Misoprostol

Class: Prostaglandins
ATC Class: A02BB01
VA Class: GA309
Chemical Name: 11α,13E)-(±)-11,16-Dihydroxy-16-methyl-9-oxo-prost-13-en-1-oic acid methyl ester
Molecular Formula: C₂₂H₃₈O₅
CAS Number: 59122-46-2
Brands: Arthrotec, Cytotec

• 
  

  May cause serious fetal harm; contraindicated in pregnant women.^{1 5 70} Pregnancy must be excluded before the start of treatment and prevented thereafter by use of reliable contraception. (See Fetal/Neonatal Morbidity and Mortality and also see Contraindications under Cautions.)¹

  
  

Introduction

Gastric antisecretory agent with protective effects on the gastroduodenal mucosa;^{1 2 3 13 15 16 25 26 27 31 35 37 47 57 60 72 76 77 78 79 80 84 85 86 87 88 89 91 94 95 127} a synthetic analog of prostaglandin E₁ (alprostadil).^{1 5 10 11 13 20 25 26 27 31 55 76 78 85 95}

Uses for Misoprostol

Prevention of NSAIA-induced Ulcers

Treatment to reduce the risk of NSAIA-induced gastric ulcers in patients at high risk (e.g., concomitant debilitating disease, geriatric patients, history of upper GI ulcer) of developing complications (e.g., bleeding, perforation, death) from these ulcers.^{1 5 56 61 67 68 70 85 95 96 135 233}

Not recommended for use in women of childbearing potential unless the woman is at high risk of developing gastric ulcers or of complications resulting from NSAIA-induced gastric ulcers.¹

Gastric Ulcer

Short-term treatment of active, benign, gastric ulcer†;^{2 55 58 72 76 85 87} however, not considered a drug of choice.¹⁴⁰

Maintenance treatment following healing of active gastric ulcer to reduce ulcer recurrence†.⁷²

Duodenal Ulcer

Short-term treatment of endoscopically or radiographically confirmed active duodenal ulcer†;^{2 23 55 78 79 80 83 84 85 86 89 91 92 93 94} however, not considered a drug of choice.¹⁴⁰

Termination of Pregnancy

Use as an adjunct to mifepristone for medical termination of an intrauterine pregnancy.²³⁴ (See Pregnancy under Cautions.)

Labor Induction

Treatment to improve cervical inducibility (cervical “ripening”) in appropriately selected pregnant women with unfavorable cervices with a medical or obstetric need for labor induction†.^{235 237 238} However, avoid such use in women with prior uterine surgery or cesarean section because of the risk of possible uterine rupture.^{235 237 238}

Postpartum Hemorrhage

Prevention or treatment of serious postpartum hemorrhage† in the presence of uterine atony.^{1 237}

Misoprostol Dosage and Administration

Administration

Administer orally.^{1 2 3 4 5}

Also has been administered intravaginally†, using tablets formulated for oral administration.^{1 235 237 238}

Oral Administration

Administer in divided doses after meals and at bedtime.^{1 3}

Avoid concomitant administration with a magnesium-containing or other laxative antacid to minimize the incidence of misoprostol-induced diarrhea.¹ (See GI Effects under Cautions and also see Interactions.)

Dosage

Available as mifoprostol; dosage expressed in terms of mifoprostol.¹

Adults

Prevention of NSAIA-Induced Ulcers

Oral

200 mcg 4 times daily.^{1 56 57 59 76 81 95} May reduce dosage to 100 mcg 4 times daily if higher dosage is not well tolerated;^{1 61 70} however, reduced dosage may be less effective.^{1 61 67 73 95} Alternatively, 200 mcg twice daily.^{1 60} Continue therapy for the duration of NSAIA therapy.¹

Gastric Ulcer†

Oral

100 or 200 mcg 4 times daily for 8 weeks.^{2 55 58 72 76 87}

Duodenal Ulcer†

Oral

100 or 200 mcg 4 times daily or 400 mcg twice daily for 4–8 weeks.^{2 23 55 78 80 84 89 91 93}

Termination of Pregnancy

Oral

400 mcg administered orally on day 3 (2 days after mifepristone administration) unless abortion has occurred and has been confirmed by clinical examination or ultrasonographic scan.²³⁴ See Mifepristone 76:00.

Induction of Labor†

Intravaginal

Initially, 25 mcg (¼ of a 100-mcg oral tablet).^{235 237 238} Subsequently, 25-mcg every 3–6 hours.^{235 237 238}

Prescribing Limits

Adults

Induction of Labor†

Intravaginal

Maximum 25 mcg.^{235 237 238} Subsequently, maximum 25-mcg every 3–6 hours.^{235 237 238} (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Special Populations

Renal Impairment

Routine dosage reduction not required;^{1 5} however, dosage can be reduced if not tolerated.^{1 5}

Geriatric Patients

Routine dosage reduction not required;^{1 5} however, dosage can be reduced if not tolerated.^{1 5}

Cautions for Misoprostol

Contraindications

• 
  

  Pregnancy (for reducing the risk of NSAIA-induced gastric ulcers).¹

  
  


• 
  

  Known hypersensitivity to prostaglandins.^{1 5}

  
  

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

Possible teratogenic and abortifacient effects; possible serious fetal harm when administered to pregnant women.^{1 5 70} Possible uterine contractions and uterine bleeding and total or partial expulsion of the products of conception in pregnant women.^{1 3 23 55} Spontaneous abortions may result in dangerous uterine bleeding, premature birth, or birth defects.^{1 5} Possible congenital abnormalities (e.g., skull defects, cranial nerve palsies, facial malformations, and limb defects); sometimes associated with fetal death.¹

Do not use in pregnant women for reducing the risk of NSAIA-induced gastric ulcers.¹ (See Contraindications under Cautions.) Do not initiate therapy in women of childbearing potential until pregnancy is excluded and other necessary precautions (effective contraception) are ensured.^{1 5 13 64 70 85} Initiate therapy only after determining that patient is reliable and able to comply with effective contraceptive measures.¹ Perform a reliable, blood pregnancy test within 2 weeks prior to beginning therapy.¹ Initiate therapy on the second or third day of the next normal menstrual cycle, after a negative pregnancy test is reported.¹ (See Pregnancy and also see Lactation under Cautions.)

If inadvertently administered during pregnancy or if the patient becomes pregnant while receiving the drug, discontinue therapy and inform patient of the potential hazard to the fetus.¹

Intravaginal use may result in uterine hyperstimulation, uterine tetany, uterine rupture, amniotic fluid embolism, pelvic pain, retained placenta, severe genital bleeding, shock, fetal bradycardia, and fetal and maternal death, especially with dosages >25 mcg.^{1 237} (See Prescribing Limits under Dosage and Administration.) Risk of uterine rupture increases with advancing gestational age, prior uterine surgery (including cesarean delivery), and grand multiparity.^{1 237} Intravaginal use is not recommended in patients with a previous cesarean delivery or prior major uterine surgery.²³⁷

Sensitivity Reactions

Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylaxis, reported.¹

General Precautions

GI Effects

Possible diarrhea; ^{1 3 5 15 22 23 55 56 57 58 59 61 64 76 78 79 80 81 84 85 86 89 91 92 93 121 151} usually apparent after about 2 weeks of therapy.¹ Generally is self-limiting,^{1 58 61 78 80 85 89} resolving within about a week after onset.^{1 61} Possible increased risk of profound (e.g., voluminous, watery) and life-threatening diarrhea in patients with inflammatory bowel disease.^{1 151} Use with extreme caution in these patients; careful monitoring recommended.^{1 151} Careful monitoring recommended in patients prone to dehydration or in whom its consequences would be dangerous.¹ Administer in divided doses after meals and at bedtime;^{1 3} avoid concomitant administration with a magnesium-containing or other laxative antacid to minimize diarrhea.¹ (See Interactions.)

Cardiovascular Effects

Chest pain, edema, diaphoresis, hypotension, hypertension, arrhythmia, phlebitis, increased serum concentrations of cardiac enzymes, syncope, MI (some fatal), and thromboembolic events (e.g., pulmonary embolism, arterial thrombosis, cerebrovascular accident) reported; causal relationship to drug not established.¹ Use with caution in patients with preexisting cardiovascular disease.¹

Use of Fixed Combination

When used in fixed combination with other agents, consider the cautions, precautions, and contraindications associated with the concomitant agents.

Specific Populations

Pregnancy

Category X. (See Fetal/Neonatal Morbidity and Mortality and also see Contraindications under Cautions.)

