Flucytosine

Class: Pyrimidines
VA Class: AM700
CAS Number: 2022-85-7
Brands: Ancobon

Introduction

Antifungal; fluorinated pyrimidine analog structurally related to fluorouracil and floxuridine.^{120 150}

Uses for Flucytosine

Aspergillosis

Has been used in conjunction with IV amphotericin B for treatment of invasive aspergillosis† or other infections caused by Aspergillus (e.g., osteomyelitis and joint infections).^{137 148 157 167} Unclear whether concomitant amphotericin B and flucytosine offers any benefit over amphotericin B alone for treatment of invasive aspergillosis,^{157 167} and there are concerns related to possible increased risk of adverse effects.^{137 157}

Flucytosine is not included in current IDSA guidelines for treatment of aspergillosis.⁴²³ IDSA considers voriconazole the drug of choice for primary treatment of invasive aspergillosis in most patients and IV amphotericin B the preferred alternative.⁴²³

Candida Infections

Treatment of serious Candida infections, including urinary tract or pulmonary infections, candidemia, endocarditis, meningitis, and endophthalmitis.^{108 120 133 146 167 425 441} Usually used in conjunction with IV amphotericin B.^{108 120 133 146 167 425 441} Should not be used alone for systemic candidiasis or severe, life-threatening infections since it may be ineffective or result in emergence of flucytosine resistance.^{120 167 425}

For treatment of CNS candidiasis, IDSA recommends initial treatment with IV amphotericin B (with or without oral flucytosine), then follow-up treatment with fluconazole.⁴²⁵ Although not recommended as a regimen of choice, fluconazole given with flucytosine has been effective in some patients with Candida meningitis.⁴²⁵

IDSA states that oral flucytosine alone is an alternative for treatment of symptomatic candiduria caused by fluconazole-resistant Candida, but is not recommended as primary therapy for uncomplicated Candida cystitis.⁴²⁵ IV amphotericin B (with or without oral flucytosine) or oral flucytosine alone is an alternative for treatment of pyelonephritis; IV amphotericin B (with or without oral flucytosine) is an alternative for fungus balls caused by fluconazole-resistant Candida.⁴²⁵

Has been used orally or topically† for treatment of Candida ophthalmic infections† (keratitis, endophthalmitis).¹⁴⁰ IDSA states that IV amphotericin B with oral flucytosine is the regimen of choice for treatment of Candida endophthalmitis when lesions are advancing or threaten the macula.⁴²⁵ Efficacy of subconjunctival injection† of flucytosine in these infections not established.¹⁴⁰

Cryptococcosis

Treatment of serious cryptococcal infections, including pulmonary infections, septicemia, and meningitis.^{108 109 110 111 112 113 115 116 119 120 128 133 145 147 167 427 436 440 441} Should not be used alone for treatment of cryptococcosis.^{120 167 427 436 440 441}

Usually used in conjunction with IV amphotericin B for initial treatment of cryptococcal infections, especially cryptococcal meningitis in HIV-infected patients.^{108 123 128 134 135 145 167 427 436 440 441} Addition of flucytosine to the amphotericin B regimen for initial treatment may reduce the time required for sterilization of CSF in those with CNS involvement.^{107 110 111 116 118 122 427 440} Has also been used in conjunction with fluconazole for treatment of cryptococcal meningitis in HIV-infected individuals.^{166 427 441}

For treatment of cryptococcal meningitis in HIV-infected adults, adolescents, and children, CDC, NIH, IDSA, and others state that the preferred regimen is initial (induction) therapy with IV amphotericin B (conventional formulation) given in conjunction with oral flucytosine for at least 2 weeks until there is evidence of clinical improvement and negative CSF cultures after repeat lumbar puncture, then follow-up (consolidation) therapy with oral fluconazole administered for at least 8 weeks.^{108 427 436 440 441} A lipid formulation of amphotericin B (e.g., amphotericin B lipid complex, amphotericin B liposomal) could be substituted for conventional amphotericin B in this preferred regimen in patients who have or are predisposed to renal dysfunction.^{427 440 441}

Alternative regimens for treatment of cryptococcal meningitis in HIV-infected adults, adolescents, and children who cannot receive the preferred regimen are induction and consolidation therapy with IV amphotericin B (conventional or lipid formulation) given for 4–6 weeks; induction therapy with IV amphotericin B (conventional formulation) given in conjunction with oral fluconazole for at least 2 weeks until there is evidence of clinical improvement and negative CSF cultures after repeat lumbar puncture, then consolidation therapy with oral fluconazole administered for at least 8 weeks;^{108 427 440 441} induction and consolidation therapy with oral fluconazole used in conjunction with oral flucytosine for 4–6 weeks;^{108 427 440 441} or induction and consolidation therapy with oral fluconazole given for 10–12 weeks.⁴²⁷ These alternative regimens may be less effective and are recommended only in patients who cannot tolerate or have not responded to the preferred regimen.^{427 440 441}

Although data are limited, IDSA states that recommendations for treatment of CNS, pulmonary, or disseminated infections caused by Cryptococcus gattii and recommendations for secondary prophylaxis of C. gattii infections are the same as recommendations for C. neoformans infections.⁴²⁷ IDSA states that single, small cryptococcoma may be treated with oral fluconazole, but induction therapy with a regimen of conventional IV amphotericin B and oral flucytosine given for 4–6 weeks, followed by consolidation therapy with fluconazole given for 6–18 months should be considered for very large or multiple cryptococcomas caused by C. gattii.⁴²⁷ Regimens that include IV amphotericin B (conventional or liposomal formulation), flucytosine, and fluconazole have been effective in a few patients with CNS infections known to be caused by C. gattii.^{163 164 165}

Chromomycosis

Treatment of chromomycosis† (chromoblastomycosis) caused by various dematiaceous fungi (e.g., Cladosporium, Exophiala, Phialophora).^{133 138 139 143 161 167}

Optimum regimens for chromomycosis have not been identified.^{133 138 143}

Flucytosine may be a drug of choice used alone or in conjunction with another antifungal (e.g., IV amphotericin B, oral itraconazole, oral ketoconazole).^{133 137 138 139 143}

Flucytosine Dosage and Administration

Administration

Oral Administration

Administer orally.¹²⁰

Has been administered IV, but a parenteral preparation not commercially available in the US.¹⁵⁰

Nausea or vomiting associated with oral flucytosine may be reduced or avoided if each dose is administered by ingesting the capsules a few at a time over a 15-minute period.¹²⁰

Dosage

Prolonged serum flucytosine concentrations >100 mcg/mL may be associated with an increased risk of toxicity (e.g., adverse hematologic, GI, and hepatic effects),^{120 150 169 170} adjust to ensure that serum concentrations remain <100 mcg/mL.^{133 150 169 170 436} Optimal serum concentrations have not been identified,¹⁷⁰ and a variety of target ranges have been recommended.^{108 150 167 168 169 170 427 440 441}

Measure serum flucytosine concentrations after 3–5 days of therapy⁴²⁷ and whenever there is evidence of toxicity or a change in renal function.¹⁶⁸ Peak serum concentrations usually are measured using samples taken 2 hours after an oral dose.^{427 440}

AAP, CDC, NIH, IDSA, and others recommend target concentrations of 40–60 mcg/mL.^{108 150 441} For treatment of cryptococcal infections, IDSA recommends target concentrations of 30–80 mcg/mL.⁴²⁷

Pediatric Patients

General Pediatric Dosage†

Oral

50–150 mg/kg daily, administered in 4 equally divided doses at 6-hour intervals.¹⁰⁸

Candida Infections

Invasive Candidiasis (Including CNS Infections)

