Online PLR Content Marketing Saint Vincent and the Grenadines: August 2012

Friday, August 31, 2012

Ketoconazole

Class: Azoles
VA Class: AM700
CAS Number: 65277-42-1
Brands: Nizoral

Oral ketoconazole has been associated with hepatoxicity, including some fatalities.²⁶³ Inform patients of the risk and monitor closely.²⁶³

Concomitant use with cisapride or with astemizole or terfenadine (drugs no longer commercially available in the US) is contraindicated.²⁶³ Pharmacokinetic interactions can occur and serious cardiovascular events have been reported with concomitant use.²⁶³ VT, VF, and torsades de pointes have been reported in patients receiving concomitant cisapride; death, VT, and torsades de pointes have been reported in patients receiving concomitant terfenadine.²⁶³ (See Interactions.)

Introduction

Antifungal; azole (imidazole derivative).¹²⁷ ²²²

Uses for Ketoconazole

Blastomycosis

Treatment of North American blastomycosis caused by Blastomyces dermatitidis.²¹³ ²²⁰ ²³⁴ ²³⁸ ²⁶³ ²⁶⁴ ²⁸⁸ ²⁹⁰ ²⁹¹ ²⁹² ²⁹⁹ ³⁰⁰

Drugs of choice are IV amphotericin B (especially for severe infections and those involving the CNS) or oral itraconazole;²³⁴ ²³⁸ ²⁶⁴ ²⁸⁸ ²⁹⁰ ²⁹² ²⁹⁶ ²⁹⁷ ²⁹⁸ ²⁹⁹ ³³² ³³³ fluconazole and ketoconazole are considered alternatives.²³⁸ ²⁶⁴ ²⁸⁸ ²⁹⁰ ²⁹² ²⁹⁶ ²⁹⁷ ²⁹⁹

Oral ketoconazole usually has been effective when used in immunocompetent individuals with mild to moderate pulmonary or extrapulmonary blastomycosis.²¹³ ²²⁰ ²⁹⁰ ²⁹¹ ²⁹² ²⁹⁷ Consider that treatment failures have been reported when ketoconazole was used for treatment of cutaneous or pulmonary blastomycosis in individuals who had asymptomatic or subclinical CNS involvement at the time of the initial diagnosis.²¹¹ ²⁹⁵ ²⁹⁶ (See Meningitis and Other CNS Infections under Cautions.)

Candida Infections

Treatment of candidiasis, candiduria, chronic mucocutaneous candidiasis, or oropharyngeal and esophageal candidiasis.²¹² ²³⁸ ²⁶³ ²⁷⁹ ²⁹¹ ²⁹² ³²⁰ ³²² ³²³ ³²⁶ ³²⁸ ³²⁹ ³³¹ ³³⁴ ³⁴¹

Has been used for treatment of uncomplicated vulvovaginal candidiasis†.³⁴⁰ ³⁴³ ³⁴⁴ Not a drug of choice for initial treatment; single-dose fluconazole is the only oral regimen included in current CDC recommendations for treatment of uncomplicated vulvovaginal candidiasis.²⁷⁰ ²⁷² Recommended by CDC and others as one of several alternatives for maintenance treatment of recurrent vulvovaginal candidiasis† in women with a history of recurrent infections.²⁷⁰ ²⁷¹ ³⁴⁰ ³⁴³ ³⁴⁴ ³⁴⁶

Chromomycosis

Treatment of chromomycosis (chromoblastomycosis) caused by Phialophora.²⁶³ ²⁸⁸ ³³⁵ A response may not be attained in those with more extensive disease.³³⁵

Optimum regimens for chromomycosis have not been identified.²⁸⁸ ³³⁵ Flucytosine may be a drug of choice used alone or in conjunction with another antifungal (e.g., IV amphotericin B, oral itraconazole, oral ketoconazole).²⁸⁸ ³³⁵

Coccidioidomycosis

Treatment of mild to moderate coccidioidomycosis caused by Coccidioides immitis.²³⁸ ²⁶³ ²⁸⁰ ²⁹⁰ ²⁹¹ ²⁹² ²⁹³ ³⁰³ ³⁰⁴ ³⁰⁵ ³²⁷

