose as prescribed.

After taking very high doses, pin-point pupils, vomiting, fall in blood pressure, fast heart beat, collapse, disturbed consciousness up to coma (deep unconsciousness), epileptic fits, and difficulty in breathing up to cessation of breathing may occur. In such cases a doctor should be called immediately!

If you forget to take Zydol Soluble Tablets

If you forget to take the tablets, pain is likely to return. Do not take a double dose to make up for forgotten individual doses, simply continue taking the tablets as before.

If you stop taking Zydol Soluble Tablets

If you interrupt or finish treatment with Zydol Soluble Tablets too soon, pain is likely to return. If you wish to stop treatment on account of unpleasant effects, please tell your doctor.

Generally there will be no after-effects when treatment with Zydol Soluble Tablets is stopped. However, on rare occasions, people who have been taking Zydol Soluble Tablets for some time may feel unwell if they abruptly stop taking them. They may feel agitated, anxious, nervous or shaky. They may be hyperactive, have difficulty sleeping and have stomach or bowel disorders. Very few people may get panic attacks, hallucinations, unusual perceptions such as itching, tingling and numbness, and “ringing” in the ears (tinnitus). If you experience any of these complaints after stopping Zydol Soluble Tablets, please consult your doctor.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

Possible Side Effects

Like all medicines, Zydol Soluble Tablets can cause side effects, although not everybody gets them.

In case one of the following situations occur, see your doctor straight away:

• allergic reactions e.g. difficulty in breathing, wheezing, swelling of skin (occurs rarely),


• swollen face, tongue and/or throat and/or difficulty to swallow or hives together with difficulties in breathing (occurs rarely),


• shock/sudden circulation failure (occurs rarely).

Usually the frequency of side effects is classified as follows:

• very common (more than 1 out of 10 persons),


• common (more than 1 out of 100 persons),


• uncommon (more than 1 out of 1,000 persons),


• rare (more than 1 out of 10,000 persons)


• very rare (less than 1 out of 10,000 persons).

The most common side effects during treatment with Zydol Soluble Tablets are nausea and dizziness, which occur in more than in 1 out of 10 patients.

Heart and blood circulation disorders



uncommon: effects on the heart and blood circulation (pounding of the heart, fast heart beat, feeling faint or collapse).



These adverse effects may particularly occur in patients in an upright position or under physical strain.


rare: slow heart beat, increase in blood pressure.


Nervous system disorders


very common: dizziness.


common: headaches, drowsiness.


rare:

changes in appetite, abnormal sensations (e.g. itching, tingling, numbness), trembling, slow breathing, epileptic fits, muscle twitches, uncoordinated movement, transient loss of consciousness (syncope).



If the recommended doses are exceeded, or if other medicines that depress brain function are taken at the same time, breathing may slow down.



Epileptic fits have occurred mainly at high doses of tramadol or when tramadol was taken at the same time as other medicines which may induce fits.


Psychiatric disorders

rare:

hallucinations, confusion, sleep disorders, anxiety and nightmares.



Psychological complaints may appear after treatment with Zydol Soluble Tablets. Their intensity and nature may vary (according to the patient‘s personality and length of therapy). These may appear as a change in mood (mostly high spirits, occasionally irritated mood), changes in activity (slowing down but sometimes an increase in activity) and being less aware and less able to make decisions, which may lead to errors in judgement.



Dependence may occur.

Eye disorders


rare: blurred vision.

Respiratory disorders


rare: shortness of breath (dyspnoea).



Worsening of asthma has been reported, however it has not been established whether it was caused by tramadol.


Stomach and bowel disorders

very common: feeling sick.


common: being sick, constipation, dry mouth.


uncommon: urge to be sick (retching), stomach trouble (e.g. feeling of pressure in the stomach, bloating), diarrhoea.


Skin disorders

common: sweating


uncommon: skin reactions (e.g. itching, rash).


Muscle disorders

rare: weak muscles.


Liver and biliary disorders

very rare: increase in liver enzyme values.


Urinary disorders

rare: passing water difficult or painful, less urine than normal.


General disorders

common: tiredness, weariness, weakness, low energy.

If Zydol Soluble Tablets is taken over a long period of time dependence may occur, although the risk is very low. When treatment is stopped abruptly signs of withdrawal may appear (see ”If you stop taking Zydol Soluble Tablets”).

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

HOW TO STORE Zydol Soluble Tablets

Keep out of the reach and sight of children.

Do not use Zydol Soluble Tablets after the expiry date which is stated on the carton and the blister. The expiry date refers to the last day of that month. Do not store above 30°C.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required.

These measures will help to protect the environment

Further Information

What Zydol Soluble Tablets contains

The active substance is tramadol hydrochloride.

Each tablet contains 50 mg tramadol hydrochloride.

The other ingredients are: microcrystalline cellulose, maize starch, saccharin sodium, aniseed flavour, peppermint flavour, colloidal anhydrous silica and magnesium stearate.

What Zydol Soluble Tablets looks like and contents of the pack

Zydol Soluble Tablets are white and round and have “T4” and

the company logo

marked on them.

Zydol Soluble Tablets are packed in blister strips and are supplied in boxes of 10, 20, 100 tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder:

Grünenthal Ltd.

Regus Lakeside House

1 Furzeground Way

Stockley Park East

Uxbridge

Middlesex

UB11 1BD

United Kingdom

Manufacturer:

Grünenthal GmbH

Zieglerstr. 6

D-52078

Germany

Other formats:

To listen to or request a copy of this leaflet in Braille, large print or audio please call, free of charge:

0800 198 5000 (UK Only)

Please be ready to give the following information:

Product name: Zydol 50 mg Soluble Tablets
Reference number: PL 21727/0006

This is a service provided by the Royal National Institute of the Blind.

This leaflet was last approved:

02/2009

Zydol is a registered trademark

93007451 50/030/023