Ruptured ectopic pregnancy (rarely resulting in fatal hemorrhage); serious, rarely fatal, bacterial (e.g., Clostridium sordellii) infection and sepsis; or MI reported in a limited number of patients receiving intravaginal misoprostol with mifepristone for termination of pregnancy; causal relationship to regimen not established.^{234 241 242 244}

Lactation

Not known whether misoprostol is distributed into milk.¹ Use not recommended.¹

Pediatric Use

Safety and efficacy not established in children <18 years of age.¹

Geriatric Use

No substantial differences in safety relative to younger adults.¹

Renal Impairment

Possible increased half-life,^{1 3} peak plasma misoprostol acid concentrations, and areas under the plasma concentration-time curves (AUCs).^{1 3} (See Special Populations under Pharmacokinetics.)

Common Adverse Effects

Diarrhea,^{1 3 5 15 22 23 55 56 57 58 59 61 64 76 78 79 80 81 84 85 86 89 91 92 93 121 151} abdominal pain.^{1 5 22 32 55 56 57 61 76 81 91 92 121}

Interactions for Misoprostol

Drugs Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interaction unlikely.^{1 3 5 41 126 127}

Specific Drugs and Foods

Drug or Food	Interaction	Comments
Aspirin	Possible decreased AUCs of aspirin1 127	Interaction not clinically important1 5 56 127 129
Cyclosporine	Possible beneficial renal effects127 129 144 149 and reversal of cyclosporine-induced nephrotoxicity134 138
Food and antacids	Potential decreased rate of absorption of misoprostol, decreased peak plasma concentrations of misoprostol acid1 3 5 95 and decreased oral bioavailability of misoprostol1 5 Magnesium-containing antacids may increase the incidence of misoprostol-induced diarrhea1	Avoid concomitant administration of a magnesium-containing or other laxative antacid1 93
NSAIAs (ibuprofen, piroxicam, diclofenac)	Pharmacokinetic interactions unlikely 1 5 127 129

Misoprostol Pharmacokinetics

Absorption

Bioavailability

Rapidly and almost completely absorbed from the GI tract;^{1 2 5 41 42 45 95} 88% of a dose is absorbed.⁴⁵

Onset

Following oral administration, inhibition of gastric acid secretion reaches a maximum within 60–90 minutes.^{1 5 12 24 36 95}

Duration

Following oral administration, inhibition of gastric acid secretion persists for at least 3 hours.^{1 5 12 24 36 95} Duration is directly related to dose.^{1 2 12 24 33 46 55 109}

Food

Food and antacids decrease the rate of absorption of misoprostol, resulting in delayed and decreased peak plasma concentrations.^{1 3 95 131}

Special Populations

Increased peak plasma misoprostol acid concentrations and AUCs in patients with renal impairment.^{1 3} In geriatric patients, possible increased AUCs;^{1 3 5 43 131} however, peak plasma concentrations are not affected.^{3 43 131}

Distribution

Extent

Distribution into human body tissues and fluids has not been fully characterized.^{2 5 41} Not known whether misoprostol and/or misoprostol acid cross the placenta⁵ or are distributed into milk in humans.^{1 5}

Plasma Protein Binding

Approximately 80–90%.^{1 2 41}

Elimination

Metabolism

Rapidly and extensively metabolized to misoprostol acid (the free acid),^{1 2 5 41 42 43 45 95} at least in part in the GI tract.^{46 143} Misoprostol acid undergoes extensive, rapid metabolism^{1 2 3 41} to form inactive metabolites.^{1 45 127}

Elimination Route

Excreted in urine (73%)^{1 45 100} mainly as metabolites and in feces (15%) via biliary excretion^{2 45} .

Half-life

Biphasic; half-life of free acid is 20–40 minutes.^{1 5 41 131}

Special Populations

In patients with renal impairment, possible increased half-life.^{1 3}

Stability

Storage

Oral

Tablets

Well-closed containers⁴ a≤25°C.^{1 5}

ActionsActions

• 
  

  Inhibits gastric acid secretion and protects the gastroduodenal mucosa.^{1 2 3 15 16 25 26 27 31 35 37 47 57 60 77 85}

  
  


• 
  

  Exhibits substantial dose-related^{1 2 12 24 33 46 55 109} inhibitory effects on basal, nocturnal, and food- or histamine-stimulated gastric acid secretion^{1 2 6 12 14 24 32 36 95} via a direct action at the parietal cells.^{1 2 3 4 5 9 14 20 24 33 64}

  
  


• 
  

  Protective effect may result from increased mucus secretion,^{1 2 3 5 10 23 25 26 27 33 35 51 95} increased bicarbonate secretion from nonparietal cells,^{1 2 3 5 10 23 25 26 31 33 35 53 95} enhancement or maintenance of blood flow of the mucosa (possibly via direct vasodilation),^{2 9 10 17 25 26 33 35 95} protection of submucosal cell proliferation,^{23 26} stabilization of mucosal membrane systems,^{23 25 35} prevention of mucosal barrier disruption,^{2 10 33 35} enhancement of transmucosal diffusion potential,^{2 117} and inhibition or reduction of back diffusion of hydrogen ions into the mucosa.^{2 3 33}

  
  


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  Stimulates intestinal fluid secretion and effects motility.¹³⁷

  
  


• 
  

  Increases the amplitude and frequency of uterine contractions and stimulates uterine bleeding and total or partial expulsion of uterine contents in pregnant women.^{1 3 23 55}

  
  

Advice to Patients

• 
  

  Importance of providing patient a copy of manufacturer’s patient information.¹ Patients should read the patient information before initiating misoprostol therapy and every time the prescription is refilled.¹

  
  


• 
  

  Risk of serious fetal harm if administered in pregnant women.¹ Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy during therapy and advise pregnant women of risk to the fetus.^{1 5 23 95} (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

  
  


• 
  

  Importance of informing patient that sharing the drug with another individual, particularly a woman of childbearing potential, could be hazardous.¹

  
  


• 
  

  Importance of promptly informing clinicians if they have problems with or questions about misoprostol.¹

  
  


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  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements.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.

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

Misoprostol

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	100 mcg*	Cytotec	Pfizer
			Misoprostol Tablets	Teva
		200 mcg*	Cytotec	Pfizer
			Misoprostol Tablets	Teva

Misoprostol Combinations

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, enteric-coated core, film-coated	200 mcg Misoprostol outer layer with 50 mg Diclofenac Sodium enteric-coated core	Arthrotec (with povidone)	Pfizer
		200 mcg Misoprostol outer layer with 75 mg Diclofenac Sodium enteric-coated core	Arthrotec (with povidone)	Pfizer

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 04/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Arthrotec 50 50-200MG-MCG Tablets (PFIZER U.S.): 60/$178.68 or 180/$523.27

Arthrotec 75 75-200MG-MCG Tablets (PFIZER U.S.): 60/$186.32 or 180/$530.89

Cytotec 100MCG Tablets (PFIZER U.S.): 60/$89.99 or 180/$245.96

Cytotec 200MCG Tablets (PFIZER U.S.): 60/$119.99 or 180/$339.98

Misoprostol 100MCG Tablets (IVAX PHARMACEUTICALS INC.): 60/$39.99 or 180/$106.99

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 01, 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. Pharmacia. Cytotec (misoprostol) tablets prescribing information. Chicago, IL; 2003 Feb.

2. Monk JP, Clissold SP. Misoprostol: a preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of peptic ulcer disease. Drugs. 1987; 33:1-30. [IDIS 228650] [PubMed 3102205]

3. Nicholson PA. A review of the therapeutic efficacy of misoprostol, a prostaglandin E₁ analogue. S Afr Med J. 1988; 74:56-8. [IDIS 249363] [PubMed 3133797]

4. USP DI Update. No. 3. Misoprostol (systemic). Rockville, MD; The United States Pharmacopeial Convention, Inc; 1989:84-9.

5. Searle. Cytotec (misoprostol) product information form for the American Hospital Formulary Service. Skokie, IL; 1988 Dec.

6. Nakamura T, Niwa H, Muto H. Misoprostol inhibits basal gastric secretion in humans. Gastroenterology. 1986; 90(5 Part 2):1562.

7. Feldman M. Gastric bicarbonate secretion in humans: effect of pentagastrin, bethanechol, and 11,16,16-trimethyl prostaglandin E₂. J Clin Invest. 1983; 72:295-303. [IDIS 173782] [PubMed 6135708]

8. Kauffman GL Jr, Reeve JJ Jr, Grossman MI. Gastric bicarbonate secretion: effect of topical and intravenous 16,16-dimethyl prostaglandin E₂. Am J Physiol. 1980; 239:G44-8.