Drugs of choice are IV amphotericin B (especially for severe infections and those in immunocompromised patients including HIV-infected individuals) or oral fluconazole; itraconazole and ketoconazole are considered alternatives.²³⁴ ²³⁸ ²⁷⁹ ²⁸⁰ ²⁸⁸ ²⁹⁰ ²⁹² ²⁹³

Dermatophytoses

Treatment of certain dermatophytoses of the skin, scalp, and nails, including tinea capitis (scalp ringworm), tinea corporis (ringworm of the body), tinea cruris (jock itch; groin ringworm), tinea pedis (athlete’s foot, foot ringworm), tinea manuum (hand ringworm), and tinea unguium (onychomycosis; nail ringworm) caused by Epidermophyton, Microsporum, or Trichophyton.²⁶³ ²⁹¹ ³²⁴ ³²⁵

Used for severe recalcitrant cutaneous dermatophyte infections in patients who have not responded to topical therapy or have not responded to or are unable to take other oral antifungals (e.g., griseofulvin).²⁶³

Tinea corporis and tinea cruris generally can be effectively treated using a topical antifungal; an oral antifungal may be necessary if the disease is extensive, dermatophyte folliculitis is present, the infection does not respond to topical therapy, or the patient is immunocompromised or has a coexisting disease.³⁵² ³⁵³ ³⁵⁶ ³⁵⁷ ³⁵⁸ ³⁶⁰ Tinea capitis and tinea barbae generally are treated using an oral antifungal.³²⁵ ³⁵³ ³⁵⁹

While topical antifungals usually are effective for treatment of uncomplicated tinea manuum and tinea pedis,³⁵³ ³⁵⁶ ³⁵⁸ ³⁶⁰ an oral antifungal usually is necessary for treatment of severe, chronic, or recalcitrant tinea pedis, for treatment of chronic moccasin-type (dry-type) tinea pedis, and for treatment of tinea unguium (onychomycosis).³⁵³ ³⁵⁷ ³⁵⁸ ³⁶⁰

Histoplasmosis

Treatment of histoplasmosis caused by Histoplasma capsulatum.²¹³ ²³⁸ ²⁶³ ²⁸⁸ ²⁹⁰ ²⁹¹ ²⁹² ²⁹³ ³⁷⁵

Drugs of choice are IV amphotericin B (especially for life-threatening infections including those in HIV-infected individuals) or oral itraconazole; ketoconazole and fluconazole are considered alternatives.²³⁸ ²⁷⁹ ²⁸⁰ ²⁹⁰ ²⁹¹ ²⁹² ³⁷⁵

Paracoccidioidomycosis

Treatment of paracoccidioidomycosis (South American blastomycosis) caused by Paracoccidioides brasiliensis.²³⁸ ²⁶³ ²⁸⁸ ²⁹¹ ³¹¹ ³³⁵

Drug of choice for initial treatment of severe infections is IV amphotericin B;²³⁸ ²⁸⁸ ²⁹¹ ²⁹³ ³¹⁰ ³¹¹ ³³⁵ oral azole antifungals (e.g., ketoconazole, itraconazole) can be used in patients with less severe infections.²³⁸ ²⁸⁸ ²⁹¹ ³³⁵

Pityriasis (Tinea) Versicolor

Has been effective for treatment of pityriasis (tinea) versicolor†, a superficial infection caused by Malassezia furfur (Pityrosporum orbiculare or P. ovale).²³⁴ ³⁵⁴ ³⁵⁵

Pityriasis (tinea) versicolor generally can be treated topically with an imidazole-derivative azole antifungal (e.g., clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, sulconazole), an allylamine antifungal (e.g., terbinafine), ciclopirox olamine, or certain other topical therapies (e.g., selenium sulfide 2.5%).²³⁴ ³²⁴ ³⁵² ³⁵⁴ ³⁵⁵ ³⁵⁷ An oral antifungal (e.g., itraconazole, ketoconazole) may be indicated, with or without a topical agent, in patients who have extensive or severe infections or who fail to respond to or have frequent relapses with topical therapy.³²⁴ ³⁵⁴ ³⁵⁵ ³⁵⁷

