Nucynta

Generic Name: Tapentadol Hydrochloride
Class: Opiate Agonists
ATC Class: N02AX06
VA Class: CN101
Chemical Name: 3-[(1R, 2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol monohydrochloride
Molecular Formula: C₁₄H₂₃NO HCL
CAS Number: 175591-23-8

REMS:

FDA approved a REMS for tapentadol hydrochloride to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of tapentadol hydrochloride and consists of the following: medication guide and elements to assure safe use. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Synthetic, centrally active analgesic; structurally and pharmacologically related to tramadol.^{1 6 8 9 10 15}

Uses for Nucynta

Acute Pain

Relief of moderate to severe acute pain.^{1 2 3 9}

Nucynta Dosage and Administration

Administration

Oral Administration

Administer orally without regard to food.¹

Dosage

Available as tapentadol hydrochloride; dosage expressed in terms of tapentadol.¹

Individualize dosage according to severity of pain, prior experience with similar agents, and clinician's ability to monitor the patient.¹

Adults

Acute Pain

Oral

Usually 50–100 mg administered every 4–6 hours depending on pain intensity.¹ On day 1, patients not experiencing adequate pain relief may receive a second dose as early as 1 hour following first dose.¹ Administer subsequent doses every 4–6 hours; adjust dosage to maintain adequate analgesia and minimize adverse effects.¹

Prescribing Limits

Adults

Acute Pain

Oral

Dosages >700 mg on day 1 and dosages >600 mg on subsequent days are not recommended.¹

Special Populations

Hepatic Impairment

No dosage adjustment necessary in mild hepatic impairment.¹

In patients with moderate hepatic impairment, initial dosage of 50 mg administered no more frequently than once every 8 hours (maximum 3 doses in 24 hours).¹ Adjust subsequent dosage by shortening or lengthening the dosing interval to maintain adequate analgesia and minimize adverse effects.¹

Not recommended in patients with severe hepatic impairment.¹ (See Special Populations under Pharmacokinetics: Absorption and also see under Pharmacokinetics: Elimination.)

Renal Impairment

No dosage adjustment necessary in mild or moderate renal impairment.¹ Not recommended in patients with severe renal impairment.¹ (See Special Populations under Pharmacokinetics: Elimination.)

Geriatric Patients

Because geriatric patients are more likely to have renal or hepatic impairment, consider initiating tapentadol therapy at the lower end of the usual dosage range.¹ (See Geriatric Use under Cautions.)

Cautions for Nucynta

Contraindications

• 
  

  Concurrent or recent (i.e., within 2 weeks) therapy with an MAO inhibitor.^{1 9}

  
  


• 
  

  Substantial respiratory depression in unmonitored settings or in the absence of resuscitative equipment.¹

  
  


• 
  

  Acute or severe bronchial asthma or hypercapnia in unmonitored settings or in the absence of resuscitative equipment.¹

  
  


• 
  

  Known or suspected paralytic ileus.¹

  
  

Warnings/Precautions

Opiate Agonist Precautions

May cause effects similar to those produced by other opiate agonists;^{1 2 3 9 12 13} observe many of the usual precautions of opiate agonist therapy.¹

Respiratory Depression

The major toxicity associated with opiate agonists.¹

Occurs more frequently in geriatric and debilitated patients and those with conditions accompanied by hypoxia, hypercapnia, or upper airway obstruction when even moderate therapeutic doses may dangerously decrease pulmonary ventilation.¹

Use with caution in patients having a substantially decreased respiratory reserve, hypoxia, or hypercapnia, including patients with asthma, COPD, cor pulmonale, severe obesity, sleep apnea, myxedema, kyphoscoliosis, CNS depression, or coma.¹ In such patients, even therapeutic tapentadol doses may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea.¹ Consider alternative nonopiate agonists; use tapentadol only under careful medical supervision and at the lowest effective dosage.¹

If respiratory depression occurs, follow usual guidelines for management of opiate agonist-induced respiratory depression.¹

CNS Depression

Performance of activities requiring mental alertness and physical coordination (e.g., driving, operating machinery) may be impaired, especially at the beginning of therapy, during periods of dosage adjustment, or with concomitant use of alcohol or tranquilizers.¹ (See Advice to Patients.)

Concurrent use of other CNS depressants may cause additive CNS depression, possibly resulting in respiratory depression, hypotension, profound sedation, coma, or death; if concomitant therapy is necessary, consider reducing the dosage of one or both drugs.^{1 9} (See Specific Drugs under Interactions.)

Increased Intracranial Pressure or Head Injury

The respiratory depressant effects of tapentadol (with carbon dioxide retention and secondary elevation of CSF pressure) may be markedly exaggerated in the presence of head injury or other intracranial lesions.¹

Opiate agonists produce effects (e.g., pupillary changes, altered consciousness) that may obscure neurologic signs of a further increase in pressure in patients with head injuries.¹

Use with caution in patients with head injury, intracranial lesions, or other sources of preexisting increased intracranial pressure.¹ Avoid use in patients susceptible to effects of increased CSF pressure (e.g., those with evidence of head injury and increased intracranial pressure).¹

Dependence and Abuse

Physical and psychic dependence and tolerance may develop with repeated administration; abuse potential exists.^{1 13}

Abuse potential similar to that of hydromorphone.^{1 9} Abuse of tapentadol poses a risk of overdose and death; concurrent abuse of alcohol and other substances increases risk of toxicity.¹

Consider abuse potential when prescribing or dispensing tapentadol in situations where increased risk of misuse and abuse may be present.¹ Carefully monitor all patients receiving opiate agonists for signs of abuse and addiction; however, concerns about abuse and addiction should not prevent the proper management of pain.¹

Abrupt cessation of therapy may result in withdrawal symptoms (e.g., anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and, rarely, hallucinations).^{1 6 7} To reduce symptoms, taper dosage when discontinuing the drug.¹

Seizures

Seizures reported in <1% of tapentadol-treated patients in clinical studies.¹

Not systematically evaluated in patients with seizure disorders; such patients were excluded from clinical studies.¹ Use with caution in patients with a history of seizure disorder and those at increased risk for seizures.¹ (See Advice to Patients.)

Serotonin Syndrome

Potentially life-threatening serotonin syndrome with SNRIs, including tapentadol, particularly with concurrent use of other serotonergic drugs (e.g., 5-HT₁ receptor agonists [“triptans”], SSRIs, tricyclic antidepressants) or drugs that impair serotonin metabolism (e.g., MAO inhibitors).^{1 4 5} (See Actions.)