9. Colton DG, Driskill DR, Phillips EL et al. Effect of SC-29333, an inhibitor of gastric secretion, on canine gastric mucosal blood flow and serum gastrin levels. Arch Int Pharmacodyn Ther. 1978; 236:86-95. [PubMed 747466]

10. Collins PW. Development and therapeutic role of synthetic prostaglandins in peptic ulcer disease. J Med Chem. 1986; 29:437-3. [IDIS 215856] [PubMed 3514911]

11. Collins PW, Pappo R, Dajani EZ. Chemistry and synthetic development of misoprostol. Dig Dis Sci. 1985; 30:114-7S. [IDIS 208364] [PubMed 3967559]

12. Steiner JA. Misoprostol clinical pharmacology: establishment of activity in man. Dig Dis Sci. 1985; 30:136-41S.

13. Wilson DE. Antisecretory and mucosal protective actions of misoprostol: potential role in the treatment of peptic ulcer disease. Am J Med. 1987; 83(Suppl 1A):2-8. [IDIS 232695] [PubMed 3113241]

14. Davis GR, Fordtran JS, Dajani EZ. Dose-response, meal-stimulated gastric antisecretory study of prostaglandin E₁ analog, misoprostol, in man. Dig Dis Sci. 1988; 33:298-302. [IDIS 250905] [PubMed 3125026]

15. Jiranek GC, Kimmey MB, Saunders DR et al. Misoprostol reduces gastroduodenal injury from one week of aspirin: an endoscopic study. Gastroenterology. 1989; 96:656-61. [IDIS 250825] [PubMed 2491827]

16. Cohen MM, Clark L, Armstrong L et al. Reduction of aspirin-induced fecal blood loss with low-dose misoprostol tablets in man. Dig Dis Sci. 1985; 30:605-11. [IDIS 202507] [PubMed 3924533]

17. Sato N, Kawano S, Fukuda M et al. Misoprostol-induced changes in gastric mucosal hemodynamics. Am J Med. 1987; 83(Suppl):15-21. [IDIS 232696] [PubMed 3113240]

18. Clay GA, Goodwin JS. Evaluation of the effects of misoprostol on immunologic competence in normal volunteers. Dig Dis Sci. 1986; 31(Suppl):148-9S.

19. Bright-Asare P, Habte T, Yirgou B et al. Prostaglandins, H₂-receptor antagonists and peptic ulcer disease. Drugs. 1988; 35(Suppl 3):1-9 (IDIS 247642)

20. Tsai BS, Kessler LK, Schoenhard G et al. Demonstration of specific E-type prostaglandin receptors using enriched preparations of canine parietal cells and [³H] misoprostol free acid. Am J Med. 1987; 83(Suppl 1A):9-14. [PubMed 2887113]

21. Fich A, Arber N, Sestieri M et al. Effect of misoprostol and cimetidine on gastric cell turnover. Dig Dis Sci. 1985; 30(Suppl):133-5S.

22. Ryan JR, Vargas R, Clay GA et al. Role of misoprostol in reducing aspirin-induced gastrointestinal blood loss in arthritic patients. Am J Med. 1987; 83(Suppl 1A):41-4. [IDIS 232701] [PubMed 3113245]

23. Lewis JH. Summary of the 29th meeting of the gastrointestinal drugs advisory committee, Food and Drug Administration—June 10, 1985. Am J Gastroenterol. 1985; 80:743-5. [IDIS 206010] [PubMed 3929594]

24. Dajani EZ. Perspective on the gastric antisecretory effects of misoprostol in man. Prostaglandins. 1987; 33(Suppl):68-77. [PubMed 3122277]

25. Dajani EZ. Overview of the mucosal protective effects of misoprostol in man. Prostaglandins. 1987; 33(Suppl):117-29. [PubMed 3122272]

26. Wilson DE. Misoprostol and gastroduodenal mucosal protection (cytoprotection). Postgrad Med J. 1988; 64(Suppl 1):7-11. [PubMed 3138683]

27. Hunt JN, Smith JL, Jiang CL et al. Effect of synthetic prostaglandin E₁ analog on aspirin-induced gastric bleeding and secretion. Dig Dis Sci. 1983; 28:897-902. [IDIS 177262] [PubMed 6604619]

28. McGuigan JE, Chang Y, Dajani EZ. Effect of misoprostol, an antiulcer prostaglandin, on serum gastrin in patients with duodenal ulcer. Dig Dis Sci. 1986; 31(Suppl):120-5S.

29. Wagner BM. Gastric morphology in ulcer patients receiving misoprostol. Dig Dis Sci. 1985; 30(Suppl):129-32S. [IDIS 208366] [PubMed 3838153]

30. Brecht T. Effects of misoprostol on human circulation. Prostaglandins. 1987; 33(Suppl):51-60. [PubMed 3122275]

31. Isenberg JI, Hogan DL, Selling JA et al. Duodenal bicarbonate secretion in humans: role of prostaglandins. Dig Dis Sci. 1986; 31(Suppl):130S. [IDIS 212235] [PubMed 3080284]

32. Akdamar K, Agrawal N, Ertan A. Inhibition of nocturnal gastric secretion in normal human volunteers by misoprostol: a synthetic prostaglandin E₁ methyl ester analog. Am J Gastroenterol. 1982; 77:902-4. [IDIS 162380] [PubMed 6816064]

33. Bauer RF. Misoprostol preclinical pharmacology. Dig Dis Sci. 1985; 30(Suppl):118-25S.

34. Agrawal NM, Godiwala T, Arimura A et al. Cytoprotection by a synthetic prostaglandin against ethanol-induced gastric mucosal damage. Gastrointest Endosc. 1986; 32:67-70. [PubMed 3086177]

35. Miller TA. Protective effects of prostaglandins against gastric mucosal damage: current knowledge and proposed mechanisms. Am J Physiol. 1983; 245:G601-23. [PubMed 6195926]

36. Ramage JK, Denton A, Williams JG. Inhibition of food stimulated acid secretion by misoprostol, an orally active synthetic E₁ analogue prostaglandin. Br J Clin Pharmacol. 1985; 19:9-12. [IDIS 196422] [PubMed 3919751]

37. Gullikson G, Anglin C, Kessler L et al. Misoprostol prevents aspirin-induced damage in canine Heidenhain pouches. Gastroenterology. 1983; 84(5 Part 2):1176.

38. Moore JG, Alazraki N, Clay GD. Effect of synthetic prostaglandin E₁ analog on gastric emptying of meals in man. Dig Dis Sci. 1986; 31: 16-20. [IDIS 210928] [PubMed 3079695]

39. Konturek SJ, Pawlik W. Physiology and pharmacology of prostaglandins. Dig Dis Sci. 1986; 31(Suppl):6-19S.

40. Salmon PR, Barton T. Comparative inhibition of coffee-induced gastric acid secretion employing misoprostol and cimetidine. Dig Dis Sci. 1986; 31(Suppl):55-62S.

41. Schoenhard G, Oppermann J, Kohn FE. Metabolism and pharmacokinetic studies of misoprostol. Dig Dis Sci. 1985; 30(Suppl):126-8S.

42. Leese PT, Karim A, Rozek L. Technical and pharmacological considerations in evaluating misoprostol pharmacokinetic data. Dig Dis Sci. 1986; 31(Suppl):147S. [IDIS 212240] [PubMed 3731990]

43. Karim A, Burns TS, Miller MS et al. Pharmacokinetics and safety of the anti-ulcer prostaglandin mosiprostol in elderly male subjects. Clin Pharmacol Ther. 1987; 41:205.

44. Karim A, Rozek LF, Leese PT. Absorption of misoprostol (Cytotec), an antiulcer prostaglandin, or aspirin is not affected when given concomitantly to healthy human subjects. Gastroenterology. 1987; 92(5 Part 2):1742.

45. Karim A. Antiulcer prostaglandin misoprostol: single and multiple dose pharmacokinetic profile. Prostaglandins. 1989; 33(Suppl):40-50.

46. Tsai BS, Kessler L, Egofske P et al. Antisecretory activity and metabolism of misoprostol in isolated canine parietal cells. Dig Dis Sci. 1986; 31(Suppl):145-50S. [IDIS 212021] [PubMed 3080277]

47. Bauer RF, Bianchi RG, Casler J et al. Comparative mucosal protective properties of misoprostol, cimetidine, and sucralfate. Dig Dis Sci. 1986; 31(Suppl):81-5S.

48. Leung FW, Miller JC, Guth PH. Dissociated effects of misoprostol on gastric acid secretion and mucosal blood flow. Dig Dis Sci. 1986; 31(Suppl): 86-90S.

49. Smedfors B, Johansson C. Stimulation of duodenal bicarbonate secretion by misoprostol. Dig Dis Sci. 1986; 31(Suppl):96-100S.

50. Liss RH, Letourneau RJ, Schepis JP. Evaluation of cytoprotection against ethanol-induced injury in gastric mucosa pretreated with misoprostol, cimetidine, or placebo. Dig Dis Sci. 1986; 31(Suppl):108-14S.

51. Wilson DE, Quadros E, Rajapaksa T et al. Effects of misoprostol on gastric acid and mucus secretion in man. Dig Dis Sci. 1986; 31(Suppl): 126-9S. [IDIS 212234] [PubMed 3080283]

52. Rainsford KD. The effects of aspirin and other non-steroid anti-inflammatoryanalgesic drugs on gastro-intestinal mucus glycoprotein biosynthesis in vivo: relationship to ulceroge

Prandin

Pronunciation: re-PAG-li-nide
Generic Name: Repaglinide
Brand Name: Prandin

Prandin is used for:

Treating type 2 (non-insulin-dependent) diabetes in patients who cannot control blood sugar levels by diet and exercise alone. It is used along with diet and exercise. It may be used alone or with other antidiabetic medicines.