Oral

HIV-infected infants and children†: 100–150 mg/kg daily given in 4 equally divided doses in conjunction with IV amphotericin B.⁴⁴¹ Continue treatment for candidemia 2–3 weeks after clearance of Candida from the bloodstream is documented and neutropenia and symptoms attributable to candidemia resolve.^{425 441}

Cryptococcosis

Oral

Children with CNS or disseminated cryptococcosis†: Induction therapy with 100 mg/kg daily in 4 divided doses in conjunction with IV amphotericin B for at least 2 weeks, then consolidation therapy with oral fluconazole alone for at least 8 weeks.⁴²⁷

HIV-infected infants and children with severe pulmonary or disseminated (non-CNS) cryptococcosis†: 100 mg/kg daily in 4 divided doses in conjunction with IV amphotericin B.⁴⁴¹ Treatment duration depends on response and site and severity of infection.⁴⁴¹

HIV-infected infants, children, and adolescents with cryptococcal meningitis†: Induction therapy with 100 mg/kg daily given in 4 divided doses in conjunction with IV amphotericin B for at least 2 weeks until there is evidence of clinical improvement and negative CSF cultures after repeat lumbar puncture, then consolidation therapy with oral or IV fluconazole alone for at least 8 weeks.^{427 441}

HIV-infected infants and children with cryptococcal meningitis who cannot receive amphotericin B†: Induction therapy with 100 mg/kg daily in 4 divided doses in conjunction with oral or IV fluconazole given for at least 2 weeks, then consolidation therapy with oral or IV fluconazole alone for at least 8 weeks.⁴⁴¹

Adults

General Adult Dosage

Oral

50–150 mg/kg daily, administered in 4 equally divided doses at 6-hour intervals.¹²⁰

To reduce risk of toxicity when used in conjunction with IV amphotericin B, a low initial dosage (i.e., 75 mg/kg daily given in 4 divided doses) has been suggested.⁴³⁶ Dosage can then be adjusted based on serum flucytosine concentrations and presence or absence of amphotericin B-associated renal toxicity.⁴³⁶

Candida Infections

Treatment of CNS Candidiasis

Oral

25 mg/kg 4 times daily in conjunction with IV amphotericin B for several weeks, then follow-up therapy with fluconazole alone.⁴²⁵ Continue antifungal treatment until signs and symptoms, CSF abnormalities, and radiologic abnormalities resolve.⁴²⁵

Treatment of Symptomatic Cystitis Caused by Fluconazole-resistant Candida

Oral

25 mg/kg 4 times daily for 7–10 days.⁴²⁵

Treatment of Pyelonephritis or Fungus Balls Caused by Fluconazole-resistant Candida

Oral

Pyelonephritis: 25 mg/kg 4 times daily alone or in conjunction with IV amphotericin B for 2 weeks.⁴²⁵

Fungus balls: 25 mg/kg 4 times daily in conjunction with IV amphotericin B continued until symptoms resolve and urine cultures are negative for Candida.⁴²⁵

Treatment of Candida Endophthalmitis

Oral

Patients with advancing lesions or lesions threatening the macula: 25 mg/kg 4 times daily in conjunction with IV amphotericin B.⁴²⁵ Duration of treatment is at least 4–6 weeks as determined by repeated examinations to verify resolution.⁴²⁵

Treatment of Candida Endocarditis

IV

25 mg/kg 4 times daily in conjunction with IV amphotericin B.⁴²⁵ If infection is caused by fluconazole-susceptible strains, consider changing to follow-up therapy with oral fluconazole after patient is clinically stable and Candida have been cleared from the bloodstream.⁴²⁵

Cryptococcosis

Treatment of Cryptococcal Meningitis

Oral

HIV-infected adults: Induction therapy with 25 mg/kg 4 times daily in conjunction with IV amphotericin B given for at least 2 weeks until there is evidence of clinical improvement and negative CSF cultures after repeat lumbar puncture, then consolidation therapy with oral fluconazole alone for at least 8 weeks.^{427 440}

HIV-infected adults who cannot receive amphotericin B: Induction therapy with 25 mg/kg 4 times daily in conjunction with oral fluconazole for 4–6 weeks, then consolidation therapy with oral fluconazole alone for at least 8 weeks.^{427 440}

Special Populations

Renal Impairment

Use with extreme caution and reduce dosage.¹²⁰

Several methods of calculating flucytosine dosage for impaired renal function have been proposed.^a For greater accuracy, dosage should be based on actual serum flucytosine concentrations.^a Precise dosing is limited since flucytosine is commercially available only as 250- and 500-mg capsules.^a

Usual individual dose (12.5–37.5 mg/kg) can be administered every 12 hours in patients with Cl_cr 20–40 mL/minute, every 24 hours in those with Cl_cr 10–20 mL/minute, and every 24–48 hours or longer (as determined by serum drug concentrations) in those with Cl_cr <10 mL/minute.^a

Alternatively, consider 12–35 mg/kg at intervals equal to twice the half-life of the drug.^a In patients with Cl_cr <10 mL/minute, an initial loading dose (the usual individual dose) followed by 6–17.5 mg/kg administered at intervals equal to the half-life may be of particular value.^a

In patients undergoing hemodialysis every 48–72 hours, 20–50 mg/kg administered immediately after dialysis generally produces therapeutically effective and nontoxic peak and postdialysis serum drug concentrations.^a

Cautions for Flucytosine

Contraindications

• 
  

  Hypersensitivity to flucytosine.¹²⁰

  
  

Warnings/Precautions

Warnings

Bone Marrow Toxicity

Moderate hypoplasia of bone marrow, resulting in anemia, leukopenia, pancytopenia, thrombocytopenia, or agranulocytosis may occur.^{120 a} Eosinophilia and aplastic anemia also reported.¹²⁰

Bone marrow toxicity can be irreversible and may be fatal in immunosuppressed patients.¹²⁰

Risk of bone marrow toxicity is increased with prolonged, high serum flucytosine concentrations (i.e., ≥100 mcg/mL), particularly in renal dysfunction or during concomitant therapy with amphotericin B.^a

Use with extreme caution in bone marrow depression, including patients with hematologic disease and those who currently or previously received treatment with radiation or drugs associated with bone marrow depression.¹²⁰

Monitor hematologic function frequently during therapy.¹²⁰

Sensitivity Reactions

Hypersensitivity Reactions

Allergic reactions (including anaphylaxis) reported rarely.^{103 120}

General Precautions

Laboratory Monitoring

Prior to initiation of therapy, determine serum electrolytes (hypokalemia) and hematologic and renal status of the patient.¹²⁰

During therapy, frequently monitor hematologic, renal, and hepatic function.¹²⁰

Whenever possible, monitor serum flucytosine concentrations to minimize risk of toxicity, especially in patients with renal impairment.^{133 150} (See Dosage under Dosage and Administration.)