Serotonin syndrome may occur with usual dosages of tapentadol.¹ Manifestations may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile BP, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).^{1 4 5}

Pancreatic and Biliary Disease

May cause spasm of the sphincter of Oddi.¹ Use with caution in patients with biliary tract disease, including acute pancreatitis.¹

Specific Populations

Pregnancy

Category C.¹

Effect on labor and delivery unknown.¹ Not recommended for use during and immediately prior to labor and delivery.¹ Neonates born to women who have received tapentadol should be monitored for respiratory depression and withdrawal symptoms; an opiate antagonist (e.g., naloxone) should be available to reverse opiate-induced respiratory depression in the neonate.¹

Lactation

May distribute into milk; do not use in nursing women.¹

Pediatric Use

Safety and efficacy not established in children <18 years of age.¹ Not recommended for use in this population.¹

Geriatric Use

No overall differences in efficacy of tapentadol in those ≥65 years of age compared with younger adults.¹ Incidence of constipation was higher in patients ≥65 years of age compared with those <65 years of age (12 versus 7%).¹ (See Special Populations under Pharmacokinetics: Absorption.)

Because of possible renal or hepatic impairment in geriatric patients, consider initiating therapy at the lower end of the recommended dosage range.¹

Hepatic Impairment

Higher serum tapentadol concentrations reported in patients with hepatic impairment compared with individuals without impairment.¹ (See Special Populations under Pharmacokinetics: Absorption.) Use with caution in moderate hepatic impairment.¹ Not studied and, therefore, not recommended in severe hepatic impairment.¹ (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Safety and efficacy not established in severe renal impairment; use in this population not recommended.¹ (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Nausea,^{1 2 3 7 9} dizziness,^{1 2 3 7 9} vomiting,^{1 2 3 7 9} somnolence,^{1 2 3 7 9} constipation,^{1 2 3 7} pruritus,^{1 2 3 7} dry mouth,^{1 7} hyperhidrosis,^{1 2} fatigue^{1 3 7} . In several clinical studies, adverse GI effects (nausea, vomiting, constipation) reported more commonly with oxycodone than with tapentadol.^{2 3 6 7}

Interactions for Nucynta

Metabolized primarily by glucuronidation.^{1 6 8}

Metabolized to a lesser extent by CYP isoenzymes 2C9, 2C19, and 2D6.^{1 8}

Does not induce CYP isoenzymes 1A2, 2D6, or 3A4 and does not inhibit CYP isoenzymes 1A2, 2A6, 2C9, 2C19, 2E1, or 3A4 in vitro.^{1 6 8} Inhibits CYP2D6 to a limited extent in vitro.⁸

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Clinically relevant CYP-mediated interactions are unlikely.^{1 6 8}

Drugs Associated with Serotonin Syndrome

Potential pharmacologic interaction (potentially serious, sometimes fatal serotonin syndrome) with serotonergic agents.^{1 4 5} (See Serotonin Syndrome under Cautions and see Actions.)

Protein-bound Drugs

Pharmacokinetic interaction unlikely.^{1 6 8}

Specific Drugs

Drug	Interaction	Comments
Acetaminophen	Acetaminophen did not affect pharmacokinetics of tapentadol1 14
Alcohol	Additive CNS effects causing CNS depression, cognitive/physical impairment, respiratory depression, hypotension, profound sedation, coma, death1 Increased risk of overdosage and death with concurrent abuse1	Avoid concomitant use1
Antidepressants, SSRIs or other SNRIs	Potentially life-threatening serotonin syndrome1
Antidepressants, tricyclics (TCAs)	Potentially life-threatening serotonin syndrome1
Aspirin	Aspirin did not affect pharmacokinetics of tapentadol1 14
CNS depressants (e.g., other opiate agonists, general anesthetics, antiemetics, tranquilizers, sedatives and hypnotics, phenothiazines)	Additive CNS depression with possible respiratory depression, hypotension, profound sedation, coma, or death1 9	If concomitant therapy is necessary, consider reducing dosage of one or both agents1
5-HT1 receptor agonists (“triptans”)	Potentially life-threatening serotonin syndrome1 4
MAO inhibitors	Potentially life-threatening serotonin syndrome1 Potential adverse cardiovascular effects secondary to increased norepinephrine levels1 9	Tapentadol contraindicated in patients currently receiving or having recently (within 2 weeks) received MAO inhibitors1 9
Metoclopramide	Metoclopramide did not affect pharmacokinetics of tapentadol1
Naproxen	Naproxen increased tapentadol AUC by 17%; not considered clinically relevant1 14	Dosage adjustments not necessary1
Omeprazole	Omeprazole did not affect pharmacokinetics of tapentadol1
Probenecid	Probenecid increased tapentadol AUC by 57%; not considered clinically relevant1	Dosage adjustments not necessary1

Nucynta Pharmacokinetics

Absorption

Bioavailability

Mean absolute bioavailablity is approximately 32% following a single oral dose.^{1 6} Peak plasma concentration and AUC are dose proportional over dosing range of 50–150 mg.¹ Peak plasma concentrations attained approximately 1.25 hours following oral administration.¹

Food

High-fat, high-calorie meal increases tapentadol AUC by 25% and peak plasma concentration by 16%.¹

Special Populations

Mean peak plasma tapentadol concentrations were 16% lower in geriatric patients compared with younger adults; AUCs were similar.¹

In patients with mild hepatic impairment, tapentadol AUC and peak plasma concentration were increased 1.7- and 1.4-fold, respectively; in those with moderate hepatic impairment, AUC and peak plasma concentration were increased 4.2- and 2.5-fold, respectively.¹

Distribution

Extent

Widely distributed throughout the body.¹

May distribute into human milk.¹

Plasma Protein Binding

Approximately 20%.^{1 6 8}

Elimination

Metabolism

Principally undergoes conjugation with glucuronic acid to form inactive metabolites; major inactive metabolite, tapentadol-O-glucuronide, formed via uridine diphosphate-glucuronosyltransferase enzymes (UGT) 1A9 and 2B7.^{1 6 8}

Metabolized to a lesser extent by CYP2C9 and CYP2C19 to form N-desmethyl tapentadol and by CYP2D6 to form hydroxytapentadol, both of which undergo secondary conjugation.^{1 8}

Elimination Route

Tapentadol and its metabolites are excreted primarily (99%) by the kidneys.^{1 6} Following oral administration, approximately 70% of a dose is excreted in urine as conjugates (55% as O-glucuronide and 15% as sulfate conjugate of tapentadol); 3% of a dose is eliminated as unchanged drug.^{1 6}