Prandin is a meglitinide antidiabetic. It works to lower blood glucose (sugar) by stimulating the release of insulin from the pancreas gland. Prandin does not work in type 1 (insulin-dependent) diabetes, because in this condition the pancreas gland is not capable of making or releasing insulin.

Do NOT use Prandin if:

• you are allergic to any ingredient in Prandin


• you have type 1 diabetes (insulin-dependent diabetes)


• you have certain severe problems associated with diabetes (eg, diabetic ketoacidosis, diabetic coma)


• you are taking gemfibrozil

Contact your doctor or health care provider right away if any of these apply to you.

Before using Prandin:

Some medical conditions may interact with Prandin. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have adrenal, pituitary, liver, or kidney problems, or if you have a history of high blood acid levels (acidosis)


• if you drink alcohol, have very poor health, have a high fever, have a severe infection or injury, or have had poor nutrition


• if you will be having surgery

Some MEDICINES MAY INTERACT with Prandin. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Anticoagulants (eg, warfarin), beta-blockers (eg, propranolol), chloramphenicol, cyclosporine gemfibrozil, imidazoles (eg, itraconazole, ketoconazole), macrolides and ketolides (eg, clarithromycin, erythromycin), monoamine oxidase inhibitors (MAOIs) (eg, phenelzine), montelukast, nonsteroidal anti-inflammatory drugs (NSAIDs) (eg, ibuprofen), probenecid, salicylates (eg, aspirin), sulfonamides (eg, sulfamethoxazole), or trimethoprim because the risk of side effects, such as low blood sugar, may be increased


• Calcium channel blockers (eg, nifedipine), corticosteroids (eg, prednisone), diuretics (eg, furosemide, hydrochlorothiazide), estrogen, hormonal contraceptives (eg, birth control pills), isoniazid, nicotinic acid, phenothiazines (eg, chlorpromazine), phenytoin, sympathomimetics (eg, pseudoephedrine), or thyroid hormones (eg, levothyroxine) because the risk of high blood sugar may be increased


• Insulin because it may increase the risk of Prandin's side effects


• Barbiturates (eg, phenobarbital), carbamazepine, or rifampin because they may decrease Prandin's effectiveness

This may not be a complete list of all interactions that may occur. Ask your health care provider if Prandin may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Prandin:

Use Prandin as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Take Prandin by mouth at least 15 to 30 minutes before each meal. If you skip a meal, do not take the dose for the skipped meal. If you add an extra meal, take an extra dose with that meal.


• If you miss a dose of Prandin, skip the missed dose and go back to your regular dosing schedule.

Ask your health care provider any questions you may have about how to use Prandin.

Important safety information:

• Dizziness may occur while you are taking Prandin. This effect may be worse if you take it with alcohol or certain medicines. Use Prandin with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Do not drink large amounts of alcohol while you use Prandin. Talk to your doctor or health care provider before you drink alcohol while you use Prandin.


• Follow the diet and exercise program given to you by your health care provider.


• Carry an ID card at all times that says you have diabetes. Check your blood sugar levels as directed by your doctor. If they are often higher than they should be and you take Prandin exactly as prescribed, tell your doctor.


• Prandin may lower your blood sugar levels. Low blood sugar may make you anxious, sweaty, weak, dizzy, drowsy, or faint. It may also make your heart beat faster; make your vision change; give you a headache, chills, or tremors; or increase hunger. It is a good idea to carry a reliable source of glucose (eg, tablets or gel) to treat low blood sugar. If this is not available, you should eat or drink a quick source of sugar like table sugar, honey, candy, orange juice, or non-diet soda. This will raise your blood sugar level quickly. Tell your doctor right away if this happens. To prevent low blood sugar, eat meals at the same time each day and do not skip meals.


• It may be harder to control your blood sugar during times of stress such as fever, infection, injury, or surgery. Talk with your doctor about how to control your blood sugar if any of these occur. Do not change the dose of your medicine without checking with your doctor.


• Tell your doctor or dentist that you take Prandin before you receive any medical or dental care, emergency care, or surgery.


• Lab tests, including fasting blood sugar and hemoglobin A_1c levels, may be performed while you take Prandin. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Use Prandin with caution in the ELDERLY; they may be more sensitive to its effects. Low blood sugar levels may also be more difficult to recognize in the elderly.


• Prandin should be used with extreme caution in CHILDREN; safety and effectiveness in children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of taking Prandin while you are pregnant. It is not known if Prandin is found in breast milk. Do not breast-feed while you are taking Prandin.

Possible side effects of Prandin:

All medicines may cause side effects, but many people have no, or minor side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Diarrhea; headache; joint or back pain; nasal or chest congestion; sinus inflammation.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); chest pain; fever, chills, or persistent sore throat; low blood sugar symptoms (eg, anxiety, fast heartbeat; lightheadedness; severe or persistent dizziness, drowsiness or headache; tremors; unusual sweating; weakness); severe or persistent blurred vision or other vision problems.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Prandin side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include confusion; dizziness; fatigue; loss of consciousness; nausea; personality changes; seizure; shakiness.

Proper storage of Prandin:

Store Prandin at room temperature, between 59 and 86 degrees F (15 and 30 degrees C), in a tightly closed container. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Prandin out of the reach of children and away from pets.

General information:

• If you have any questions about Prandin, please talk with your doctor, pharmacist, or other health care provider.


• Prandin is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Prandin. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Prandin resources

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

• Prandin Prescribing Information (FDA)


• Prandin Consumer Overview


• Prandin Monograph (AHFS DI)


• Prandin Advanced Consumer (Micromedex) - Includes Dosage Information


• Repaglinide Professional Patient Advice (Wolters Kluwer)

Compare Prandin with other medications

• Diabetes, Type 2

alfuzosin

Generic Name: alfuzosin (al FUE zoe sin)

Brand Names: Uroxatral

What is alfuzosin?

Alfuzosin is in a group of drugs called alpha-adrenergic (AL-fa ad-ren-ER-jik) blockers. Alfuzosin relaxes the muscles in the prostate and bladder neck, making it easier to urinate.

Alfuzosin is used to improve urination in men with benign prostatic hyperplasia (enlarged prostate).

Alfuzosin may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about alfuzosin?

You should not use alfuzosin if you are allergic to it, if you have severe liver disease, or if you are also using ketoconazole (Nizoral), itraconazole (Sporanox), or ritonavir (Norvir). Do not take alfuzosin with other similar medicines such as doxazosin (Cardura), prazosin (Minipress), silodosin (Rapaflo), tamsulosin (Flomax), or terazosin (Hytrin). Alfuzosin may cause dizziness or fainting. Be careful if you drive or do anything that requires you to be alert. Avoid standing for long periods of time or becoming overheated during exercise and in hot weather. Avoid getting up too fast from a sitting or lying position, or you may feel dizzy.

Alfuzosin can affect your pupils during cataract surgery. Tell your eye surgeon ahead of time that you are using this medication. Do not stop using alfuzosin before surgery unless your surgeon tells you to.

There are many other drugs that can interact with alfuzosin. Tell your doctor about all medications you use.

What should I discuss with my healthcare provider before taking alfuzosin?

You should not use alfuzosin if you are allergic to it, or if you have:

• 
  

  severe liver disease;

  
  


• 
  

  if you are also taking similar medicines such as doxazosin (Cardura), prazosin (Minipress), silodosin (Rapaflo), tamsulosin (Flomax), or terazosin (Hytrin); or

  
  


• 
  

  if you are also using ketoconazole (Nizoral), itraconazole (Sporanox), or ritonavir (Norvir).

  
  

If you have any of these other conditions, you may need an alfuzosin dose adjustment or special tests:

• 
  

  prostate cancer;

  
  


• liver disease;


• kidney disease;


• 
  

  a personal or family history of Long QT syndrome;

  
  


• 
  

  angina (chest pain);

  
  


• 
  

  coronary artery disease (hardened arteries);

  
  


• 
  

  a history of low blood pressure (even when caused by taking medications); or

  
  


• 
  

  if you are taking certain medicines to treat HIV or AIDS.

  
  

Alfuzosin can affect your pupils during cataract surgery. Tell your eye surgeon ahead of time that you are using this medication. Do not stop using alfuzosin before surgery unless your surgeon tells you to.

Although this medication is not for use in women, alfuzosin is not expected to harm an unborn baby. If you are a woman using this medication, tell your doctor if you are pregnant or breast-feeding. Alfuzosin is not for use in children.

How should I take alfuzosin?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Your doctor may occasionally change your dose to make sure you get the best results.