Specific Populations

Pregnancy

Category C.¹²⁰

Lactation

Not know whether distributed into human milk.¹²⁰ Discontinue nursing or the drug.¹²⁰

Pediatric Use

Safety and efficacy not systematically studied in children.¹²⁰

Has been used in some neonates† (with or without concomitant amphotericin B) without unusual adverse effects.¹²⁰ Hypokalemia, acidemia, anemia, and thrombocytopenia have been reported.¹²⁰

Renal Impairment

Use with extreme caution in impaired renal function because of increased risk of adverse effects.¹²⁰

Substantially eliminated by the kidneys; renal impairment may lead to drug accumulation.¹²⁰

Dosage adjustments necessary in renal impairment.¹²⁰ (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Bone marrow suppression; GI effects (anorexia, abdominal bloating or pain, diarrhea, dry mouth, duodenal ulcer, GI hemorrhage, nausea, vomiting, ulcerative colitis); renal effects; hepatic effects; CNS effects (confusion, hallucinations, psychosis).^{120 167 a}

Interactions for Flucytosine

Specific Drugs

Drug	Interaction	Comments
Amphotericin B	Possible increased risk of flucytosine toxicity; may be related to increased cellular uptake and/or decreased renal excretion of the drug124 In vitro evidence of synergistic antifungal effects against Candida and Cryptococcus neoformans120 a	When used concomitantly, especially in HIV-infected patients, carefully monitor serum flucytosine concentrations and hematologic function109 115 116 118 122 Consider initiating flucytosine at a low dosage (i.e., 75 mg/kg daily) and adjust subsequent dosage based on serum flucytosine concentrations436
Cytarabine	May antagonize antifungal activity of flucytosine120 167	Concomitant use not recommended167
Fluconazole or itraconazole	In vitro evidence of synergistic, additive, or indifferent antifungal effects with fluconazole or itraconazole against C. neoformans; no evidence of antagonism129 130 153

Flucytosine Pharmacokinetics

Absorption

Bioavailability

Rapidly and almost completely absorbed from GI tract;¹²⁰ bioavailability is 78–89%.¹²⁰

In normal renal function, peak serum flucytosine concentrations reached within 2 hours following a single 2-g oral dose.¹²⁰

Food

Food decreases rate, but not extent, of absorption.^a

Special Populations

In a limited number of neonates receiving oral flucytosine, mean time to peak serum concentrations was 2.5 hours after a dose.¹²⁰ Considerable interindividual variation in serum concentrations, not correlated with gestational age, reported in neonates.¹²⁰

Peak serum concentrations are higher, more prolonged, and reached more slowly in impaired renal function.

In anephric patients, peak serum concentrations may be 50% higher than in patients with normal renal function.^a

Distribution

Extent

Widely distributed into body tissues and fluids including liver, kidney, spleen, heart, aqueous humor, and bronchial secretions.^a

Distributed into CSF;¹²⁰ concentrations in CSF may be 60–100% of serum concentrations.^a

Not known whether distributed into milk.^a

Plasma Protein Binding

2–4% bound to serum proteins.^a

Elimination

Metabolism

Only minimal amounts are metabolized.^a Deaminated (probably by gut bacteria) to fluorouracil.¹²⁰ AUC ratio of fluorouracil to flucytosine is 4%.¹²⁰

Elimination Route

>75–90% of an oral dose excreted unchanged in urine.^a

Unabsorbed flucytosine excreted unchanged in feces.^a

Removed by peritoneal dialysis.^a

Removed by hemodialysis.^a

Half-life

2.4–6 hours in normal renal function.^a

Special Populations

In a limited number of infants, median half-life was 7.4 hours.¹²⁰

Half-life prolonged in renal impairment.^a

Half-life is 6–14 hours in those with Cl_cr 40 mL/minute, 12–15 hours in those with Cl_cr 20 mL/minute, 21–27 hours in those with Cl_cr 10 mL/minute, and 30–250 hours in those with Cl_cr <10 mL/minute.^a Half-lives up to 1160 hours have been reported when Cl_cr <2 mL/minute.^a

Stability

Storage

Oral

Capsules

25°C; may be exposed to 15–30°C.¹²⁰

Actions and SpectrumActions

• 
  

  May be fungistatic or fungicidal in action, depending on concentration of the drug.¹⁵¹

  
  


• 
  

  Appears to enter fungal cells via the action of fungal-specific cytosine permease.^{120 150 167} Inside the cell, flucytosine is converted into fluorouracil (5-FU) by cytosine deaminase and then converted into 5-fluorouridine triphosphate (FUTP).^{150 151 167} FUTP is incorporated into fungal RNA and interferes with protein synthesis.^{150 151 167}

  
  


• 
  

  Flucytosine also appears to be converted to 5-fluorodeoxyuridine monophosphate, which noncompetitively inhibits thymidylate synthetase and interferes with DNA synthesis.^{150 151 167}

  
  


• 
  

  Does not appear to have antineoplastic activity.^a

  
  


• 
  

  Active against Candida,^{120 152 162} Cryptococcus neoformans,^{120 152 153 162} C. gattii,^{158 162} and some other fungi.^a Inactive against bacteria.^a

  
  


• 
  

  Candida: Active in vitro and in vivo against C. albicans,^{152 162} C. glabrata,^{152 162} C. guilliermondii,¹⁶² C. krusei,¹⁶² C. parapsilosis,^{152 162} and C. tropicalis.^{152 162} Some strains of C. lusitaniae may be susceptible,^{154 155 162} but others are resistant.^{154 155} C. kefyr usually resistant.¹⁶²

  
  


• 
  

  Other fungi: Has some in vitro activity against Sporothrix schenckii,^a Aspergillus,^a Cladosporium,^a Exophiala,¹⁴³ and Phialophora.^a Active against some strains of Penicillium marneffei.¹⁵⁹ Has little or no activity against Coccidioides immitis, Paracoccidioides brasiliensis, Histoplasma capsulatum, Blastomyces dermatitidis, Madurella species, phycomycetes, or dermatophytes.^a

  
  


• 
  

  Resistance has been reported in some strains of Candida or Cryptococcus;^{150 151} resistant strains of Candida, C. neoformans, or Cladosporium have emerged in patients receiving oral flucytosine alone or in conjunction with IV amphotericin B.^{137 150 151}

  
  


• 
  

  Resistance can develop during prolonged monotherapy.¹²⁰ No cross-resistance between flucytosine and amphotericin B.¹²⁰

  
  

Advice to Patients

• 
  

  Advise patients that incidence and severity of nausea or vomiting may be decreased or eliminated if each dose is administered by ingesting the capsules a few at a time over a 15-minute period.¹²⁰

  
  


• 
  

  Importance of informing clinician of existing or contemplated therapy, including prescription and OTC drugs, or any concomitant illness.¹²⁰

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹²⁰

  
  


• 
  

  Importance of advising patients of other important precautionary information.¹²⁰ (See Cautions.)

  
  

Preparations

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

Flucytosine

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	250 mg	Ancobon	Valeant
		500 mg	Ancobon	Valeant

Disclaimer

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

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

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions December 2010. 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

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147. Leggiaro RJ, Kline MW, Hughes WT. Extrapulmonary cryptococcosis in children with acquired immunodeficiency syndrome. Pediatr Infect Dis J. 1991; 10:658-62. [PubMed 1923678]

148. Denning DW. Treatment of invasive aspergillosis. J Infect. 1994; 28(Suppl 1):25-33. [IDIS 329939] [PubMed 8077688]

150. Francis P, Walsh TJ. Evolving role of flucytosine in immunocompromised patients: new insights into safety and pharmacokinetics, and antifungal therapy. Clin Infect Dis. 1992; 15:1003-18. [IDIS 305999] [PubMed 1457631]

151. Alexander BD, Perfect JR. Antifungal resistance trends towards the year 2000. Implications for therapy and new approaches. Drugs. 1997; 54:657-78. [PubMed 9360056]

152. Hoban DJ, Zhanel GG, Karlowsky JA. In vitro susceptibilities of Candida and Cryptococcus neoformans isolates from blood cultures of neutropenic patients. Antimicrob Agents Chemother. 1999; 43:1463-4. [PubMed 10348771]