Half-life

Mean terminal half-life is 4 hours.¹

Special Populations

In patients with increased hepatic impairment, rate of formation of tapentadol-O-glucuronide was reduced.¹ Tapentadol half-life was increased 1.2- or 1.4-fold in patients with mild or moderate hepatic impairment, respectively.¹

In patients with mild, moderate, or severe renal impairment, AUC of tapentadol-O-glucuronide is 1.5-, 2.5-, or 5.5-fold higher, respectively, than AUC in patients with normal renal function.¹

Stability

Storage

Oral

Tablets

≤25°C (may be exposed to 15–30°C).¹ Protect from moisture.¹

Actions

• 
  

  Precise mechanism of analgesic action unknown; thought to be related to agonist activity at the μ-opiate receptor and inhibition of norepinephrine reuptake.^{1 6 7 8 9 10 16 17}

  
  


• 
  

  Also inhibits serotonin reuptake, but serotonergic activity is much lower than noradrenergic activity.^{10 16 17}

  
  


• 
  

  Inhibition of norepinephrine reuptake may work synergistically with μ-receptor activation to enhance analgesic efficacy and/or attenuate adverse effects seen with traditional opiate analgesics (e.g., GI effects) by reducing the requirement for μ-receptor activation.^{6 10}

  
  


• 
  

  Drug is 18 times less potent than morphine in μ-receptor binding in humans;¹ animal data indicate that tapentadol is almost as potent as venlafaxine in inhibiting the reuptake of norepinephrine.¹⁰

  
  


• 
  

  Tapentadol is 2–3 times less potent than morphine in producing analgesia in animals.^{1 10}

  
  


• 
  

  Possesses a reduced emetogenic potential compared with morphine and produces less physical dependence at equianalgesic doses.¹⁰

  
  


• 
  

  Abuse potential is similar to that seen with hydromorphone^{1 9} but appears to be greater than that seen with tramadol;^{9 13} tapentadol, unlike tramadol, is subject to control under the Federal Controlled Substances Act of 1970 as a scheduled drug.^{9 13}

  
  


• 
  

  Antinociceptic effect antagonized by μ-receptor antagonists (e.g., naloxone); norepinephrine reuptake inhibition sensitive to norepinephrine modulators.¹

  
  


• 
  

  Possesses weak antagonist activity for muscarinic receptors.¹⁰

  
  

Advice to Patients

• 
  

  Importance of reading the patient information (medication guide) provided by the manufacturer before initiating therapy and each time the prescription is refilled.¹

  
  


• 
  

  Importance of informing clinician of any breakthrough pain or adverse effects (e.g., constipation) that occur during therapy, so that therapy may be adjusted based on individual patient requirements.¹

  
  


• 
  

  Importance of taking tapentadol only as directed; do not increase dosage or abruptly discontinue therapy without consulting a clinician.¹

  
  


• 
  

  Importance of informing patients that tapentadol is a drug of potential abuse and also should be protected from theft.¹ Importance of informing patients that this drug should never be given to anyone other than the individual for whom it was prescribed.¹

  
  


• 
  

  Potential for tapentadol to impair mental alertness and/or physical coordination; avoid driving or operating machinery until effects on individual are known.¹

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.¹ Importance of avoiding concomitant therapy with MAO inhibitors and of not combining tapentadol with alcohol.¹

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹ Importance of avoiding breast-feeding while receiving tapentadol.¹

  
  


• 
  

  Importance of informing patients with a history of seizures that tapentadol may precipitate seizures and of advising them to use tapentadol with care.¹ Importance of advising patients to discontinue tapentadol if seizures occur and to contact their clinician immediately.¹

  
  


• 
  

  Importance of informing patients of the potential risk of serotonin syndrome with concurrent use of tapentadol and other serotonergic drugs (e.g., SSRIs, SNRIs, tricyclic antidepressants).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.

Subject to control under the Federal Controlled Substances Act of 1970 as schedule II (C-II) drug.

Tapentadol Hydrochloride

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	50 mg (of tapentadol)	Nucynta ( C-II)	Ortho-McNeil-Janssen
		75 mg (of tapentadol)	Nucynta ( C-II)	Ortho-McNeil-Janssen
		100 mg (of tapentadol)	Nucynta ( C-II)	Ortho-McNeil-Janssen

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Nucynta 50MG Tablets (JANSSEN): 20/$65.99 or 30/$98.97

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 October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Ortho-McNeil Janssen. Nucynta (tapentadol) immediate-release tablets prescribing information. Raritan, NJ; 2009 Mar.

2. Daniels SE, Upmalis D, Okamoto A et al. A randomized, double-blind, phase III study comparing multiple doses of tapentadol IR, oxycodone IR, and placebo for postoperative (bunionectomy) pain *. Curr Med Res Opin. 2009; :.

3. Hartrick C, Van Hove I, Stegmann JU et al. Efficacy and tolerability of tapentadol immediate release and oxycodone HCl immediate release in patients awaiting primary joint replacement surgery for end-stage joint disease: a 10-day, phase III, randomized, double-blind, active- and placebo-controlled study. Clin Ther. 2009; 31:260-71. [PubMed 19302899]

4. Food and Drug Administration. Public health advisory: combined use of 5-hydroxytryptamine receptor agonists (triptans), selective serotonin reuptake inhibitors (SSRIs) or selective serotonin/norepinephirne reuptake inhibitors (SNRIs) may result in life-threatening serotonin syndrome. Rockville, MD; 2006 Jul 19. From the FDA website.

5. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005; 352:1112-20. [PubMed 15784664]

6. Hartrick CT. Tapentadol immediate release for the relief of moderate-to-severe acute pain. Expert Opin Pharmacother. 2009; 10:2687-96. [PubMed 19795998]

7. Hale M, Upmalis D, Okamoto A et al. Tolerability of tapentadol immediate release in patients with lower back pain or osteoarthritis of the hip or knee over 90 days: a randomized, double-blind study. Curr Med Res Opin. 2009; 25:1095-104. [PubMed 19301989]

8. Kneip C, Terlinden R, Beier H et al. Investigations into the drug-drug interaction potential of tapentadol in human liver microsomes and fresh human hepatocytes. Drug Metab Lett. 2008; 2:67-75. [PubMed 19356073]

9. . Tapentadol (Nucynta)--a new analgesic. Med Lett Drugs Ther. 2009; 51:61-2. [PubMed 19661853]

10. Tzschentke TM, Christoph T, Kögel B et al. (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl): a novel mu-opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties. J Pharmacol Exp Ther. 2007; 323:265-76. [PubMed 17656655]

11. Ortho-McNeil Janssen, Raritan, NJ: Personal communication.

12. Daniels S, Casson E, Stegmann JU et al. A randomized, double-blind, placebo-controlled phase 3 study of the relative efficacy and tolerability of tapentadol IR and oxycodone IR for acute pain. Curr Med Res Opin. 2009; 25:1551-61. [PubMed 19445652]

13. Drug Enforcement Administration. Schedules of controlled substances: placement of tapentadol into Schedule II. 21 CFR Part 1308. Final Rule. [Docket No. DEA-319F] Fed Regist. 2009; 74:23790-3.