Acanthamoeba Infections

Has been used in conjunction with a topical anti-infective (e.g., miconazole, neomycin, metronidazole, propamidine isethionate) in the treatment of Acanthamoeba keratitis†.¹³⁴ ¹³⁵ ¹³⁶ ¹³⁷ ¹³⁸ ¹³⁹ ¹⁴⁰ ²²⁶ Optimum therapy for Acanthamoeba keratitis remains to be clearly established, but prolonged local and systemic therapy with multiple anti-infectives and often surgical treatment (e.g., penetrating keratoplasty) usually required.¹³⁴ ¹³⁵ ¹³⁶ ¹³⁷ ¹³⁸ ¹³⁹ ¹⁴⁰

A regimen of oral ketoconazole, rifampin, and co-trimoxazole has been used for treatment of chronic Acanthamoeba meningitis† in several immunocompetent children.¹⁸⁷ ²²⁵ (See Meningitis and Other CNS Infections under Cautions.)

Leishmaniasis

Has been used for treatment of cutaneous or mucocutaneous leishmaniasis† caused by various Leishmania spp. (e.g., Leishmania major†, L. mexicana†, L. panamensis†, L. braziliensis†, L. tropica†).²⁰³ ²⁰⁴ ²⁰⁵ ²⁰⁶ ²⁰⁷ ²⁰⁸ ²⁰⁹ ²³⁴ ²⁵⁰ ³¹⁴ ³¹⁶ ³¹⁷ Usual drugs of choice are pentavalent antimony compounds (e.g., sodium stibogluconate or meglumine antimonate [drugs not commercially available in the US]).²²⁵ ²³⁴ ³¹⁷ ³¹⁹ Preferred alternatives or additional drugs of choice are IV amphotericin B (conventional or liposomal formulations) and parenteral pentamidine; other alternatives include oral azole antifungals (e.g., itraconazole, ketoconazole) or topical paromomycin (for cutaneous leishmaniasis when there is a low potential for mucosal spread).²²⁵ ²³⁴ ³¹⁹

Has been used in a limited number of patients for treatment of antimony-resistant visceral leishmaniasis (kala-azar) caused by L. donovani†,²⁶¹ ²⁶² ³¹⁵ ³¹⁷ ³¹⁸ but may be less effective in these infections than in the treatment of cutaneous leishmaniasis.²⁶¹ ²⁶² ³¹⁷ Usual drugs of choice for initial treatment of visceral leishmaniasis are pentavalent antimony compounds, but resistance and treatment failures are becoming increasingly common;²⁸⁸ ³¹⁷ IV amphotericin B and pentamidine are considered alternatives.²⁸⁸ ³¹⁷ ³¹⁹

Prostate Cancer

Because of ketoconazole’s ability to inhibit testicular and adrenal steroid synthesis, the drug has been used in the treatment of advanced prostatic carcinoma†.¹⁰⁶ ¹⁰⁷ ¹⁰⁸ ¹⁵¹ ¹⁷⁹ ¹⁸⁰ ¹⁸¹ ¹⁸² ¹⁸³ ¹⁸⁴ ²⁸⁴ ²⁸⁵ ²⁸⁶ ³⁶⁸ ³⁶⁹

Cushing’s Syndrome

Has been used effectively for palliative treatment of Cushing’s syndrome† (hypercortisolism), including adrenocortical hyperfunction associated with adrenal or pituitary adenoma or ectopic corticotropin-secreting tumors.¹¹² ¹¹³ ¹¹⁴ ¹⁵¹ ¹⁵⁴ ²²⁴ ³⁴²

Has been used in a limited number of geriatric patients ≥75 years of age for treatment of corticotropin-dependent Cushing’s syndrome; may provide an effective alternative in patients who cannot tolerate surgical treatment.³⁴²