153. Barchiesi F, Gallo D, Caselli F et al. In-vitro interactions of itraconazole with flucytosine against clinical isolates of Cryptococcus neoformans. J Antimicrob Chemother. 1999; 44:65-70. [PubMed 10459811]

154. Favel A, Michel-Nguyen A, Chastin C et al. In-vitro susceptibility pattern of Candida lusitaniae and evaluation of the Etest method. J Antimicrob Chemother. 1997; 39:591-6. [IDIS 387158] [PubMed 9184357]

155. Pfaller MA, Messer SA, Hollis RJ. Strain delineation and antifungal susceptibilities of epidemiologically related and unrelated isolates of Candida lusitaniae. Diagn Microbiol Infect Dis. 1994; 20:127-33. [PubMed 7874879]

157. Stevens DA, Kan VL, Judson MA et al. Practice guidelines for diseases caused by Aspergillus. Clin Infect Dis. 2000; 30:696-709. [IDIS 448067] [PubMed 10770732]

158. Gomez-Lopez A, Zaragoza O, Dos Anjos Martins M et al. In vitro susceptibility of Cryptococcus gattii clinical isolates. Clin Microbiol Infect. 2008; 14:727-30. [PubMed 18558948]

159. Sar B, Boy S, Keo C et al. In vitro antifungal-drug susceptibilities of mycelial and yeast forms of Penicillium marneffei isolates in Cambodia. J Clin Microbiol. 2006; 44:4208-10. [PubMed 16971649]

160. Kirby A, Hassan I, Burnie J. Recommendations for managing Aspergillus osteomyelitis and joint infections based on a review of the literature. J Infect. 2006; 52:405-14. [PubMed 16239033]

161. Park SG, Oh SH, Suh SB et al. A case of chromoblastomycosis with an unusual clinical manifestation caused by Phialophora verrucosa on an unexposed area: treatment with a combination of amphotericin B and 5-flucytosine. Br J Dermatol. 2005; 152:560-4. [PubMed 15787829]

162. Cuenca-Estrella M, Gomez-Lopez A, Mellado E et al. Head-to-head comparison of the activities of currently available antifungal agents against 3,378 Spanish clinical isolates of yeasts and filamentous fungi. Antimicrob Agents Chemother. 2006; 50:917-21. [PubMed 16495251]

163. Okamoto K, Hatakeyama S, Itoyama S et al. Cryptococcus gattii genotype VGIIa infection in man, Japan, 2007. Emerg Infect Dis. 2010; 16:1155-7. [PubMed 20587194]

164. Grosse P, Tintelnot K, Söllner O et al. Encephalomyelitis due to Cryptococcus neoformans var gattii presenting as spinal tumour: case report and review of the literature. J Neurol Neurosurg Psychiatry. 2001; 70:113-6. [PubMed 11118259]

165. Galanis E, Hoang L, Kibsey P et al. Clinical presentation, diagnosis and management of Cryptococcus gattii cases: Lessons learned from British Columbia. Can J Infect Dis Med Microbiol. 2009; 20:23-8. [PubMed 20190892]

Itrabest

Itrabest may be available in the countries listed below.

Ingredient matches for Itrabest

Itraconazole

Itraconazole is reported as an ingredient of Itrabest in the following countries:

• Greece

International Drug Name Search

Emoquette

desogestrel and ethinyl estradiol

Dosage Form: tablets
Emoquette™

(DESOGESTREL AND ETHINYL ESTRADIOL TABLETS USP) 0.15 mg and 0.03 mg


Rx only


Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.

DESCRIPTION

Emoquette tablets provide an oral contraceptive regimen of 21 white round tablets each containing 0.15 mg desogestrel (13-ethyl-11-methylene-18, 19-dinor-17 alpha-pregn-4-en-20-yn-17-ol) and 0.03 mg ethinyl estradiol (19-nor-17 alpha-pregna-1,3,5 (10)- trien-20-yne-3, 17, diol). Inactive ingredients include colloidal silicon dioxide, hypromellose, lactose monohydrate, povidone, polyethylene glycol, pregelatinized starch, stearic acid and vitamin E. Each light-green tablet contains the following inactive ingredients: FD&C Blue No. 2 aluminum lake, hypromellose, iron oxide yellow, lactose monohydrate, magnesium stearate, polyethylene glycol, and pregelatinized starch.

Emoquette™ meets USP Dissolution Test 2.

CLINICAL PHARMACOLOGY

Pharmacodynamics

Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus, which increase the difficulty of sperm entry into the uterus, and changes in the endometrium which reduce the likelihood of implantation.

Receptor binding studies, as well as studies in animals, have shown that 3-keto-desogestrel, the biologically active metabolite of desogestrel, combines high progestational activity with minimal intrinsic androgenicity.91,92 The relevance of this latter finding in humans is unknown.

Pharmacokinetics

Desogestrel is rapidly and almost completely absorbed and converted into 3-keto-desogestrel, its biologically active metabolite. Following oral administration, the relative bioavailability of desogestrel, as measured by serum levels of 3-keto-desogestrel, is approximately 84%.

In the third cycle of use after a single dose of Emoquette, maximum concentrations of 3-keto-desogestrel of 2,805 ± 1,203 pg/mL (mean ± SD) are reached at 1.4 ± 0.8 hours. The area under the curve (AUC0-∞) is 33,858 ± 11,043 pg/mL∙hr after a single dose. At steady state, attained from at least day 19 onwards, maximum concentrations of 5,840 ± 1,667 pg/mL are reached at 1.4 ± 0.9 hours. The minimum plasma levels of 3-keto-desogestrel at steady state are 1,400 ± 560 pg/mL. The AUC0-24 at steady state is 52,299 ± 17,878 pg/mL∙hr. The mean AUC0-∞ for 3-keto-desogestrel at single dose is significantly lower than the mean AUC0-24 at steady state.

This indicates that the kinetics of 3-keto-desogestrel are non-linear due to an increase in binding of 3-keto-desogestrel to sex hormone-binding globulin in the cycle, attributed to increased sex hormone-binding globulin levels which are induced by the daily administration of ethinyl estradiol. Sex hormone-binding globulin levels increased significantly in the third treatment cycle from day 1 (150 ± 64 nmol/L) to day 21 (230 ± 59 nmol/L).

The elimination half-life for 3-keto-desogestrel is approximately 38 ± 20 hours at steady state. In addition to 3-keto-desogestrel, other phase I metabolites are 3α-OH-desogestrel, 3β-OH-desogestrel, and 3α-OH-5α-H-desogestrel. These other metabolites are not known to have any pharmacologic effects, and are further converted in part by conjugation (phase II metabolism) into polar metabolites, mainly sulfates and glucuronides.

Ethinyl estradiol is rapidly and almost completely absorbed. In the third cycle of use after a single dose of Emoquette, the relative bioavailability is approximately 83%.

In the third cycle of use after a single dose of Emoquette, maximum concentrations of ethinyl estradiol of 95 ± 34 pg/mL are reached at 1.5 ± 0.8 hours. The AUC0-∞ is 1,471 ± 268 pg/mL∙hr after a single dose. At steady state, attained from at least day 19 onwards, maximum ethinyl estradiol concentrations of 141 ± 48 pg/mL are reached at about 1.4 ± 0.7 hours. The minimum serum levels of ethinyl estradiol at steady state are 24 ± 8.3 pg/mL. The AUC0-24, at steady state is 1,117 ± 302 pg/mL∙hr. The mean AUC0-∞ for ethinyl estradiol following a single dose during treatment cycle 3 does not significantly differ from the mean AUC0-24 at steady state. This finding indicates linear kinetics for ethinyl estradiol.