14. Smit JW, Oh C, Rengelshausen J et al. Effects of acetaminophen, naproxen, and acetylsalicylic acid on tapentadol pharmacokinetics: results of two randomized, open-label, crossover, drug-drug interaction studies. Pharmacotherapy. 2010; 30:25-34. [PubMed 20030470]

15. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 22-3304: Summary review for tapentadol. From FDA web site.

16. Guay DR. Is tapentadol an advance on tramadol?. Consult Pharm. 2009; 24:833-40. [PubMed 20092221]

17. Wade WE, Spruill WJ. Tapentadol hydrochloride: a centrally acting oral analgesic. Clin Ther. 2009; 31:2804-18. [PubMed 20110020]

More Nucynta resources

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

• Nucynta Prescribing Information (FDA)


• Nucynta Consumer Overview


• Nucynta Advanced Consumer (Micromedex) - Includes Dosage Information


• Nucynta MedFacts Consumer Leaflet (Wolters Kluwer)


• Tapentadol Professional Patient Advice (Wolters Kluwer)


• Nucynta ER Prescribing Information (FDA)


• Nucynta ER Extended-Release Tablets MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Nucynta with other medications

• Pain

Losartan potassium 25mg, 50mg and 100mg Film Coated tablets

Losartan potassium 25mg,

50mg and 100mg Film-coated Tablets

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 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 pharmacist.


• The full name of this medicine is Losartan potassium 25mg, 50mg and 100mg Film-coated Tablets but within the leaflet it will be referred to as Losartan tablets.

In this leaflet:

1 What Losartan tablets are and what they are used for

2 Before you take

3 How to take

4 Possible side effects

5 How to store

6 Further information

What Losartan tablets are and what they are used for

Losartan belongs to a group of medicines known as angiotensin-II receptor antagonists.

Angiotensin-II is a substance produced in the body which binds to receptors in blood vessels, causing them to tighten. This results in an increase in blood pressure. Losartan prevents the binding of angiotensin-II to these receptors, causing the blood vessels to relax which in turn lowers the blood pressure.

Losartan tablets are used to treat patients with high blood pressure (hypertension).

Losartan tablets may also be prescribed to treat conditions not listed in this leaflet. If you have any questions, ask your doctor or pharmacist.

Before you take

Do not take Losartan tablets if you:

• are allergic (hypersensitive) to losartan or to any of its other ingredients


• have severe liver problems


• are more than 3 months pregnant (It is also better to avoid Losartan tablets in early pregnancy – see pregnancy section).

Take special care with Losartan tablets

It is important to tell your doctor before taking Losartan tablets if you:

• have had a history of angio-oedema (swelling of the face, lips, throat, and/or tongue) (see also section 4 ‘Possible side effects’)


• suffer from excessive vomiting or diarrhoea leading to an extreme loss of fluid and/or salt in your body


• take diuretics (medicines that increase the amount of water that you pass out through your kidneys) or are under dietary salt restriction leading to an extreme loss of fluid and salt in your body (see section 3 ‘Dosage in special patient groups’)


• are known to have narrowing or blockage of the blood vessels leading to your kidneys or if you have received a kidney transplant recently


• have liver problems (see sections 2 “Do not take Losartan” and 3 ‘Dosage in special patient groups’)


• suffer from heart failure with or without kidney problems or severe life threatening cardiac arrhythmias. Special caution is necessary when you are treated with a beta-blocker at the same time


• have problems with your heart valves or heart muscle


• suffer from coronary heart disease (reduced blood flow in the blood vessels of the heart) or from cerebrovascular disease (reduced blood circulation in the brain)


• suffer from primary hyperaldosteronism (a syndrome associated with increased secretion of the hormone aldosterone by the adrenal gland, causing headaches, tiredness, night time urination and high blood pressure)


• think you are (or might become) pregnant. Losartan tablets are not recommended in early pregnancy, and must not be taken if you are more than 3 months pregnant, as it may cause serious harm to your baby if used at that stage (see pregnancy section).

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 or herbal medicines and natural products.

Especially:

• other blood pressure lowering medicines as they may additionally reduce your blood pressure. Blood pressure may also be lowered by one of the following drugs/ class of drugs: tricyclic antidepressants, antipsychotics, baclofen, amifostine,


• medicines which retain potassium or may increase potassium levels (e.g. potassium supplements, potassium-containing salt substitutes or potassium-sparing medicines such as certain diuretics [amiloride, triamterene, spironolactone] or heparin),


• non-steroidal anti-inflammatory drugs such as indometacin, including cox-2-inhibitors (medicines that reduce inflammation, and can be used to help relieve pain) as they may reduce the blood lowering effect of losartan.

If your kidney function is impaired, the concomitant use of these medicines may lead to a worsening of the kidney function.

Lithium containing medicines should not be taken in combination with losartan without close supervision by your doctor. Special precautionary measures (e.g. blood tests) may be appropriate.

Taking Losartan tablets with food and drink

Losartan tablets may be taken with or without food.

Pregnancy and breast-feeding

Pregnancy

You must tell your doctor if you think you are (or might become) pregnant. Your doctor will normally advise you to stop taking Losartan tablets before you become pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of Losartan tablets. Losartan tablets are not recommended in early pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious harm to your baby if used after the third month of pregnancy.

Breastfeeding

Tell your doctor if you are breast-feeding or about to start breastfeeding. Losartan tablets are not recommended for mothers who are breast-feeding, and your doctor may choose another treatment for you if you wish to breast-feed, especially if your baby is newborn, or was born prematurely.

Use in children and adolescents

Losartan tablets have been studied in children, for more information, talk to your doctor.

Driving and using machines

No studies on the effects on the ability to drive and use machines have been performed.

Losartan tablets are unlikely to affect your ability to drive or use machines. However, as with many other medicines used to treat high blood pressure, losartan may cause dizziness or drowsiness in some people. If you experience dizziness or drowsiness, you should consult your doctor before attempting such activities.

How to take

Always take Losartan tablets exactly as your doctor has instructed you. Your doctor will decide on the appropriate dose of Losartan tablets, depending on your condition and whether you are taking other medicines.