Alfuzosin is usually taken once a day, just after a meal. Try to take this medication at the same time each day. Do not take it on an empty stomach. Do not crush, chew, or break an extended-release tablet. Swallow it whole. Breaking the pill may cause too much of the drug to be released at one time. Alfuzosin lowers blood pressure and may cause dizziness or fainting, especially when you first start taking it, or when you start taking it again. Call your doctor if you have severe dizziness or feel like you might pass out.

You may feel very dizzy when you first wake up. Be careful when standing or sitting up from a lying position.

Your blood pressure and prostate will need to be checked often. Visit your doctor regularly.

Some things can cause your blood pressure to get too low. This includes vomiting, diarrhea, heavy sweating, heart disease, dialysis, a low-salt diet, or taking diuretics (water pills). Tell your doctor if you have a prolonged illness that causes diarrhea or vomiting.

Store at room temperature away from moisture, heat, and light.

See also: Alfuzosin dosage (in more detail)

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include extreme dizziness or fainting.

What should I avoid while taking alfuzosin?

Alfuzosin may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

To prevent dizziness, avoid standing for long periods of time or becoming overheated during exercise and in hot weather.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall. Drinking alcohol can increase certain side effects of alfuzosin.

Alfuzosin side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using alfuzosin and call your doctor at once if you have a serious side effect such as:

• 
  

  new or worsening chest pain;

  
  


• 
  

  nausea, stomach pain, low fever, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);

  
  


• 
  

  feeling like you might pass out; or

  
  


• 
  

  penis erection that is painful or lasts 4 hours or longer.

  
  

Less serious side effects may include:

• 
  

  mild dizziness;

  
  


• 
  

  headache;

  
  


• 
  

  tired feeling; or

  
  


• 
  

  cold symptoms such as stuffy nose, sneezing, sore throat.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Alfuzosin Dosing Information

Usual Adult Dose for Benign Prostatic Hyperplasia:

10 mg orally once a day immediately after the same meal each day.

What other drugs will affect alfuzosin?

Many drugs can interact with alfuzosin. Below is just a partial list. Tell your doctor if you are using:

• 
  

  atenolol (Tenormin);

  
  


• 
  

  arsenic trioxide (Trisenox);

  
  


• 
  

  cimetidine (Tagamet);

  
  


• 
  

  conivaptan (Vaprisol);

  
  


• 
  

  diltiazem (Cardizem CD, Cartia XT, Tiazac);

  
  


• 
  

  droperidol (Inapsine);

  
  


• 
  

  enoxacin (Penetrex);

  
  


• 
  

  imatinib (Gleevec);

  
  


• 
  

  isoniazid (for treating tuberculosis);

  
  


• 
  

  an antibiotic such as clarithromycin (Biaxin), dalfopristin/quinupristin (Synercid), erythromycin (E.E.S., EryPed, Ery-Tab, Erythrocin), levofloxacin (Levaquin), moxifloxacin (Avelox), pentamidine (NebuPent, Pentam); or telithromycin (Ketek);

  
  


• 
  

  an antidepressant such as amitriptylline (Elavil, Vanatrip), clomipramine (Anafranil), desipramine (Norpramin), or nefazodone;

  
  


• 
  

  an antifungal medication such as clotrimazole (Mycelex Troche) o voriconazole (Vfend);

  
  


• 
  

  anti-malaria medications such as chloroquine (Arelan) or mefloquine (Lariam);

  
  


• 
  

  a nitrate heart medication, such as nitroglycerin (Nitrostat, Nitrolingual, Nitro-Dur, Nitro-Bid, and others), isosorbide dinitrate (Dilatrate-SR, Isordil, Sorbitrate), or isosorbide mononitrate (Imdur, ISMO, Monoket);

  
  


• 
  

  heart or blood pressure medication such as diltiazem (Cartia, Cardizem), felodipine (Plendil), nifedipine (Nifedical, Procardia), verapamil (Calan, Covera, Isoptin, Verelan), and others;

  
  


• 
  

  heart rhythm medicine such as amiodarone (Cordarone, Pacerone), dofetilide (Tikosyn), disopyramide (Norpace), ibutilide (Corvert), procainamide (Pronestyl), propafenone (Rythmol), quinidine (Quin-G), or sotalol (Betapace);

  
  


• 
  

  HIV/AIDS medicine such as atazanavir (Reyataz), delavirdine (Rescriptor), fosamprenavir (Lexiva), indinavir (Crixivan), nelfinavir (Viracept), saquinavir (Invirase), or ritonavir (Norvir);

  
  


• 
  

  medicine to prevent or treat nausea and vomiting, such as dolasetron (Anzemet) or ondansetron (Zofran);

  
  


• 
  

  medicines to treat psychiatric disorders, such as chlorpromazine (Thorazine), clozapine (FazaClo, Clozaril), haloperidol (Haldol), pimozide (Orap), thioridazine (Mellaril), or ziprasidone (Geodon);

  
  


• 
  

  migraine headache medicine such as sumatriptan (Imitrex) or zolmitriptan (Zomig); or

  
  


• 
  

  narcotic medication such as methadone (Dolophine, Methadose).

  
  

This list is not complete and there are many other drugs that can interact with alfuzosin. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor. Keep a list of all your medicines and show it to any healthcare provider who treats you.

More alfuzosin resources

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

• alfuzosin Advanced Consumer (Micromedex) - Includes Dosage Information


• Alfuzosin Prescribing Information (FDA)


• Alfuzosin MedFacts Consumer Leaflet (Wolters Kluwer)


• Alfuzosin Hydrochloride Monograph (AHFS DI)


• Uroxatral Prescribing Information (FDA)


• Uroxatral Consumer Overview

Compare alfuzosin with other medications

• Benign Prostatic Hyperplasia

Where can I get more information?

• Your pharmacist can provide more information about alfuzosin.

See also: alfuzosin side effects (in more detail)

Pyrrolidine anticonvulsants

A drug may be classified by the chemical type of the active ingredient or by the way it is used to treat a particular condition. Each drug can be classified into one or more drug classes.

Pyrrolidine anticonvulsant, levetiracetam, is used in the treatment of epilepsy. The exact mechanism of action is not known but appears to slow down nerve transmission. They are used as adjunct therapy to treat partial and tonic-clonic seizures.

See also

Medical conditions associated with pyrrolidine anticonvulsants:

• Bipolar Disorder
• Epilepsy
• Hyperekplexia
• Neuralgia
• New Daily Persistent Headache
• Seizures

Drug List:

Keppra-Xr-Extended-Release-Tablets

Keppra

Fluconazole 150mg capsules

1. Name Of The Medicinal Product

Fluconazole 150 mg capsules, hard

2. Qualitative And Quantitative Composition

Each capsule, hard contains 150 mg fluconazole.

Excipient: 151.68 mg lactose/hard capsule

For a full list of excipients, see section 6.1

3. Pharmaceutical Form

Capsules, hard

Size '1' hard gelatin capsule filled with white to off-white powder and imprinted with 'E' on white to off-white opaque cap and '97' on white to off-white opaque body with yellow ink.

4. Clinical Particulars

4.1 Therapeutic Indications

Acute or recurrent vaginal candidiasis when systemic therapy is considered appropriate.

Mucosal candidal infection. These include oropharyngeal, oesophageal, mucocutaneous and non-invasive bronchopulmonary candidiasis and candiduria, in patients with compromised immune function.

Systemic candidiasis in non-neutropenic patients.

Acute cryptococcal meningitis in adults. Fluconazole can be used as maintenance therapy to prevent relapse of cryptococcal disease in patients with AIDS.

Prophylaxis of deep-seated candida infections (particularly Candida albicans) in patients with neutropenia due to bone marrow transplantation.

Consideration should be given to official guidance on the appropriate use of antifungal agents.

Paediatric use

Not all indications are applicable for paediatric patients; see details in section 4.2.

Fluconazole should not be used for tinea captis

4.2 Posology And Method Of Administration

Oral use, capsules should be swallowed whole, independent of food intake.

The dose is depending on the type and severity of the fungal infection. The treatment of infections requiring multiple dosing must be continued until clinical parameters or laboratory results show that the active fungal infection has declined. An insufficient treatment period may lead to recurrence of the active infection.

Depending on the severity of the disease and the clinical state of the patients intravenous administration may be required. It is not necessary to change the daily dose of fluconazole when changing the route of administration from intravenous to oral.

Adults:

Vaginal candidiasis: 150 mg as a single dose.

Mucous membrane candidiasis:

Oropharyngeal candidiasis: Normal daily dose: 50-100 mg for 7-14 days. Duration of treatment depends on clinical response.

Oesophageal mucocutaneous, non-invasive bronchopulmonary candidiasis and candiduria: Normal dose is 50 mg daily for 14-30 days. In severe and particular recurrent cases the dose can be increased to 100 mg.