Hirsutism and Precocious Puberty

Has been used with some success in a limited number of patients for treatment of dysfunctional hirsutism†.¹¹⁵ ³⁷⁰

Has been used in a limited number of boys for treatment of precocious puberty†.¹¹⁶ ¹⁸⁵ ¹⁸⁶

Hypercalcemia

Has been used with some success for treatment of hypercalcemia in adults with sarcoidosis†.³⁶³ ³⁶⁴ ³⁶⁵ ³⁶⁶ Has reduced serum calcium concentrations in some, but not all, patients with sarcoidosis-associated hypercalcemia;³⁶⁴ ³⁶⁵ ³⁶⁶ hypercalcemia and increased serum 1,25-dihydroxyvitamin D concentrations may recur when ketoconazole dosage is decreased or the drug discontinued.³⁶⁵ ³⁶⁶

Has been effective in a few adolescents for treatment of tuberculosis-associated hypercalcemia†.³⁶⁷

Ketoconazole Dosage and Administration

Administration

Oral Administration

Administer orally.²⁶³

To ensure absorption in patients with achlorhydria, each 200-mg ketoconazole tablet should be dissolved in 4 mL of 0.2N hydrochloric acid solution²⁶³ or taken with 200 mL of 0.1N hydrochloric acid.^a The resultant solution should be administered via a plastic or glass straw to avoid contact with the teeth, and a glass of water should be administered immediately after the solution.²⁶³ Alternatively, some clinicians recommend that each 200 mg of ketoconazole be given with ≥680 mg of glutamic acid hydrochloride.¹⁹⁸ ¹⁹⁹ Other clinicians suggest that each 200 mg of ketoconazole be administered with an acidic beverage (e.g., Coca-Cola, Pepsi)²⁷³ or the dose dissolved in 60 mL of citrus juice to ensure absorption; however, this strategy may not be adequate in all patients with achlorhydria and patients should be monitored closely for therapeutic failure.²⁷³

Dosage

Pediatric Patients

General Pediatric Dosage

Treatment of Fungal Infections

Oral

Children >2 years of age: 3.3–6.6 mg/kg once daily has been used.²³⁴ ²⁶³

Adults

General Adult Dosage

Treatment of Fungal Infections

Oral

200 mg once daily.²⁶³ Dosage may be increased to 400 mg once daily for severe infections or if the expected clinical response is not achieved.²⁶³

Blastomycosis

Oral

Some clinicians suggest 400 mg once or twice daily.²¹³ ²²⁰ ²³⁸ ²⁸⁸ ²⁹⁰ ²⁹² ²⁹⁶ ²⁹⁹ ³⁰¹ ³²⁷ ³⁷⁵ Treatment usually continued for 6–12 months.^a

Candidiasis

Oropharyngeal and Esophageal Candidiasis

Oral

200–400 mg daily.²³⁸ ²⁷⁹

Vulvovaginal Candidiasis†

Oral

Treatment of uncomplicated vulvovaginal candidiasis† in nonpregnant women: 200–400 mg twice daily for 5 days.³⁴⁰ ³⁴³ ³⁴⁴

When used as a maintenance regimen to reduce the frequency of recurrent episodes of vulvovaginal candidiasis† in women who have received an initial intensive antifungal regimen (i.e., 7–14 days of an intravaginal azole antifungal or a 2-dose fluconazole regimen), ketoconazole has been given in a dosage of 100 mg once daily for up to 6 months.²⁷⁰ ³⁴⁰ ³⁴¹ ³⁴³ ³⁴⁴ ³⁴⁶

Chromomycosis

Oral

200–400 mg daily.³³⁵ Treatment usually continued for 6–12 months.

Coccidioidomycosis

Oral

400 mg once or twice daily.²¹³ ²²⁰ ²³⁸ ²⁸⁸ ²⁹⁰ ²⁹² ²⁹⁶ ²⁹⁹ ³⁰¹ ³²⁷ ³⁷⁵ Treatment usually continued for 6–12 months.