It is important to continue taking Losartan tablets for as long as your doctor prescribes it in order to maintain smooth control of your blood pressure.

Dose:

Treatment usually starts with 50mg once a day. The maximum blood pressure lowering effect should be reached 3-6 weeks after beginning treatment. In some patients the dose may later be increased to 100mg once daily.

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

Dosage in special patient groups

The doctor may advise a lower dose, especially when starting treatment in certain patients such as those treated with diuretics in high doses, in patients with liver impairment, or in patients over the age of 75 years. The use of losartan is not recommended in patients with severe hepatic impairment (see section “Do not take losartan”).

Administration

The tablets should be swallowed with a glass of water. You should try to take your daily dose at about the same time each day. It is important that you continue to take Losartan tablets until your doctor tells you otherwise.

If you take more Losartan tablets than you should

If you accidentally take too many tablets, or a child swallows some, contact your doctor immediately. Symptoms of overdose are low blood pressure, increased heartbeat, possibly decreased heartbeat.

If you forget to take Losartan tablets

If you accidentally miss a daily dose, just take the next dose as normal. Do not take a double dose to make up for a forgotten tablet. If you have any further questions on the use of this product, ask your doctor or pharmacist.

Possible side effects

Like all medicines, Losartan tablets can cause side effects, although not everybody gets them.

Stop taking losartan tablets and tell your doctor immediately or go to the casualty department of your nearest hospital if you experience the following signs of a severe allergic reaction:

a rash, itching, swelling of the face, lips, mouth or throat that may cause difficulty in swallowing or breathing.

This is a serious but rare side effect, which affects more than 1 out of 10,000 patients but fewer than 1 out of 1,000 patients. You may need urgent medical attention or hospitalisation.

Tell your doctor if you notice any of the following side effects or notice any other effects not listed:

Common (less than 1 in 10 users)

• dizziness, weakness, tiredness


• low blood pressure


• low blood sugar (hypoglycaemia)


• high levels of potassium in the blood (hyperkalaemia).

Uncommon (less than 1 in 100 users)

• drowsiness, sleep disorders


• headache


• feeling of increased heart rate (palpitations)


• severe chest pain (angina pectoris)


• low blood pressure (especially after excessive loss of water from within blood vessels e.g. in patients with severe heart failure or under treatment with high dose diuretics)


• dizziness or fainting when standing up due to low blood pressure (orthostatic hypotension)


• shortness of breath


• abdominal pain, severe constipation, diarrhoea


• feeling or being sick


• hives, itching or rash


• localised swelling (oedema).

Rare: (less than 1 in 1000 users)

• inflammation of blood vessels (vasculitis including Henoch- Schonlein purpura)


• numbness or tingling sensation (paraesthesia)


• fainting


• very rapid and irregular heartbeat (artrial fibrillation) or stroke


• inflammation of the liver (hepatitis, causing tiredness or stomach, muscle or joint pain)


• elevated blood alanine aminotransferase (ALT) levels, usually resolved upon stopping treatment.

Not known: (cannot be estimated from the available data)

• reduced number of red blood cells (anaemia) or platelets (thrombocytopenia)


• migraine


• cough, flu-like symptoms


• liver function abnormalities (seen in blood tests)


• muscle and joint pain


• changes in kidney function (may be reversible upon discontinuation of treatment) including kidney failure


• increase in blood urea


• serum creatinine and serum potassium in patients with heart failure


• back pain and urinary track infection.

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

How to store

Keep out of the reach and sight of children.

Do not use Losartan tablets after the expiry date which is stated on the blister and carton. The expiry date refers to the last day of that month.

25mg: Store in the original package in order to protect from light.

50/100mg: Do not store above 25 °C. Store in the original package in order to protect from light.

Tablet containers: Do not require any special storage requirements.

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 Losartan tablets contains

• The active substance is losartan. Each tablet contains either 25mg, 50mg or 100mg of losartan potassium.


• The other ingredients are:
  Tablet core: mannitol, microcystalline cellulose, croscarmellose sodium, povidone K29/32, magnesium stearate.
  Tablet film coating: Hypromellose 6, titanium dioxide (E171), talc, propylene glycol.

What Losartan tablets look like and contents of the pack

Appearance of the tablets:

25mg: White, round biconvex, coated tablets, no score, marked 2 L, size: 8mm

50mg: White, round biconvex, scored, coated tablets, marked 3 L, size: 10mm

100mg: White, oval biconvex, scored, coated tablets, marked 4 L, size: 18.3mm x 9.2mm

Pack sizes:

Blister packs: 7, 10, 14, 15, 20, 21, 28, 30, 50, 56, 98, 100, 210 film-coated tablets

Clinic pack: 280 film-coated tablets.

Tablet container: 100, 250 tablets

Not all pack sizes may be marketed

Marketing Authorisation Holder

Actavis Group hf.

Reykjavíkurvegur 76-78

220 Hafnarfjörður

Iceland

Manufacturers

Actavis hf.

Reykjavíkurvegur 76

IS-222 Hafnarfjörður

Iceland

Balkanpharma - Dupnitsa AD

3 Samokovsko Str.

Dupnitsa 2600

Bulgaria

This leaflet was last revised in April 2010

If you would like a leaflet with larger text, please contact 01271 311257.

Actavis

Barnstaple

EX32 8NS

UK

L18829CIP-30

Diflucan Capsules 50mg and 200mg, Powder for Oral Suspension 50mg / 5ml and 200mg / 5ml, Intravenous Infusion 2mg / ml

1. Name Of The Medicinal Product

DIFLUCAN™ POWDER FOR ORAL SUSPENSION 50MG/5ML

DIFLUCAN™ POWDER FOR ORAL SUSPENSION 200MG/5ML

DIFLUCAN™ INTRAVENOUS INFUSION 2MG/ML

2. Qualitative And Quantitative Composition

Diflucan contains as its active ingredient fluconazole as 50mg or 200mg per 5ml as powder for oral suspension on reconstitution with water, and as 2mg/ml in a saline solution for intravenous infusion.

3. Pharmaceutical Form

Diflucan Powder for Oral Suspension is a dry white to off-white powder which yields, on reconstitution with water (24ml), an orange flavoured suspension containing the equivalent of 50mg or 200mg fluconazole per 5ml.

Diflucan Intravenous Infusion 2mg/ml is available in a 0.9% aqueous sodium chloride solution, presented in glass infusion vials (25 or 100ml).

4. Clinical Particulars

4.1 Therapeutic Indications

Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly.