Systemic candidiasis:

The dose in candidaemia and other invasive Candida infections is 400-800 mg on the first day and 200-400 mg daily thereafter. The dose depends on the type and severity of the infection. In most cases a loading dose of 800 mg on the first day followed by 400 mg daily thereafter may be preferable. The duration of treatment, often up to several weeks, is determined by the clinical response.

Prevention of candida infections in neutropenic patients:

400 mg once daily. Prophylaxis with fluconazole should begin in time before the appearance of expected neutropenia. Treatment should be continued for 7 days after the neutrophil counts have increased to > 1x10⁹/ l.

Cryptococcal meningitis in immunosuppressed patients: For infections with cryptococcal meningitis the usual dose is 400 mg on the first day followed by 200-400 mg once daily. Duration of treatment for cryptococcal infections depends on the clinical response, but is usually at least 6-8 weeks for cryptococcal meningitis.

For the prevention of relapse of cryptococcal meningitis in patients with AIDS, fluconazole may be administered at a daily dose of 200 mg.

Duration of maintenance treatment in AIDS patients should be carefully justified, because of the increased risk of resistance to fluconazole.

Paediatric use:

As with similar infections in adults, the duration of treatment is based on the clinical and mycological response. Fluconazole is administered as a single daily dose.

The capsules formulation may be unsuitable for children younger than 5-6 years.

For children with impaired renal function, see dosing in “Use in patients with impaired renal function”.

Children over four weeks of age:

The recommended dose of fluconazole for mucosal candidiasis is 3 mg/kg daily. A loading dose of 6 mg/kg may be used on the first day to achieve steady state levels more rapidly.

For the treatment of systemic candidiasis and cryptococcal infection, the recommended dosage is 6 - 12 mg/kg daily, depending on the severity of the disease.

For the prevention of fungal infections in immunocompromised patients considered at risk as a consequence of neutropenia following cytotoxic chemotherapy or radiotherapy, the dose should be 3 - 12 mg/kg daily, depending on the extent and duration of the induced neutropenia (see adult dosing).

A maximum dosage of 400 mg daily should not be exceeded in children.

Children four weeks of age and younger:

Neonates excrete fluconazole slowly. In the first two weeks of life the same mg/kg dosing as in older children should be used but administered every 72 hours. During weeks 3 - 4 of life the same dose should be given every 48 hours. There are few PK data to support this Posology in term newborn babies (see section 5.2).

A maximum dosage of 12 mg/kg every 72 hours should not be exceeded in children below two weeks of life. For children between 3 - 4 weeks of life 12 mg/kg every 48 hours should not be exceeded.

The pharmacokinetics of fluconazole has not been studied in children with renal insufficiency.

Use in the elderly

The normal dose should be used if there is no evidence of renal impairment. In patients with renal impairment (creatinine clearance less than 50 ml/min) the dosage schedule should be adjusted as described below.

Use in patients (adults and paediatric) with impaired renal function

Fluconazole is excreted predominantly in the urine as unchanged drug. No adjustments in single dose therapy are required. In patients with impaired renal function who will receive multiple doses of fluconazole, the normal recommended dose (according to indication) should be given on day 1 and 2, followed by a daily dose based on the following table:

Creatinine clearance (ml/min.)	Percentage of recommended dose
>50	100%
	50%
Regular dialysis	100% after each dialysis

The pharmacokinetics of fluconazole has not been studied in children with renal insufficiency.

4.3 Contraindications

• Hypersensitivity to fluconazole or to related azole compounds or to any of the excipients.

• Co-administration of terfenadine is contra-indicated in patients receiving fluconazole at multiple doses of 400 mg per day or higher based upon results of a multiple dose interaction study.

• Co-administration of other drugs known to prolong the QT interval and which are metabolised via the enzyme CYP3A4 such as cisapride, astemizole, pimozide and quinidine are contra-indicated in patients receiving fluconazole (see sections 4.4 and 4.5).

4.4 Special Warnings And Precautions For Use

Fluconazole should be administered with caution to patients with liver dysfunction (see also section 4.2).

Fluconazole has been associated with rare cases of serious hepatic toxicity including fatalities, primarily in patients with serious underlying medical conditions. In cases of fluconazole-associated hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, sex or age of patient has been observed. Fluconazole hepatotoxicity has usually been reversible on discontinuation of therapy.

Patients who develop abnormal liver function tests during fluconazole therapy should be monitored for the development of more serious hepatic injury. Fluconazole should be discontinued if clinical signs or symptoms consistent with liver disease develop that may be attributable to fluconazole.

Patients have rarely developed exfoliative cutaneous reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, during treatment with fluconazole. AIDS patients are more prone to the development of severe cutaneous reactions to many drugs. If a rash, which is considered attributable to fluconazole, develops in a patient treated for a superficial fungal infection, further therapy with this agent should be discontinued. If patients with invasive/systemic fungal infections develop rashes, they should be monitored closely and fluconazole discontinued if bullous lesions or erythema multiforme develop.

The coadministration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored (see sections 4.3 and 4.5).

In rare cases, as with other azoles, anaphylaxis has been reported.

Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, there have been very rare cases of QT prolongation and torsade de pointes in patients taking fluconazole. These reports included seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities and concomitant medications that may have been contributory.

Fluconazole should be administered with caution to patients with these potentially proarryhthmic conditions.

Fluconazole should be administered with caution to patients with renal dysfunction (see also 4.2).

Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole treated patients who are concomitantly treated with drugs with a narrow therapeutic window metabolised through CYP2C9 and CYP3A4, should be monitored (see section 4.5).

This medicinal product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant use of the following other medicinal products is contraindicated:

Cisapride: There have been reports of cardiac events including Torsades de pointes in patients to whom fluconazole and cisapride were co-administered. A controlled study found that concomitant fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant increase in cisapride plasma levels and prolongation of QT interval. Concomitant treatment with fluconazole and Cisapride is contra-indicated (see section 4.3).

Terfenadine: Because of the occurrence of serious cardiac dysrhythmias secondary to prolongation of the QTc interval in patients receiving azole antifungals in conjunction with terfenadine, interaction studies have been performed. One study at a 200 mg daily dose of fluconazole failed to demonstrate a prolongation in QTc interval. Another study at a 400 mg and 800 mg daily dose of fluconazole demonstrated that fluconazole taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. The combined use of fluconazole at doses of 400 mg or greater with terfenadine is contraindicated (see section 4.3). The coadministration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored.

Astemizole: Concomitant administration of fluconazole with astemizole may decrease the clearance of astemizole. Resulting increased plasma concentrations of astemizole can lead to QT prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and astemizole is contraindicated.

Pimozide: Although not studied in vitro or in vivo, concomitant administration of fluconazole with pimozide may result in inhibition of pimozide metabolism. Increased pimozide plasma concentrations can lead to QT prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and pimozide is contraindicated.

Concomitant use of the following other medicinal products cannot be recommended:

Erythromycin: Concomitant use of fluconazole and erythromycin has the potential to increase the risk of cardiotoxicity (prolonged QT interval, Torsades de Pointes) and consequently sudden heart death. This combination should be avoided.

Concomitant use of the following other medicinal products lead to precautions and dose adjustments:

The effect of other medicinal products on fluconazole

Hydrochlorothiazide: In a pharmacokinetic interaction study, coadministration of multiple-dose hydrochlorothiazide to healthy volunteers receiving fluconazole increased plasma concentrations of fluconazole by 40%. An effect of this magnitude should not necessitate a change in the fluconazole dose regimen in subjects receiving concomitant diuretics, although the prescriber should bear it in mind.

Rifampicin: Concomitant administration of fluconazole and rifampicin resulted in a 25% decrease in the AUC and a 20% shorter half-life of fluconazole. In patients receiving concomitant rifampicin, an increase of the fluconazole dose should be considered.

The effect of fluconazole on other medicinal products

Fluconazole is a potent inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and a moderate inhibitor of CYP3A4. In addition to the observed /documented interactions mentioned below, there is a risk of increased plasma concentration of other compounds metabolized by CYP2C9 and CYP3A4 co-administered with fluconazole. Therefore caution should be exercised when using these combinations and the patients should be carefully monitored. The enzyme inhibiting effect of fluconazole persists 4- 5 days after discontinuation of fluconazole treatment due to the long half-life of fluconazole (See section 4.3).

Alfentanil: A study observed a reduction in clearance and distribution volume as well as prolongation of T_½ of alfentanil following concomitant treatment with fluconazole. A possible mechanism of action is fluconazole's inhibition of CYP3A4. Dosage adjustment of alfentanil may be necessary.

Amitriptyline, nortriptyline: Fluconazole increases the effect of amitriptyline and nortriptyline. 5- nortriptyline and/or S-amitnptyline may be measured at initiation of the combination therapy and after one week. Dosage of amitriptyline/nortriptyline should be adjusted, if necessary

Amphotericine B: Concurrent administration of fluconazole and amphotericin B in infected normal and immunosuppressed mice showed the following results: a small additive antifungal effect in systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus neoformans, and antagonism of the two drugs in systemic infection with A. fumigatus. The clinical significance of results obtained in these studies is unknown.