The elimination half-life is 26 ± 6.8 hours at steady state. Ethinyl estradiol is subject to a significant degree of presystemic conjugation (phase II metabolism). Ethinyl estradiol escaping gut wall conjugation undergoes phase I metabolism and hepatic conjugation (phase II metabolism). Major phase I metabolites are 2-OH-ethinyl estradiol and 2-methoxy-ethinyl estradiol. Sulfate and glucuronide conjugates of both ethinyl estradiol and phase I metabolites, which are excreted in bile, can undergo enterohepatic circulation.

INDICATIONS AND USAGE

Emoquette tablets are indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception.

Oral contraceptives are highly effective. Table I lists the typical accidental pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, the IUD, and the Norplant System depends upon the reliability with which they are used. Correct and consistent use of these methods can result in lower failure rates.

In a clinical trial with Emoquette, 1,195 subjects completed 11,656 cycles and a total of 10 pregnancies were reported. This represents an overall user-efficacy (typical user-efficacy) pregnancy rate of 1.12 per 100 women-years. This rate includes patients who did not take the drug correctly.

TABLE I: PERCENTAGE OF WOMEN EXPERIENCING AN UNINTENDED PREGNANCY DURING THE FIRST YEAR OF TYPICAL USE AND THE FIRST YEAR OF PERFECT USE OF CONTRACEPTION AND THE PERCENTAGE CONTINUING USE AT THE END OF THE FIRST YEAR. UNITED STATES.

Method (1)	% of Women Experiencing an Unintended Pregnancy Within the First Year of Use		% of Women Continuing Use at One Year1
	Typical Use2 (2)	Perfect Use3 (3)	(4)
Chance6	85	85
Spermicides7	26	6	40
Periodic abstinence	25		63
Calendar		9
Ovulation Method		3
Sympto-Thermal8		2
Post-Ovulation		1
Withdrawal	19	4
Cap9
Parous Women	40	26	42
Nulliparous Women	20	9	56
Sponge
Parous Women	40	20	42
Nulliparous Women	20	9	56
Diaphragm9	20	6	56
Condom10
Female (Reality)	21	5	56
Male	14	3	61
Pill	5		71
Progestin Only		0.5
Combined		0.1
IUD
Progesterone T	2.0	1.5	81
Copper T380A	0.8	0.6	78
LNg20	0.1	0.1	81
Depo-Provera	0.3	0.3	70
Norplant and Norplant-2	0.05	0.05	88
Female Sterilization	0.5	0.5	100
Male Sterilization	0.15	0.10	100

Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%.4

Lactation Amenorrhea Method: LAM is a highly effective, temporary method of contraception.5

Source: Trussel J. Contraceptive efficacy. In Hatcher RA, Trussel J, Stewart F, Cates W, Stewart GK, Kowel D, Guest F, Contraceptive Technology: Seventeenth Revised Edition. New York, NY; Irvington Publishers, 1998.

1 Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year.

2 Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason.

3 Among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason.

4 The treatment schedule is one dose within 72 hours after unprotected intercourse, and a second dose 12 hours after the first dose. The FDA has declared the following brands of oral contraceptives to be safe and effective for emergency contraception: Ovral® (1 dose is 2 white pills), Alesse® (1 dose is 5 pink pills), Nordette® or Levlen® (1 dose is 4 yellow pills).

5 However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency of duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches 6 months of age.

6 The percents becoming pregnant in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percent who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether.

7 Foams, creams, gels, vaginal suppositories, and vaginal film.

8 Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases.

9 With spermicidal cream or jelly.

10 Without spermicides.

Emoquette has not been studied for and is not indicated for use in emergency contraception.

CONTRAINDICATIONS

Oral contraceptives should not be used in women who currently have the following conditions:

• Thrombophlebitis or thromboembolic disorders


• A past history of deep vein thrombophlebitis or thromboembolic disorders


• Cerebral vascular or coronary artery disease (current or history)


• Valvular heart disease with complications


• Severe hypertension


• Diabetes with vascular involvement


• Headaches with focal neurological symptoms


• Major surgery with prolonged immobilization


• Known or suspected carcinoma of the breast or personal history of breast cancer


• Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia


• Undiagnosed abnormal genital bleeding


• Cholestatic jaundice of pregnancy or jaundice with prior pill use


• Acute or chronic hepatocellular disease with abnormal liver function


• Hepatic adenomas or carcinomas


• Known or suspected pregnancy


• Hypersensitivity to any component of this product

WARNINGS

Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.

The use of oral contraceptives is associated with increased risks of several serious conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia, and gallbladder disease, although the risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as hypertension, hyperlipidemias, obesity and diabetes.

Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks.

The information contained in this package insert is principally based on studies carried out in patients who used oral contraceptives with formulations of higher doses of estrogens and progestogens than those in common use today. The effect of long term use of the oral contraceptives with formulations of lower doses of both estrogens and progestogens remains to be determined.

Throughout this labeling, epidemiological studies reported are of two types: retrospective or case control studies and prospective or cohort studies. Case control studies provide a measure of the relative risk of a disease, namely, a ratio of the incidence of a disease among oral contraceptive users to that among nonusers. The relative risk does not provide information on the actual clinical occurrence of a disease. Cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral contraceptive users and nonusers. The attributable risk does provide information about the actual occurrence of a disease in the population (Adapted from refs. 2 and 3 with the author’s permission). For further information, the reader is referred to a text on epidemiological methods.

1. Thromboembolic Disorders and Other Vascular Problems

a. Thromboembolism

An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. Case control studies have found the relative risk of users compared to non-users to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease.2, 3, 19-24 Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization.25 The risk of thromboembolic disease associated with oral contraceptives is not related to length of use and disappears after pill use is stopped.

Several epidemiologic studies indicate that third generation oral contraceptives including those containing desogestrel, are associated with a higher risk of venous thromboembolism than certain second generation oral contraceptives. In general, these studies indicate an approximate 2 fold increased risk, which corresponds to an additional 1 to 2 cases of venous thromboembolism per 10,000 women-years of use. However, data from additional studies have not shown this 2 fold increase in risk.

A two- to four-fold increase in relative risk of post-operative thromboembolic complications has been reported with the use of oral contraceptives.9 The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions.26 If feasible, oral contraceptives should be discontinued at least four weeks prior to and for two weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. Since the immediate postpartum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than four weeks after delivery in women who elect not to breast feed.

b. Myocardial Infarction

An increased risk of myocardial infarction has been attributed to oral contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for current oral contraceptive users has been estimated to be two to six.4-10 The risk is very low in women under the age of 30.

Smoking in combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarctions in women in their mid-thirties or older with smoking accounting for the majority of excess cases.11 Mortality rates associated with circulatory disease have been shown to increase substantially in smokers, especially in those 35 years of age and older and in nonsmokers over the age of 40 among women who use oral contraceptives (see Table II).

TABLE II. CIRCULATORY DISEASE MORTALITY RATES PER 100,000 WOMAN-YEARS BY AGE, SMOKING STATUS AND ORAL CONTRACEPTIVE USE (Adapted From P.M. Layde and V. Beral, ref # 12.)

Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity.13 In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism.14-18 Oral contraceptives have been shown to increase blood pressure among users (see section 9 in WARNINGS).

Similar effects on risk factors have been associated with an increased risk of heart disease. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.