Diflucan is indicated for the treatment of the following conditions:

1. Genital candidiasis. Vaginal candidiasis, acute or recurrent. Candidal balanitis. The treatment of partners who present with symptomatic genital candidiasis should be considered.

2. Mucosal candidiasis. These include oropharyngeal, oesophageal, non-invasive bronchopulmonary infections, candiduria, mucocutaneous and chronic oral atrophic candidiasis (denture sore mouth). Normal hosts and patients with compromised immune function may be treated.

3. Tinea pedis, tinea corporis, tinea cruris, tinea versicolor and dermal Candida infections. Diflucan is not indicated for nail infections and tinea capitis.

4. Systemic candidiasis including candidaemia, disseminated candidiasis and other forms of invasive candidal infection. These include infections of the peritoneum, endocardium and pulmonary and urinary tracts. Candidal infections in patients with malignancy, in intensive care units or those receiving cytotoxic or immunosuppressive therapy may be treated.

5. Cryptococcosis, including cryptococcal meningitis and infections of other sites (e.g. pulmonary, cutaneous). Normal hosts, and patients with AIDS, organ transplants or other causes of immunosuppression may be treated. Diflucan can be used as maintenance therapy to prevent relapse of cryptococcal disease in patients with AIDS.

6. For the prevention of fungal infections in immunocompromised patients considered at risk as a consequence of neutropenia following cytotoxic chemotherapy or radiotherapy, including bone marrow transplant patients.

4.2 Posology And Method Of Administration

Diflucan may be administered either orally or by intravenous infusion at a rate of approximately 5-10ml/min, the route being dependent on the clinical state of the patient. On transferring from the intravenous route to the oral route or vice versa, there is no need to change the daily dose. Diflucan intravenous infusion is formulated in 0.9% sodium chloride solution, each 200mg (100ml bottle) containing 15mmol each of Na⁺ and Cl^-.

The daily dose of Diflucan should be based on the nature and severity of the fungal infection. Most cases of vaginal candidiasis respond to single dose therapy. Therapy for those types of infections requiring multiple dose treatment should be continued until clinical parameters or laboratory tests indicate that active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. Patients with AIDS and cryptococcal meningitis usually require maintenance therapy to prevent relapse.

Use in adults

1. Candidal vaginitis or balanitis - 150mg single oral dose.

2. Mucosal Candidiasis

Oropharyngeal candidiasis - the usual dose is 50mg once daily for 7 - 14 days. Treatment should not normally exceed 14 days except in severely immunocompromised patients.

For atrophic oral candidiasis associated with dentures - the usual dose is 50mg once daily for 14 days administered concurrently with local antiseptic measures to the denture.

For other candidal infections of mucosa except genital candidiasis (see above), e.g. oesophagitis, non-invasive bronchopulmonary infections, candiduria, mucocutaneous candidiasis etc., the usual effective dose is 50mg daily, given for 14 - 30 days.

In unusually difficult cases of mucosal candidal infections the dose may be increased to 100mg daily.

3. For tinea pedis, corporis, cruris, versicolor and dermal Candida infections the recommended dosage is 50mg once daily. Duration of treatment is normally 2 to 4 weeks but tinea pedis may require treatment for up to 6 weeks. Duration of treatment should not exceed 6 weeks.

4. For candidaemia, disseminated candidiasis and other invasive candidal infections the usual dose is 400mg on the first day followed by 200mg daily. Depending on the clinical response the dose may be increased to 400mg daily. Duration of treatment is based upon the clinical response.

5a. For cryptococcal meningitis and cryptococcal infections at other sites, the usual dose is 400mg on the first day followed by 200mg - 400mg once daily. Duration of treatment for cryptococcal infections will depend on the clinical and mycological response, but is usually at least 6-8 weeks for cryptococcal meningitis.

5b. For the prevention of relapse of cryptococcal meningitis in patients with AIDS, after the patient receives a full course of primary therapy, Diflucan may be administered indefinitely at a daily dose of 100 - 200mg.

6. 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 50 to 400mg once daily, based on the patient's risk for developing fungal infection. For patients at high risk of systemic infection, e.g. patients who are anticipated to have profound or prolonged neutropenia such as during bone marrow transplantation, the recommended dose is 400mg once daily. Diflucan administration should start several days before the anticipated onset of neutropenia, and continue for 7 days after the neutrophil count rises above 1000 cells per mm³.

Use in children

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

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

For the treatment of systemic candidiasis and cryptococcal infections, the recommended dosage is 6-12mg/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 3-12mg/kg daily, depending on the extent and duration of the induced neutropenia (see adult dosing).

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

Despite extensive data supporting the use of Diflucan in children there are limited data available on the use of Diflucan for genital candidiasis in children below 16 years. Use at present is not recommended unless antifungal treatment is imperative and no suitable alternative agent exists.

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 and 4 of life, the same dose should be given every 48 hours.

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

To facilitate accurate measurement of doses less than 10mg, Diflucan should only be administered to children in hospital using the 50mg/5ml suspension orally or the intravenous infusion, depending on the clinical condition of the child. A suitable measuring device should be used for administration of the suspension. Once reconstituted the suspension should not be further diluted.

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 50ml/min) the dosage schedule should be adjusted as described below.

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

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

Compatibility of intravenous infusion

Although further dilution is unnecessary Diflucan Intravenous Infusion is compatible with the following administration fluids:

a) Dextrose 20%

b) Ringer's solution

c) Hartmann's solution

d) Potassium chloride in dextrose

e) Sodium bicarbonate 4.2%

f) Normal saline (0.9%)

Diflucan may be infused through an existing line with one of the above listed fluids. No specific incompatibilities have been noted, although mixing with any other drug prior to infusion is not recommended.

4.3 Contraindications

Diflucan should not be used in patients with known hypersensitivity to fluconazole or to related azole compounds or any other ingredient in the formulation.

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 contraindicated in patients receiving fluconazole (see sections 4.4 Special Warnings and Special Precautions for Use and 4.5 Interaction with Other Medicaments and Other Forms of Interaction).

4.4 Special Warnings And Precautions For Use

In some patients, particularly those with serious underlying diseases such as AIDS and cancer, abnormalities in haematological, hepatic, renal and other biochemical function test results have been observed during treatment with Diflucan but the clinical significance and relationship to treatment is uncertain.

Very rarely, patients who died with severe underlying disease and who had received multiple doses of Diflucan had post-mortem findings which included hepatic necrosis. These patients were receiving multiple concomitant medications, some known to be potentially hepatotoxic, and/or had underlying diseases which could have caused the hepatic necrosis.

In cases of hepatotoxicity, no obvious relationship to total daily dose of Diflucan, duration of therapy, sex or age of the patient has been observed; the abnormalities have usually been reversible on discontinuation of Diflucan therapy.