Anticoagulants: In an interaction study, fluconazole increased the prothrombin time (12%) after warfarin administration in healthy males. In post-marketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena) have been reported, in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. Prothrombin time in patients receiving coumarin-type anticoagulants should be carefully monitored. Dose adjustment of warfarin may be necessary.

Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects assessed the effect of a single 1200 mg oral dose of azithromycin on the pharmacokinetics of a single 800 mg oral dose of fluconazole as well as the effects of fluconazole on the pharmacokinetics of azithromycin. There was no significant pharmacokinetic interaction between fluconazole and azithromycin.

Benzodiazepines (Short Acting): Following oral administration of midazolam, fluconazole resulted in substantial increases in midazolam concentrations and psychomotor effects. This effect on midazolam appears to be more pronounced following oral administration of fluconazole than with fluconazole administered intravenously. If concomitant benzodiazepine therapy is necessary in patients being treated with fluconazole, consideration should be given to decreasing the benzodiazepine dosage, and the patients should be appropriately monitored.

Fluconazole increases the AUC of triazolam (single dose) by approximately 50%, Cmax with 20-32% and increases t½ by 25-50 % due to the inhibition of metabolism of triazolam. Dosage adjustments of triazolam may be necessary.

Carbamazepine: Fluconazole inhibits the metabolism of carbamazepine and an increase in serum carbamazepine of 30% has been observed. There is a risk of developing carbamazepine toxicity. Dosage adjustment of carbamazepine may be necessary depending on concentration measurements/effect.

Calcium Channel Blockers: Certain dihydropyridine calcium channel antagonists (nifedipine, isradipine, amlodipine and felodipine) are metabolized by CYP3A4. Fluconazole has the potential to increase the systemic exposure of the calcium channel antagonists. Frequent monitoring for adverse events is recommended.

Celecoxib: During concomitant treatment with fluconazole (200 mg daily) and celecoxib (200 mg) the celecoxib Cmax and AUC increased by 68% and 134%, respectively. Half of the celecoxib dose may be necessary when combined with fluconazole.

Ciclosporin: Fluconazole significantly increases the concentration and AUC of ciclosporin. This combination may be used by reducing the dosage of ciclosporin depending on ciclosporin concentration.

Cyclophosphamide: Combination therapy with cyclophosphamide and fluconazole results in an increase in serum bilirubin and serum creatinine. The combination may be used while taking increased consideration to the risk of increased serum bilirubin and serum creatinine.

Fentanyl: One fatal case of possible fentanyl fluconazole interaction was reported. The author judged that the patient died from fentanyl intoxication. Furthermore, in a randomized crossover study with twelve healthy volunteers it was shown that fluconazole delayed the elimination of fentanyl significantly. Elevated fentanyl concentration may lead to respiratory depression.

Halofantrine: Fluconazole can increase halofantrine plasma concentration due to an inhibitory effect on CYP3A4.

HMG-CoA reductase inhibitors: The risk of myopathy and rhabdomyolysis increases when fluconazole is coadministered with HMG-CoA reductase inhibitors metabolised through CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin. If concomitant therapy is necessary, the patient should be observed for symptoms of myopathy and rhabdomyolysis and creatinine kinase should be monitored. HMG-CoA reductase inhibitors should be discontinued if a marked increase in creatinine kinase is observed or myopathy/rhabdomyolysis is diagnosed or suspected.

Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74) which is responsible for most of the angiotensin Il-receptor antagonism which occurs during treatment with losartan. Patients should have their blood pressure monitored continuously.

Methadone: Fluconazole may enhance the serum concentration of methadone. Dosage adjustment of methadone may be necessary.

Non-steroidal anti-inflammatory drugs: The Cmax and AUC of flurbiprofen was increased by 23% and 81%, respectively, when coadministered with fluconazole compared to administration of flurbiprofen alone. Similarly, the Cmax and AUC of the pharmacologically active isomer [S-(+)-ibuprofen] was increased by 15% and 82%, respectively, when fluconazole was coadministered with racemic ibuprofen (400 mg) compared to administration of racemic ibuprofen alone.

Although not specifically studied, fluconazole has the potential to increase the systemic exposure of other NSAIDs that are metabolized by CYP2C9 (e.g. naproxen, lornoxicam, meloxicam, diclofenac). Frequent monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of dosage of NSAIDs may be needed.

Oral Contraceptives: Two pharmacokinetic studies with a combined oral contraceptive have been performed using multiple doses of fluconazole. There were no relevant effects on hormone level in the 50 mg fluconazole study, while at 200 mg daily, the AUCs of ethinyl estradiol and levonorgestrel were increased 40% and 24%, respectively. Thus, multiple dose use of fluconazole at these doses is unlikely to have an effect on the efficacy of the combined oral contraceptive.

Phenytoin: Fluconazole inhibits the hepatic metabolism of phenytoin. With coadministration, serum phenytoin concentration levels should be monitored in order to avoid phenytoin toxicity.

Prednisone: There was a case report that a liver-transplanted patient treated with prednisone developed acute adrenal cortex insufficiency when a three month therapy with fluconazole was discontinued. The discontinuation of fluconazole presumably caused an enhanced CYP3A4 activity which led to increased metabolism of prednisone. Patients on long-term treatment with fluconazole and prednisone should be carefully monitored for adrenal cortex insufficiency when fluconazole is discontinued.

Rifabutin: Fluconazole increases serum concentrations of rifabutin, leading to increase in the AUC of rifabutin up to 80%. There have been reports of uveitis in patients to whom fluconazole and rifabutin were coadministered. In combination therapy, symptoms of rifabutin toxicity should be taken into consideration.

Saquinavir: Fluconazole increases the AUC of saquinavir with approximately 50%, Cmax with approximately 55% and decreases clearance of saquinavir with approximately 50% due to inhibition of saquinavir's hepatic metabolism by CYP3A4 and inhibition of P-glycoprotein. Dosage adjustment of saquinavir may be necessary.

Sirolimus: Fluconazole increases plasma concentrations of sirolimus presumably by inhibiting the metabolism of sirolimus via CYP3A4 and P-glycoprotein. This combination may be used with a dosage adjustment of sirolimus depending on the effect/concentration measurements.

Sulfonylureas: Fluconazole has been shown to prolong the serum half-life of concomitantly administered oral sulfonylureas (e.g., chlorpropamide, glibenclamide, glipizide, tolbutamide) in healthy volunteers. Frequent monitoring of blood glucose and appropriate reduction of sulfonylurea dosage is recommended during coadministration.

Tacrolimus: Fluconazole may increase the serum concentrations of orally administered tacrolimus up to 5 times due to inhibition of tacrolimus metabolism through CYP3A4 in the intestines. No significant pharmacokinetic changes have been observed when tacrolimus is given intravenously. Increased tacrolimus levels have been associated with nephrotoxicity. Dosage of orally administered tacrolimus should be decreased depending on tacrolimus concentration.

Theophylline: In a placebo controlled interaction study, the administration of fluconazole 200 mg for 14 days resulted in an 18% decrease in the mean plasma clearance rate of theophylline. Patients who are receiving high dose theophylline or who are otherwise at increased risk for theophylline toxicity should be observed for signs of theophylline toxicity while receiving fluconazole. Therapy should be modified if signs of toxicity develop.

Vinca Alkaloids: Although not studied, fluconazole may increase the plasma levels of the vinca alkaloids (e.g. vincristine and vinblastine) and lead to neurotoxicity, which is possibly due to an inhibitory effect on CYP3A4.

Vitamin A: Based on a case-report in one patient receiving combination therapy with all-trans-retinoid acid (an acid form of vitamin A) and fluconazole, CNS related undesirable effects have developed in the form of pseudotumour cerebri, which disappeared after discontinuation of fluconazole treatment. This combination may be used but the incidence of CNS related undesirable effects should be borne in mind.

Zidovudine: Fluconazole increases Cmax and AUC of zidovudine by 85% and 75%, respectively, due to an approx. 45% decrease in oral zidovudine clearance. The half-life of zidovudine was likewise prolonged by approximately 128% following combination therapy with fluconazole. Patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions. Dosage reduction of zidovudine may be considered.

Interaction studies have shown that when oral fluconazole is coadministered with food, cimetidine, antacids or following total body irradiation for bone marrow transplantation, no clinically significant impairment of fluconazole absorption occurs.

4.6 Pregnancy And Lactation

Pregnancy

Data from several hundred pregnant women treated with standard doses (<200 mg/day) of fluconazole, administered as a single or repeated dosage in the first trimester, show no undesired effects in the foetus.