Dermatophytoses

Oral

200–400 mg daily has been given for 1–2 months.^a Infections involving glabrous skin require a minimum of 4 weeks of treatment; palmar and plantar infections may respond more slowly.²⁶³ Tinea unguium (onychomycosis) may require ≥6–12 months of treatment.^a

Histoplasmosis

Oral

400 mg once or twice daily.²¹³ ²²⁰ ²³⁸ ²⁸⁸ ²⁹⁰ ²⁹² ²⁹⁶ ²⁹⁹ ³⁰¹ ³²⁷ ³⁷⁵ A dosage of 200 mg once or twice daily also has been used.³⁷⁵

A minimum of 6 months of therapy usually required, but 2–6 months has been effective in some patients.^a

Paracocciodioidomycosis

Oral

200–400 mg daily.³³⁵

A minimum of 6 months of therapy usually required, but 2–6 months has been effective in some patients.^a

Leishmaniasis†

Cutaneous and Mucocutaneous Leishmaniasis†

Oral

400–600 mg daily for 4–8 weeks has been used.²⁰³ ²⁰⁴ ²⁰⁷ ²⁰⁸ ³¹⁷

Visceral Leishmaniasis (Kala-Azar)†

Oral

400–600 mg daily for 4–8 weeks has been used.³¹⁵ ³¹⁷ ³¹⁸

Prostate Cancer†

Oral

400 mg every 8 hours has been used for treatment of prostatic carcinoma†¹⁰⁶ ¹⁰⁸ ¹⁸⁰ ¹⁸¹ ¹⁸² ¹⁸³ ²⁸⁵ or as an adjunct in the management of disseminated intravascular coagulation (DIC) associated with prostatic carcinoma†.¹⁵² ¹⁷⁸ Risk of depressed adrenocortical function at this high dosage should be considered.²⁶³ (See Endocrine and Metabolic Effects under Cautions.)

Cautions for Ketoconazole

Contraindications

Hypersensitivity to ketoconazole.²⁶³

Concomitant use with certain drugs metabolized by CYP3A4 isoenzymes (e.g., astemizole [no longer commercially available in the US], cisapride, midazolam, terfenadine [no longer commercially available in the US], triazolam).²⁶³ (See Specific Drugs under Interactions.)

Warnings/Precautions

Warnings

Hepatic Effects

Hepatotoxicity (usually the hepatocellular type) has been reported.¹⁶⁴ ¹⁶⁵ ¹⁶⁶ ¹⁶⁷ ¹⁶⁸ ¹⁶⁹ ¹⁷⁰ ¹⁹¹ ¹⁹² ¹⁹³ ²⁶³

Symptomatic hepatotoxicity usually is apparent within the first few months of ketoconazole therapy (median 28 days),⁵⁰ ⁶¹ ¹⁶⁴ ¹⁶⁷ ¹⁶⁸ ¹⁶⁹ ¹⁷⁰ ¹⁸⁸ ¹⁸⁹ ¹⁹⁰ ¹⁹¹ ¹⁹² ²⁶³ but occasionally may be apparent within 3–7 days of initiation of therapy.¹⁶⁴ ¹⁶⁶ ¹⁶⁷ ¹⁹¹ ¹⁹² ²⁶³ Although ketoconazole-induced hepatotoxicity usually is reversible following discontinuance of the drug,⁵⁰ ¹⁶⁴ ¹⁶⁵ ¹⁶⁶ ¹⁶⁷ ¹⁸⁸ ¹⁸⁹ ¹⁹⁰ ¹⁹¹ ¹⁹² ²⁶³ recovery may take several months;¹⁶⁴ ¹⁶⁵ ¹⁶⁷ ¹⁸⁸ ¹⁹⁰ ²⁶³ rarely, death has occurred.¹⁶⁴ ¹⁶⁵ ¹⁶⁷ ¹⁶⁸ ¹⁶⁹ ¹⁷⁰ ¹⁹¹ ¹⁹² ¹⁹³ ²⁶³