As a causal relationship with Diflucan cannot be excluded, patients who develop abnormal liver function tests during Diflucan therapy should be monitored for the development of more serious hepatic injury. Diflucan should be discontinued if clinical signs or symptoms consistent with liver disease develop during treatment with Diflucan.

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 develops in a patient treated for a superficial fungal infection which is considered attributable to Diflucan, further therapy with this agent should be discontinued. If patients with invasive/systemic fungal infections develop rashes, they should be monitored closely and Diflucan discontinued if bullous lesions or erythema multiforme develop.

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. Although the association of fluconazole and QT-prolongation has not been fully established, fluconazole should be used with caution in patients with potentially proarrythmic conditions such as:

• Congenital or documented acquired QT prolongation

• Cardiomyopathy, in particular when heart failure is present

• Sinus bradycardia

• Existing symptomatic arrythmias

• Concomitant medication not metabolized by CY34A but known to prolong QT interval

• Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalaemia

(See Section 4.5 Interactions with other medical products and other forms of interaction)

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The following drug interactions relate to the use of multiple-dose fluconazole, and the relevance to single-dose 150mg fluconazole has not yet been established.

Concomitant use of the following other medicinal products is contraindicated:

Cisapride: There have been reports of cardiac events including Torsade de Pointes in patients to whom fluconazole and cisapride were coadministered. 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 contraindicated (see section 4.3 Contraindications).

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 Contraindications). 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:

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

Hydrochlorothiazide In a kinetic interaction study, co-administration 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.

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 T½ 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 melaena) 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.

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 markedincrease 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 maybe needed.

Oral contraceptives Two kinetic studies with combined oral contraceptives have been performed using multiple doses of fluconazole. There were no relevant effects on either hormone level in the 50mg fluconazole study, while at 200mg daily the AUCs of ethinyloestradiol 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.

In a 300 mg once weekly fluconazole study, the AUCs of ethinyl estradiol and norethindrone were increased by 24% and 13%, respectively.

Endogenous steroid Fluconazole 50mg daily does not affect endogenous steroid levels in females: 200-400mg daily has no clinically significant effect on endogenous steroid levels or on ACTH stimulated response in healthy male volunteers.

Phenytoin Concomitant administration of fluconazole and phenytoin may increase the levels of phenytoin to a clinically significant degree. If it is necessary to administer both drugs concomitantly, phenytoin levels should be monitored and the phenytoin dose adjusted to maintain therapeutic levels.

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 There have been reports that an interaction exists when fluconazole is administered concomitantly with rifabutin, leading to increased serum levels of rifabutin. There have been reports of uveitis in patients to whom fluconazole and rifabutin were co-administered. Patients receiving rifabutin and fluconazole concomitantly should be carefully monitored.

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.

Sulphonylureas Fluconazole has been shown to prolong the serum half-life of concomitantly administered oral sulphonylureas (chlorpropamide, glibenclamide, glipizide and tolbutamide) in healthy volunteers. Fluconazole and oral sulphonylureas may be co-administered to diabetic patients, but the possibility of a hypoglycaemic episode should be borne in mind.

Tacrolimus There have been reports that an interaction exists when fluconazole is administered concomitantly with tacrolimus, leading to increased serum levels of tacrolimus. There have been reports of nephrotoxicity in patients to whom fluconazole and tacrolimus were co-administered. Patients receiving tacrolimus and fluconazole concomitantly should be carefully monitored.

Theophylline In a placebo controlled interaction study, the administration of fluconazole 200mg for 14 days resulted in an 18% decrease in the mean plasma clearance of theophylline. Patients who are receiving high doses of theophylline or who are otherwise at increased risk for theophylline toxicity should be observed for signs of theophylline toxicity while receiving fluconazole, and the therapy modified appropriately 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 Two kinetic studies resulted in increased levels of zidovudine most likely caused by the decreased conversion of zidovudine to its major metabolite. One study determined zidovudine levels in AIDS or ARC patients before and following fluconazole 200mg daily for 15 days. There was a significant increase in zidovudine AUC (20%). A second randomised, two-period, two-treatment cross-over study examined zidovudine levels in HIV infected patients. On two occasions, 21 days apart, patients received zidovudine 200mg every eight hours either with or without fluconazole 400mg daily for seven days. The AUC of zidovudine significantly increased (74%) during co-administration with fluconazole. Patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions.

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

Physicians should be aware that drug-drug interaction studies with other medications have not been conducted, but that such interactions may occur.

4.6 Pregnancy And Lactation

Use during 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 being treated for 3 or more months with high dose (400-800 mg/day) fluconazole therapy for coccidioidomycosis. The relationship between fluconazole and these events is unclear.

Animal studies show teratogenic effects (see section 5.3).

Accordingly, Diflucan should not be used in pregnancy, or in women of childbearing potential unless adequate contraception is employed.

Use during 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

When driving vehicles or operating machines it should be taken into account thatoccasionally dizziness or seizures may occur.

4.8 Undesirable Effects

Fluconazole is generally well tolerated. The most common undesirable effects observed during clinical trials and associated with fluconazole are:

Nervous System Disorders: Headache.

Skin and Subcutaneous Tissue Disorders: Rash.

Gastrointestinal Disorders: Abdominal pain, diarrhoea, flatulence, nausea.

In some patients, particularly those with serious underlying diseases such as AIDS and cancer, changes in renal and haematological function test results and hepatic abnormalities have been observed during treatment with fluconazole and comparative agents, but the clinical significance and relationship to treatment is uncertain (see Section 4.4 “Special warnings and special precautions for use”).

Hepatobiliary Disorders: Hepatic toxicity including rare cases of fatalities, elevated alkaline phosphatase, elevated bilirubin, elevated SGOT, elevated SGPT.

In addition, the following undesirable effects have occurred during post-marketing:

Nervous System Disorders: Dizziness, seizures, taste perversion.

Skin and Subcutaneous Tissue Disorders: Alopecia, exfoliative skin disorders including Stevens-Johnson syndrome and toxic epidermal necrolysis.

Gastrointestinal Disorders: Dyspepsia, vomiting.

Blood and Lymphatic System Disorders: Leukopenia including neutropenia and agranulocytosis, thrombocytopenia.

Immune System Disorders:

Allegic reaction: Anaphylaxis (including angioedema, face oedema, pruritus), urticaria.

Hepatobiliary Disorders: Hepatic failure, hepatitis, hepatocellular necrosis, jaundice.

Metabolism and Nutrition Disorders: Hypercholesterolaemia, hypertriglyceridaemia, hypokalaemia.