There have been reports of multiple congenital abnormalities in infants whose mothers were treated for at least three or more months with high doses (400-800 mg daily) of fluconazole for coccidioidomycosis. The relationship between fluconazole use and these events is unclear.

Animal studies show teratogenic effects (see section 5.3).

Use in pregnancy should be avoided except in patients with severe or potentially life-threatening fungal infections in whom fluconazole may be used if the anticipated benefit outweighs the possible risk to the fetus.

Lactation

Fluconazole is found in human breast milk at concentrations similar to plasma, hence its use in nursing mothers is not recommended.

4.7 Effects On Ability To Drive And Use Machines

Fluconazole has no or negligible influence on the ability to drive and use machines.

However when driving vehicles or operating machines it should be taken into account that occasionally dizziness or seizures may occur.

4.8 Undesirable Effects

Fluconazole is generally well tolerated.

In some patients, particularly those with serious underlying diseases such as AIDS and cancer, changes in renal and hematological function test results and hepatic abnormalities (see section 4.4) have been observed during treatment with fluconazole and comparative agents, but the clinical significance and relationship to treatment is uncertain.

The following frequency data are used in the evaluation of undesirable effects:

Very common: (

Common: (

Uncommon: (

Rare (

Very rare (< 1/10,000, not known (cannot be estimated from the available data)

System Organ Class	Frequency	Undesirable effects
Blood and the lymphatic system disorders	Rare	Agranulocytosis, leukopenia, neutropenia, thrombocytopenia
Immune system disorders	Rare	Anaphylaxis
Metabolism and nutrition disorders	Uncommon	Hypokalaemia
Rare	Hypertriglyceredaemia, hypercholesterolaemia
Psychiatric disorders	Uncommon	Insomnia, somnolence
Nervous system disorders	Common	Headache
Uncommon	Seizures, dizziness, paraesthesia, taste perversion
	Rare	Tremor
Ear and labyrinth disorders	Uncommon	Vertigo
Cardiac disorders	Rare	Torsade de pointes, QT prolongation
Gastrointestinal disorders	Common	Abdominal pain, diarrhoea, nausea, vomiting
Uncommon	Dyspepsia, flatulence, dry mouth
Hepato-biliary disorders	Common	Alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased
Uncommon	Cholestasis, jaundice, bilirubin increased
Rare	Hepatic failure, hepatocellular necrosis, hepatitis, hepatocellular damage
Skin and subcutaneous tissue disorders	Common	Rash
Uncommon	Pruritus, urticaria, increased sweating, drug eruption
Rare	Toxic epidermal necrolysis , Stevens-Johnson syndrome, acute generalised exanthematous-pustulosis, dermatitis exfoliative, angioedema, face oedema, alopecia
Musculoskeletal, connective tissue and bone disorders	Uncommon	Myalgia
General disorders and administration site conditions	Uncommon	Fatigue, malaise, asthenia, fever

Pediatric population: The pattern and incidence of side effects and laboratory abnormalities recorded during paediatric use are comparable to those seen in adults.

4.9 Overdose

Symptoms:

There have been reports of overdose with fluconazole and hallucination and paranoid behaviour have been concomitantly reported.

Treatment:

In the event of overdose, symptomatic treatment (with supportive measures and gastric lavage if necessary) may be adequate.

Fluconazole is largely excreted in the urine; forced volume diuresis would probably increase the elimination rate. A three-hour hemodialysis session decreases plasma levels by approximately 50%.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic Group: Antimycotics for systemic use, Triazole derivatives;

ATC code: J02AC01.

Type of action

Fluconazole is a substance, which belongs to the triazole derivative class of drugs. The agent is particularly effective against Candida species and cryptococci.

Mechanism of action

Fluconazole has a highly specific effect on cytochrome-P450-dependent fungal enzymes and is a potent and specific inhibitor of fungal sterol synthesis.

Spectrum of activity

Fluconazole has a wide spectrum of antimycotic activity. In various in-vivo animal activity studies (p.o. and i.v.), fluconazole is active in superficial and systemic infections with Candida, Cryptococcus and various dermatophytes.

Candida krusei is resistant to fluconazole. The susceptibility of Candida glabrata is variable. Candida dubliniensis is not primarily resistant but shows a high tendency towards resistance, mainly during therapy. Fluconazole has little of no activity against Aspergillus, Mucor, Microsporum and Trichophyton species.

In animal experimental models of endemic mycosis, fluconazole was shown to be effective, including in infections with Blastomyces dermatitidis, Coccidioides immitis and Histoplasma capsulatum in normal and immunosuppressed animals. As with other azoles, due to the lack of a standardised procedure, the results of in-vitro tests are of lesser significance in terms of predicting clinical efficacy than the results of in-vivo studies.

In volunteers, 200–400 mg fluconazole daily have no clinically relevant effect on endogenous serum steroid concentrations or ACTH-stimulated cortisol release.

The efficacy of fluconazole in tinea captis has been studied in 2 randomised controlled trials in a total of 878 patients, comparing fluconazole with griseofulvin. Fluconazole at 6 mg/kg/day for 6 weeks was not superior to griseofulvin administered at 11 mg/kg/day for 6 weeks. The overall success rate at 6 weeks was low (fluconazole 6 weeks: 18.3%; fluconazole 3 weeks: 14.7%; griseofulvin: 17.7%) across all the treatment groups. These findings are not inconsistent with the natural history of tinea capitis without therapy.

5.2 Pharmacokinetic Properties

Absorption:

Fluconazole is well absorbed after oral intake. The absolute bioavailability is above 90%. The oral absorption is not affected by concomitant food intake. The maximum fasting plasma concentration is reached 0.5 - 1.5 hours after dose intake.. 90% of the steady-state level is reached 4-5 days after dosing once daily.

Plasma concentration is proportional to the dose. After administration of 200 mg fluconazole, C_max is around 4.6 mg/l and plasma concentrations at steady-state after 15 days are around 10 mg/l. After administration of 400 mg of fluconazole, C_max is around 9 mg/l and plasma concentrations at steady state after 15 days are around 18 mg/l.

Intake of a double dose on day 1 results in plasma concentrations of approximate 90% of steady-state on day 2.

Distribution:

The volume of distribution corresponds to the total body water. The protein binding in plasma is low (11-12%).

The concentration in saliva corresponds to the plasma concentration. In patients with fungal meningitis the concentration of fluconazole in the cerebrospinal fluid is approximately 80% of the corresponding plasma concentration.

In stratum corneum, epidermis-dermis and in exocrine sweat higher concentrations of fluconazole are reached compared to those in serum. Fluconazole is accumulated in the stratum corneum. At a dose of 150 mg once weekly the concentration of fluconazole in stratum corneum was after 2 doses 23.4 µg/g and seven days after the second dosing it was still 7.1 µg/g..

Elimination:

Fluconazole is mainly renally excreted. Approximately 80% of the administered dose is excreted in the urine in non-metabolized form. Fluconazole clearance is proportional to the creatinine clearance. Circulating metabolites have not been demonstrated.

The half-life in plasma is approximately 30 hours.

Pharmacokinetics in Children

Pharmacokinetic data were assessed for 113 paediatric patients from 5 studies; 2 single dose studies, 2 multiple dose studies and a study in premature neonates. Data from 1 study were not interpretable due to changes in formulation partway through the study. Additional data were available from a compassionate use study.

In children, the following pharmacokinetic data have been reported:

Age Studied	Dose (mg/kg)	Half-life (hours)	AUC (μg.h/ml)
11 days - 11 months	Single IV 3 mg/kg	23	110.1
9 months - 13 years	Single - oral 2 mg/kg	25.0	94.7
9 months - 13 years	Single - oral 8 mg/kg	19.5	362.5
5 years - 15 years	Multiple IV 2 mg/kg	17.4*	67.4
5 years - 15 years	Multiple IV 4 mg/kg	15.2*	139.1
5 years - 15 years	Multiple IV 8 mg/kg	17.6*	196.7
Mean age 7 years	Multiple oral 3 mg/kg	15.5	41.6

*Denotes final day

After administration of 2 - 8 mg/kg fluconazole to children between the ages of 9 months to 15 years, an AUC of about 38 pg.h/ml was found per 1 mg/kg dose units. The average fluconazole plasma elimination half-life varied between 15 and 18 hours and the distribution volume was approximately 880 ml/kg after multiple doses. A higher fluconazole plasma elimination half-life of approximately 24 hours was found after a single dose. This is comparable with the fluconazole plasma elimination half-life after a single administration of 3 mg/kg i.v. to children of 11 days-11 months old. The distribution volume in this age group was about 950 ml/kg.

Experience with fluconazole in neonates is limited to pharmacokinetic studies in premature newborns. The mean age at first dose was 24 hours (range 9-36 hours) and mean birth weight was 0.9 Kg (range 0.75-1.10 Kg) for 12 pre-term neonates of average gestation around 28 weeks. Seven patients complet