Most cases of hepatotoxicity have been reported in patients receiving the drug for tinea unguium (onychomycosis);⁵⁰ ¹⁶⁷ ¹⁶⁸ ¹⁶⁹ ¹⁸⁸ ¹⁸⁹ ¹⁹⁰ ¹⁹¹ ¹⁹² ¹⁹³ ²⁶³ many others were receiving the drug for chronic, refractory dermatophytoses.¹⁶⁷ ¹⁹¹ ¹⁹² Several cases of ketoconazole-induced hepatitis have been reported in children.¹⁶⁵ ¹⁶⁷ ¹⁸⁹ ¹⁹¹ ¹⁹² ²⁶³

Monitor closely for clinical and biochemical signs of hepatotoxicity.¹⁶⁴ ¹⁶⁶ ¹⁶⁷ ¹⁶⁹ ¹⁷⁰ ¹⁹² ²⁶³ Perform liver function tests (e.g., serum AST, ALT, alkaline phosphatase, γ-glutamyltransferase [γ-glutamyltranspeptidase, GGT, GGTP], bilirubin) prior to and frequently (e.g., biweekly during the first 2 months of therapy and monthly or bimonthly thereafter) during therapy, particularly in those receiving prolonged therapy, those receiving other potentially hepatotoxic drugs, and those with a history of hepatic disease.¹⁶⁴ ¹⁶⁶ ¹⁶⁷ ¹⁶⁹ ¹⁷⁰ ¹⁸⁸ ¹⁸⁹ ¹⁹⁰ ¹⁹³ ²⁶³

Minor, asymptomatic elevations in liver function test results may return to pretreatment concentrations during continued ketoconazole therapy.¹⁶⁴ ¹⁶⁷ ¹⁹¹ ¹⁹² ¹⁹³ If liver function test results are substantially elevated or if such abnormalities persist, worsen, or are accompanied by other manifestations of hepatic dysfunction, ketoconazole should be discontinued.¹⁶⁴ ¹⁶⁷ ¹⁶⁸ ¹⁶⁹ ¹⁷⁰ ¹⁸⁹ ¹⁹⁰ ¹⁹¹ ¹⁹²

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylaxis and urticaria reported rarely.¹⁰² ²⁶³

General Precautions

Endocrine and Metabolic Effects

Ketoconazole can inhibit testosterone synthesis and transient decreases in serum testosterone may occur;¹⁰⁹ ¹¹⁰ ¹⁵¹ ¹⁷⁴ ²⁶³ concentrations usually return to baseline values after the drug is discontinued.²⁶³ Testosterone concentrations are impaired with ketoconazole dosage of 800 mg daily and abolished with dosage of 1.6 g daily.²⁶³

Ketoconazole may inhibit cortisol synthesis, particularly in patients receiving relatively high daily dosage or divided daily dosing.¹⁰⁹ ¹¹² ¹¹³ ¹¹⁴ ¹⁵¹ ¹⁵⁴ ¹⁵⁶ ¹⁵⁷ ¹⁵⁸ ¹⁵⁹ ¹⁶⁶ ¹⁷³ ¹⁹² ²²⁹ ²³⁰ The adrenocortical response to corticotropin (ACTH) may be at least transiently diminished and a reduction in urinary free and serum cortisol concentrations may occur.¹⁰⁹ ¹¹⁰ ¹¹² ¹¹³ ¹¹⁴ ¹⁵¹ ¹⁵⁴ ¹⁵⁶ ¹⁵⁷ ¹⁵⁸ ¹⁵⁹ ¹⁶⁶ ¹⁷³ ¹⁹² Adrenocortical insufficiency has been reported only rarely.¹⁰⁹ ¹⁵⁹ ¹⁶⁰ ¹⁶⁶ ¹⁷³ ¹⁹² ²²⁹ Adrenocortical hypofunction generally is reversible following discontinuance of the drug,¹⁵⁴ ¹⁵⁶ ¹⁵⁷ ¹⁶⁶ but rarely may be persistent.¹⁵⁹

To minimize the risk of possible endocrine and metabolic effects, dosages greater than those usually recommended should not be used.²⁶³