Cardiac Disorders: QT prolongation, torsade de pointes (see section 4.4 Special Warnings and Special Precautions for Use).

4.9 Overdose

There have been reports of overdosage with fluconazole and in one case, a 42 year-old patient infected with human immunodeficiency virus developed hallucinations and exhibited paranoid behaviour after reportedly ingesting 8200mg of fluconazole, unverified by his physician. The patient was admitted to the hospital and his condition resolved within 48 hours.

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

As fluconazole is largely excreted in the urine, forced volume diuresis would probably increase the elimination rate. A three hour haemodialysis session decreases plasma levels by approximately 50%.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Triazole derivatives, ATC code J02AC.

Fluconazole, a member of the triazole class of antifungal agents, is a potent and selective inhibitor of fungal enzymes necessary for the synthesis of ergosterol.

Fluconazole shows little pharmacological activity in a wide range of animal studies. Some prolongation of pentobarbital sleeping times in mice (p.o.), increased mean arterial and left ventricular blood pressure and increased heart rate in anaesthetised cats (i.v.) occurred. Inhibition of rat ovarian aromatase was observed at high concentrations.

Both orally and intravenously administered fluconazole was active in a variety of animal fungal infection models. Activity has been demonstrated against opportunistic mycoses, such as infections with Candida spp. including systemic candidiasis in immunocompromised animals; with Cryptococcus neoformans, including intracranial infections; with Microsporum spp. and with Trichophyton spp. Fluconazole has also been shown to be active in animal models of endemic mycoses, including infections with Blastomyces dermatitides; with Coccidoides immitis, including intracranial infection and with Histoplasma capsulatum in normal and immunosuppressed animals.

There have been reports of cases of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to fluconazole (e.g. Candida krusei). Such cases may require alternative antifungal therapy. Fluconazole is highly specific for fungal cytochrome P-450 dependent enzymes. Fluconazole 50mg daily given up to 28 days has been shown not to affect testosterone plasma concentrations in males or steroid concentrations in females of child-bearing age. Fluconazole 200-400mg daily has no clinically significant effect on endogenous steroid levels or on ACTH stimulated response in healthy male volunteers. Interaction studies with antipyrine indicate that single or multiple doses of fluconazole 50mg do not affect its metabolism.

The efficacy of fluconazole in tinea capitis 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 week 6 was low (fluconazole 6 weeks: 18.3%; fluconazole 3 weeks: 14.7%; griseofulvin: 17.7%) across all treatment groups. These findings are not inconsistent with the natural history of tinea capitis without therapy.

5.2 Pharmacokinetic Properties

The pharmacokinetic properties of fluconazole are similar following administration by the intravenous or oral route. After oral administration fluconazole is well absorbed and plasma levels (and systemic bioavailability) are over 90% of the levels achieved after intravenous administration. Oral absorption is not affected by concomitant food intake. Peak plasma concentrations in the fasting state occur between 0.5 and 1.5 hours post-dose with a plasma elimination half-life of approximately 30 hours. Plasma concentrations are proportional to dose. Ninety percent steady-state levels are reached by day 4 -5 with multiple once daily dosing.

Administration of a loading dose (on day 1) of twice the usual daily dose enables plasma levels to approximate to 90% steady-state levels by day 2. The apparent volume of distribution approximates to total body water. Plasma protein binding is low (11-12%).

Fluconazole achieves good penetration in all body fluids studied. The levels of fluconazole in saliva and sputum are similar to plasma levels. In patients with fungal meningitis, fluconazole levels in the CSF are approximately 80% of the corresponding plasma levels.

High skin concentrations of fluconazole, above serum concentrations, are achieved in the stratum corneum, epidermis-dermis and eccrine sweat. Fluconazole accumulates in the stratum corneum. At a dose of 50mg once daily, the concentration of fluconazole after 12 days was 73 microgram/g and 7 days after cessation of treatment the concentration was still 5.8 microgram/g .

The major route of excretion is renal, with approximately 80% of the administered dose appearing in the urine as unchanged drug. Fluconazole clearance is proportional to creatinine clearance. There is no evidence of circulating metabolites.

The long plasma elimination half-life provides the basis for single dose therapy for genital candidiasis and once daily dosing for other indications.

A study compared the saliva and plasma concentrations of a single fluconazole 100mg dose administration in a capsule or in an oral suspension by rinsing and retaining in mouth for 2 minutes and swallowing. The maximum concentration of fluconazole in saliva after the suspension was observed 5 minutes after ingestion, and was 182 times higher than the maximum saliva concentration after the capsule which occurred 4 hours after ingestion. After about 4 hours, the saliva concentrations of fluconazole were similar. The mean AUC (0-96) in saliva was significantly greater after the suspension compared to the capsule. There was no significant difference in the elimination rate from saliva or the plasma pharmacokinetic parameters for the two formulations.

Pharmacokinetics in Children

In children, the following pharmacokinetic data have been reported:

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

*Denotes final day

In premature new-borns (gestational age around 28 weeks), intravenous administration of fluconazole of 6mg/kg was given every third day for a maximum of five doses while the premature new-borns remained in the intensive care unit. The mean half-life (hours) was 74 (range 44-185) on day 1 which decreased with time to a mean of 53 (range 30-131) on day 7 and 47 (range 27-68) on day 13.The area under the curve (microgram.h/ml) was 271 (range 173-385) on day 1 and increased with a mean of 490 (range 292-734) on day 7 and decreased with a mean of 360 (range 167-566) on day 13.

The volume of distribution (ml/kg) was 1183 (range 1070-1470) on day 1 and increased with time to a mean of 1184 (range 510-2130) on day 7 and 1328 (range 1040-1680) on day 13.

5.3 Preclinical Safety Data

Reproductive Toxicity Increases in fetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 and 50mg/kg and higher doses. At doses ranging from 80mg/kg (approximately 20-60x the recommended human dose) to 320mg/kg embryolethality in rats was increased and fetal abnormalities included wavy ribs, cleft palate and abnormal cranio-facial ossification. These effects are consistent with the inhibition of oestrogen synthesis in rats and may be a result of known effects of lowered oestrogen on pregnancy, organogenesis and parturition.

Carcinogenesis Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for 24 months at doses of 2.5, 5 or 10mg/kg/day. Male rats treated with 5 and 10mg/kg/day had an increased incidence of hepatocellular adenomas.

Mutagenesis Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in 4 strains of S.typhimurium and in the mouse lymphoma L5178Y system. Cytogenetic studies in vivo (murine bone marrow cells, following oral administration of fluconazole) and in vitro