There is some evidence that the risk of myocardial infarction associated with oral contraceptives is lower when the progestogen has minimal androgenic activity than when the activity is greater. Receptor binding and animal studies have shown that desogestrel or its active metabolite has minimal androgenic activity (see CLINICAL PHARMACOLOGY), although these findings have not been confirmed in adequate and well-controlled clinical trials.

c. Cerebrovascular Diseases

Oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (> 35 years), hypertensive women who also smoke. Hypertension was found to be a risk factor for both users and nonusers, for both types of strokes, and smoking interacted to increase the risk of stroke.27-29

In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension.30 The relative risk of hemorrhagic stroke is reported to be 1.2 for non-smokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users and 25.7 for users with severe hypertension.30 The attributable risk is also greater in older women.3

d. Dose-Related Risk of Vascular Disease From Oral Contraceptives

A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease.31-33 A decline in serum high density lipoproteins (HDL) has been reported with many progestational agents.14-16 A decline in serum high density lipoproteins has been associated with an increased incidence of ischemic heart disease. Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and progestogen and the nature and absolute amount of progestogens used in the contraceptives. The amount of both hormones should be considered in the choice of an oral contraceptive.

Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. For any particular estrogen/progestogen combination, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and the needs of the individual patient. New acceptors of oral contraceptive agents should be started on preparations containing the lowest estrogen content which is judged appropriate for the individual patient.

e. Persistence of Risk of Vascular Disease

There are two studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives. In a study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persists for at least 9 years for women 40 to 49 years old who had used oral contraceptives for five or more years, but this increased risk was not demonstrated in other age groups.8 In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small.34 However, both studies were performed with oral contraceptive formulations containing 0.050 mg or higher of estrogens.

2. Estimates of Mortality From Contraceptive Use

One study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (Table III). These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. Each method of contraception has its specific benefits and risks. The study concluded that with the exception of oral contraceptive users 35 and older who smoke and 40 and older who do not smoke, mortality associated with all methods of birth control is low and below that associated with childbirth.

The observation of an increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970’s.35 Current clinical recommendation involves the use of lower estrogen dose formulations and a careful consideration of risk factors. In 1989, the Fertility and Maternal Health Drugs Advisory Committee was asked to review the use of oral contraceptives in women 40 years of age and over. The Committee concluded that although cardiovascular disease risk may be increased with oral contraceptive use after age 40 in healthy non-smoking women (even with the newer low-dose formulations), there are also greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception. The Committee recommended that the benefits of low-dose oral contraceptive use by healthy non-smoking women over 40 may outweigh the possible risks.

Of course, older women, as all women who take oral contraceptives, should take an oral contraceptive which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and individual patient needs.

TABLE III: ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NONSTERILE WOMEN, BY FERTILITY CONTROL METHOD ACCORDING TO AGE

* Deaths are birth-related † Deaths are method-related
Method of control and outcome	15 to 19	20 to 24	25 to 29	30 to 34	35 to 39	40 to 44
No fertility control methods*	7.0	7.4	9.1	14.8	25.7	28.2
Oral contraceptives non smoker†	0.3	0.5	0.9	1.9	13.8	31.6
Oral contraceptives smoker†	2.2	3.4	6.6	13.5	51.1	117.2
IUD†	0.8	0.8	1.0	1.0	1.4	1.4
Condom*	1.1	1.6	0.7	0.2	0.3	0.4
Diaphragm/ Spermicide*	1.9	1.2	1.2	1.3	2.2	2.8
Periodic abstinence*	2.5	1.6	1.6	1.7	2.9	3.6

Adapted from H.W. Ory, ref. #35.

3. Carcinoma of the Reproductive Organs and Breasts

Numerous epidemiological studies have been performed on the incidence of breast, endometrial, ovarian, and cervical cancer in women using oral contraceptives.

The risk of having breast cancer diagnosed may be slightly increased among current and recent users of combination oral contraceptives. However, this excess risk appears to decrease over time after discontinuation of combination oral contraceptives and by 10 years after cessation the increased risk disappears. Some studies report an increased risk with duration of use while other studies do not and no consistent relationships have been found with dose or type of steroid. Some studies have found a small increase in risk for women who first use combination oral contraceptives before age 20. Most studies show a similar pattern of risk with combination oral contraceptives regardless of a woman’s reproductive history or her family breast cancer history.

Breast cancers diagnosed in current or previous oral contraceptive users tend to be less clinically advanced than in nonusers.

Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is usually a hormonally-sensitive tumor.

Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women.45-48 However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.

In spite of many studies of the relationship between oral contraceptive use and breast and cervical cancers, a cause-and-effect relationship has not been established.

4. Hepatic Neoplasia

Benign hepatic adenomas are associated with oral contraceptive use, although the incidence of benign tumors is rare in the United States. Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk that increases after four or more years of use especially with oral contraceptives of higher dose.49 Rupture of benign, hepatic adenomas may cause death through intra-abdominal hemorrhage.50,51

Studies from Britain have shown an increased risk of developing hepatocellular carcinoma in long-term (> 8 years) oral contraceptive users. However, these cancers are extremely rare in the U.S. and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than one per million users.

5. Ocular Lesions

There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives. Oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions. Appropriate diagnostic and therapeutic measures should be undertaken immediately.

6. Oral Contraceptive Use Before or During Early Pregnancy

Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy.56-57 The majority of recent studies also do not indicate a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned,55,56,58,59 when oral contraceptives are taken inadvertently during early pregnancy.

The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy. Oral contraceptives should not be used during pregnancy to treat threatened or habitual abortion.

It is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out. If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed period. Oral contraceptive use should be discontinued if pregnancy is confirmed.

7. Gallbladder Disease

Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens.60,61 More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal.62-64 The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens.

8. Carbohydrate and Lipid Metabolic Effects

Oral contraceptives have been shown to cause a decrease in glucose tolerance in a significant percentage of users.17 This effect has been shown to be directly related to estrogen dose.65 In general, progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents.17,66 In the nondiabetic woman, oral contraceptives appear to have no effect on fasting blood glucose.67 Because of these demonstrated effects, prediabetic and diabetic women should be carefully monitored while taking oral contraceptives.

A small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed earlier (see WARNINGS 1.a. and 1.d.), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users.

9. Elevated Blood Pressure

Women with significant hypertension should not be started on hormonal contraception.98 An increase in blood pressure has been reported in women taking oral contraceptives68 and this increase is more likely in older oral contraceptive users69 and with extended duration of use.61 Data from the Royal College of General Practitioners12 and subsequent randomized trials have shown that the incidence of hypertension increases with increasing progestational activity and concentrations of progestogens.

Women with a history of hypertension or hypertension-related diseases, or renal disease70 should be encouraged to use another method of contraception. If women elect to use oral contraceptives, they should be monitored closely and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued. For most women, elevated blood pressure will return to normal after stopping oral contraceptives,69 and there is no difference in the occurrence of hypertension among former and never users.68,70,71

10. Headache

The onset or exacerbation of migraine or development of headache with a new pattern which is recurrent, persistent or severe requires discontinuation of oral contraceptives and evaluation of the cause.

11. Bleeding Irregularities

Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use. Nonhormonal causes should be considered and adequate diagnostic measures taken to rule out malignancy or pregnancy in the event of breakthrough bleeding, as in the case of any abnormal vaginal bleeding. If pathology has been excluded, time or a change to another formulation may solve the problem. In the event of amenorrhea, pregnancy should be ruled out.

Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a condition was preexistent.

12. Ectopic Pregnancy

Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.

PRECAUTIONS

1. General

Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

2. Physical Examination and Follow-Up

It is good medical practice for all women to have annual history and physical examinations, including women using oral contraceptives. The physical examination, however, may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care.

3. Lipid Disorders

Women who are being treated for hyperlipidemias should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult.

4. Liver Function

If jaundice develops in any woman receiving oral contraceptives, the medication should be discontinued. Steroid hormones may be poorly metabolized in patients with impaired liver function.

5. Fluid Retention

Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention.

6. Emotional Disorders

Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree.

7. Contact Lenses

Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.

8. Drug Interactions

Changes in Contraceptive Effectiveness Associated With Coadministration of Other Products

Contraceptive effectiveness may be reduced when hormonal contraceptives are coadministered with antibiotics, anticonvulsants, and other drugs that increase the metabolism of contraceptive steroids. This could result in unintended pregnancy or breakthrough bleeding. Examples include rifampin, barbiturates, phenylbutazone, phenytoin, carbamazepine, felbamate, oxcarbazepine, topiramate, and griseofulvin. Several cases of contraceptive failure and breakthrough bleeding have been reported in the literature with concomitant administration of antibiotics such as ampicillin and tetracyclines. However, clinical pharmacology studies investigating drug interaction between combined oral contraceptives and these antibiotics have reported inconsistent results.

Several of the anti-HIV protease inhibitors have been studied with coadministration of oral combination hormonal contraceptives; significant changes (increase and decrease) in the plasma levels of the estrogen and progestin have been noted in some cases. The safety and efficacy of oral contraceptive products may be affected with coadministration of anti-HIV protease inhibitors. Healthcare professionals should refer to the label of the individual anti-HIV protease inhibitors for further drug-drug interaction information.

Herbal products containing St. John’s Wort (hypericum perforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids. This may also result in breakthrough bleeding.

Increase in Plasma Levels Associated With Coadministered Drugs

Coadministration of atorvastatin and certain oral contraceptives containing ethinyl estradiol increase AUC values for ethinyl estradiol by approximately 20%. Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. CYP 3A4 inhibitors such as itraconazole or ketoconazole may increase plasma hormone levels.

Changes in Plasma Levels of Coadministered Drugs

Combination hormonal contraceptives containing some synthetic estrogens (e.g., ethinyl estradiol) may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporin, prednisolone, and theophylline have been reported with concomitant administration of oral contraceptives. Decreased plasma concentrations of acetaminophen and increased clearance of temazepam, salicylic acid, morphine and clofibric acid, due to induction of conjugation, have been noted when these drugs were administered with oral contraceptives.

9. Interactions With Laboratory Tests

Certain endocrine and liver function tests and blood components may be affected by oral contraceptives:

1. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability.


2. Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG; free T4 concentration is unaltered.


3. Other binding proteins may be elevated in serum.


4. Sex hormone binding globulins are increased and result in elevated levels of total circulating sex steroids however, free or biologically active levels either decrease or remain unchanged.


5. Triglycerides may be increased and levels of various other lipids and lipoproteins may be affected.


6. Glucose tolerance may be decreased.


7. Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing oral contraceptives.

10. Carcinogenesis

See WARNINGS section.

11. Pregnancy

Teratogenic Effects

Pregnancy category X

See CONTRAINDICATIONS and WARNINGS.

12. Nursing Mothers

Small amounts of oral contraceptive steroids have been identified in the milk of nursing mothers and a few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, oral contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be advised not to use oral contraceptives but to use other forms of contraception until she has completely weaned her child.

13. Pediatric Use

Safety and efficacy of Emoquette tablets have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated.

14. Geriatric Use

This product has not been studied in women over 65 years of age and is not indicated in this population.

INFORMATION FOR THE PATIENT

See Patient Labeling Printed Below

ADVERSE REACTIONS

An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives (see WARNINGS).

• Thrombophlebitis and venous thrombosis with or without embolism


• Arterial thromboembolism


• Pulmonary embolism


• Myocardial infarction


• Cerebral hemorrhage


• Cerebral thrombosis


• Hypertension


• Gallbladder disease


• Hepatic adenomas or benign liver tumors

There is evidence of an association between the following conditions and the use of oral contraceptives


Oral contraceptives:

• Mesenteric thrombosis


• Retinal thrombosis

The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug-related:

• Nausea


• Vomiting


• Gastrointestinal symptoms (such as abdominal cramps and bloating)


• Breakthrough bleeding


• Spotting


• Change in menstrual flow


• Amenorrhea


• Temporary infertility after discontinuation of treatment


• Edema


• Melasma which may persist


• Breast changes: tenderness, enlargement, secretion


• Change in weight (increase or decrease)


• Change in cervical erosion and secretion


• Diminution in lactation when given immediately postpartum


• Choles

Icarus

Icarus may be available in the countries listed below.

Ingredient matches for Icarus

Tegafur

Tegafur is reported as an ingredient of Icarus in the following countries:

• Japan

International Drug Name Search

Comtrex Maximum Strength Cold Relief

Generic Name: acetaminophen/ chlorpheniramine/ dextromethorphan/ phenylpropanolamine (a seet a MIN oh fen/klor fen IR a meen/dex troe meth OR fan/fen ill proe pa NOLE a meen)

Brand Names: Comtrex Cold and Flu Maximum Strength, Comtrex Maximum Strength Cold Relief, Contac Severe Cold and Flu Maximum Stength

What is Comtrex Maximum Strength Cold Relief (acetaminophen/ chlorpheniramine/ dextromethorphan/ phenylpropanolamine)?

Acetaminophen is a pain reliever and a fever reducer. It is used to treat many conditions, such as headache, muscle aches, arthritis, backache, toothaches, colds, and fevers.

Chlorpheniramine is an antihistamine. It blocks the effects of the naturally occurring chemical histamine in the body. Chlorpheniramine prevents sneezing; itchy, watery eyes and nose; and other symptoms of allergies and hay fever.

Dextromethorphan is a cough suppressant. It suppresses an area in the brain that causes coughing.

Phenylpropanolamine is a decongestant. It constricts (shrinks) blood vessels (veins and arteries) allowing nasal passages to open up.

Acetaminophen/chlorpheniramine/dextromethorphan/phenylpropanolamine is used to treat nasal congestion, sinusitis (inflammation of the sinuses), runny nose, watery eyes, headache, body aches, and coughs associated with allergies, hay fever, and the common cold.

Phenylpropanolamine, an ingredient in this product, has been associated with an increased risk of hemorrhagic stroke (bleeding into the brain or into tissue surrounding the brain) in women. Men may also be at risk. Although the risk of hemorrhagic stroke is low, the U.S. Food and Drug Administration (FDA) recommends that consumers not use any products that contain phenylpropanolamine.

Acetaminophen/chlorpheniramine/dextromethorphan/phenylpropanolamine may also be used for purposes other than those listed in this medication guide.

What is the most important information I should know about Comtrex Maximum Strength Cold Relief (acetaminophen/ chlorpheniramine/ dextromethorphan/ phenylpropanolamine)?

Phenylpropanolamine, an ingredient in this product, has been associated with an increased risk of hemorrhagic stroke (bleeding into the brain or into tissue surrounding the brain) in women. Men may also be at risk. Although the risk of hemorrhagic stroke is low, the U.S. Food and Drug Administration (FDA) recommends that consumers not use any products that contain phenylpropanolamine.

Use caution when driving, operating machinery, or performing other hazardous activities. Acetaminophen/chlorpheniramine/dextromethorphan/phenylpropanolamine may cause dizziness or drowsiness. If you experience dizziness or drowsiness, avoid these activities. Use alcohol cautiously. Alcohol may increase drowsiness and dizziness while taking acetaminophen/chlorpheniramine/dextromethorphan/phenylpropanolamine. Alcohol may also cause damage to the liver when it is taken with acetaminophen.

Who should not take Comtrex Maximum Strength Cold Relief (acetaminophen/ chlorpheniramine/ dextromethorphan/ phenylpropanolamine)?

Do not take this medication without first talking to your doctor if you drink more than three alcoholic beverages per day or if you have had alcoholic liver disease. You may not be able to take acetaminophen.

Do not take this medication if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), phenelzine (Nardil), or tranylcypromine (Parnate) in the last 14 days. A dangerous drug interaction could occur, leading to serious side effects.

Before taking this medication, tell your doctor if you have

• kidney disease,


• liver disease,


• 
  

  diabetes,

  
  


• 
  

  glaucoma,

  
  


• 
  

  any type of heart disease or high blood pressure,

  
  


• 
  

  thyroid disease,

  
  


• 
  

  emphysema or chronic bronchitis, or

  
  


• 
  

  difficulty urinating or an enlarged prostate.

  
  

You may not be able to take acetaminophen/chlorpheniramine/dextromethorphan/phenylpropanolamine, or you may require a lower dose or special monitoring during treatment if you have any of the conditions listed above.

It is not known whether acetaminophen/chlorpheniramine/dextromethorphan/phenylpropanolamine will harm an unborn baby. Do not take this medication without first talking to your doctor if you are pregnant. This medication passes into breast milk and may harm a nursing infant. Do not take this medication without first talking to your doctor if you are breast-feeding a baby. Read the package label for directions or consult your doctor or pharmacist before treating a child with this medication. Children are more susceptible than adults to the effects of medicines and may have unusual reactions. If you are over 60 years of age, you may be more likely to experience side effects from acetaminophen/chlorpheniramine/dextromethorphan/phenylpropanolamine.

How should I take Comtrex Maximum Strength Cold Relief (acetaminophen/ chlorpheniramine/ dextromethorphan/ phenylpropanolamine)?

Take acetaminophen/chlorpheniramine/dextromethorphan/phenylpropanolamine exactly as directed. If you do not understand these directions, ask your pharmacist, nurse, or doctor to explain them to you.

Take each dose with a full glass of water. Do not take more of this medication than is recommended. An overdose of this medication can cause serious harm. The maximum amount of acetaminophen for adults is 1 gram (1000 mg) per dose and 4 grams (4000 mg) per day. Taking more acetaminophen could cause damage the liver. If you drink more than three alcoholic beverages per day, talk to your doctor before taking acetaminophen and never take more than 2 grams (2000 mg) per day.

Do not take acetaminophen/chlorpheniramine/dextromethorphan/phenylpropanolamine for longer than 7 days in a row. If your symptoms do not improve, if they get worse, or if you have a fever, see your doctor.

Store acetaminophen/chlorpheniramine/dextromethorphan/phenylpropanolamine at room temperature away from moisture and heat.

What happens if I miss a dose?

Take the missed dose as soon as you remember. However, if it is almost time for the next dose, skip the missed dose and take only the next regularly scheduled dose. Do not take a double dose of this medication.

What happens if I overdose?

Seek emergency medical attention.

Symptoms of an acetaminophen/chlorpheniramine/dextromethorphan/phenylpropanolamine overdose include a dry mouth, large pupils, flushing, sweating, nausea, vomiting, diarrhea, abdominal pain, seizures, confusion, an irregular heartbeat, hyperactivity, or hallucinations.

What should I avoid while taking Comtrex Maximum Strength Cold Relief (acetaminophen/ chlorpheniramine/ dextromethorphan/ phenylpropanolamine)?

Use caution when driving, operating machinery, or performing other hazardous activities. Acetaminophen/chlorpheniramine/dextromethorphan/phenylpropanolamine may cause dizziness or drowsiness. If you experience dizziness or drowsiness, avoid these activities. Use alcohol cautiously. Alcohol may increase drowsiness and dizziness while taking acetaminophen/chlorpheniramine/dextromethorphan/phenylpropanolamine. Alcohol may also cause damage to the liver when it is taken with acetaminophen.

Acetaminophen/chlorpheniramine/dextromethorphan/phenylpropanolamine may increase the effects of other drugs that cause drowsiness, including antidepressants, alcohol, other antihistamines, pain relievers, anxiety medicines, seizure medicines, and muscle relaxants. Dangerous sedation, dizziness, or drowsiness may occur if acetaminophen/chlorpheniramine/dextromethorphan/phenylpropanolamine is taken with any of these medications.

Comtrex Maximum Strength Cold Relief (acetaminophen/ chlorpheniramine/ dextromethorphan/ phenylpropanolamine) side effects

If you experience any of the following rare but serious side effects, stop taking acetaminophen/chlorpheniramine/dextromethorphan/phenylpropanolamine and seek emergency medical attention or notify your doctor immediately:

• 
  

  an allergic reaction (difficulty breathing; closing of your throat; swelling of your lips, tongue, or face; or hives);

  
  


• 
  

  liver damage (yellowing of the skin or eyes, nausea, abdominal pain or discomfort, unusual bleeding or bruising, or severe fatigue);

  
  


• 
  

  blood problems (easy or unusual bleeding or bruising); or

  
  


• 
  

  low blood sugar (fatigue, increased hunger or thirst, dizziness, or fainting).

  
  

Other, less serious side effects may be more likely to occur. Continue to take acetaminophen/chlorpheniramine/dextromethorphan/phenylpropanolamine and talk to your doctor or try another similar medication if you experience

• 
  

  dryness of the eyes, nose, and mouth;

  
  


• 
  

  drowsiness or dizziness;

  
  


• 
  

  blurred vision;

  
  


• 
  

  difficulty urinating; or

  
  


• 
  

  excitation in children.

  
  

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome.

What other drugs will affect Comtrex Maximum Strength Cold Relief (acetaminophen/ chlorpheniramine/ dextromethorphan/ phenylpropanolamine)?

Do not take acetaminophen/chlorpheniramine/dextromethorphan/phenylpropanolamine if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), phenelzine (Nardil), or tranylcypromine (Parnate) in the last 14 days. A dangerous drug interaction could occur, leading to serious side effects.

Urine glucose tests may produce false results while you are taking acetaminophen. Talk to your doctor if you are diabetic and you notice changes in your glucose levels during treatment.

Do not take other over-the-counter cough, cold, allergy, diet, pain, or sleep medicines while taking acetaminophen/chlorpheniramine/dextromethorphan/phenylpropanolamine without first talking to your doctor or pharmacist. Other medications may also contain chlorpheniramine, phenylpropanolamine, acetaminophen, or other similar drugs, and you may accidentally take too much of these medicines.

Acetaminophen/chlorpheniramine/dextromethorphan/phenylpropanolamine may increase the effects of other drugs that cause drowsiness, including antidepressants, alcohol, other antihistamines, pain relievers, anxiety medicines, seizure medicines, and muscle relaxants. Dangerous sedation, dizziness, or drowsiness may occur if acetaminophen/chlorpheniramine/dextromethorphan/phenylpropanolamine is taken with any of these medications.

Drugs other than those listed here may also interact with acetaminophen/chlorpheniramine/dextromethorphan/phenylpropanolamine. Talk to your doctor and pharmacist before taking any prescription or over-the-counter medicines.

More Comtrex Maximum Strength Cold Relief resources

• Comtrex Maximum Strength Cold Relief Drug Interactions
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Where can I get more information?

• Your pharmacist has additional information about acetaminophen/chlorpheniramine/ dextromethorphan/phenylpropanolamine written for health professionals that you may read.

What does my medication look like?

Acetaminophen/chlorpheniramine/dextromethorphan/phenylpropanolamine is available over the counter under the brand name Comtrex. Other brand or generic formulations may also be available. Ask your pharmacist any questions you have about this medication, especially if it is new to you.