Meningitis and Other CNS Infections

Because CSF concentrations of ketoconazole are unpredictable following oral administration, the drug should not be used alone to treat CNS fungal infections, including candidal, coccidioidal, or cryptococcal meningitis.²⁶³ ²⁹¹ ³⁰² ³³⁰

Specific Populations

Pregnancy

Category C.²⁶³

Lactation

Probably distributed into human milk.²⁶³ Discontinue nursing or the drug.²⁶³

Pediatric Use

Use in pediatric patients only when potential benefits justify possible risks.²⁶³ Has not been systematically studied in children of any age,²⁶³ but has been used in a limited number of children >2 years of age.²⁶³ There is essentially no information available to date on use in children <2 years of age.²⁶³

Common Adverse Effects

GI effects (nausea, vomiting), hepatic effects, pruritus.²⁶³

Interactions for Ketoconazole

Inhibits CYP3A4.²⁶³

Drugs Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions likely with drugs that are substrates of CYP3A4.²⁶³

Hepatotoxic Drugs

Monitor closely if used concomitantly with other potentially hepatotoxic drugs, especially in patients requiring prolonged therapy or with a history of liver disease.²⁶³ (See Hepatic Effects under Cautions.)

Specific Drugs

Drug	Interaction	Comments
Alcohol	Disulfiram reactions (flushing, rash, peripheral edema, nausea, headache) have occurred rarely in patients who ingested alcohol while receiving ketoconazole;²⁶³ ²⁶⁷ ²⁶⁸ usually resolved within a few hours²⁶³	Some clinicians recommend that alcohol be avoided during and for 48 hours after discontinuance of ketoconazole therapy²⁶⁷
Antacids	Because gastric acidity is necessary for dissolution and absorption of ketoconazole, concomitant administration of antacids may decrease absorption of the antifungal²⁶³	Administer antacids at least 2 hours after ketoconazole²⁶³
Anticoagulants, oral (warfarin)	Possible enhanced anticoagulant effects²⁶³	Monitor PT or other appropriate tests closely; adjust anticoagulant dosage if necessary²⁶³
Anticonvulsants (phenytoin)	Possible pharmacokinetic interaction with changes in metabolism of one or both drugs²⁶³	Monitor serum concentrations if used concomitantly²⁶³
Antidiabetic agents, sulfonylureas	Increased plasma concentrations of the antidiabetic agent and symptoms of hypoglycemia reported with other azoles (e.g., itraconazole)²⁶³ ^b	Consider the possibility that hypoglycemia may occur when ketoconazole used concomitantly with antidiabetic agents²⁶³
Antihistamines (astemizole, loratadine, terfenadine)	Aztemizole and terfenadine (drugs no longer commercially available in the US): Pharmacokinetic interaction and potential for serious or life-threatening reactions (e.g., cardiac arrhythmias, prolonged QT interval)²⁵² ²⁵³ ²⁵⁴ ²⁵⁵ ²⁵⁶ ²⁵⁷ ²⁵⁹ ²⁶⁰ ²⁶³ ²⁸⁷ Loratadine: Increased plasma concentrations and AUCs of loratadine and its active metabolite, but no evidence of changes in QT interval or incidence of adverse effects²⁶³	Aztemizole and terfenadine: Concomitant use contraindicated²⁵² ²⁵⁴ ²⁶³ ²⁶⁵
Antimycobacterials (rifampin, isoniazid)	Rifampin: Decreased serum concentrations of ketoconazole¹¹¹ ¹⁴¹ ²²¹ ²⁶³ Isoniazid: May affect ketoconazole serum concentrations¹¹¹ ²⁶³	Do not use concomitantly with rifampin or isoniazid²⁶³
Benzodiazepines (midazolam, triazolam)	Increased plasma concentrations of midazolam or triazolam; possible prolonged sedative and hypnotic effects of the drugs²⁶³	Ketoconazole should not be used concomitantly with midazolam or triazolam²⁶³ Special precaution is required if parenteral midazolam is used in patients receiving ketoconazole because the sedative effects of midazolam may be prolonged²⁶³
Cisapride	Increased cisapride plasma concentrations and increased risk of adverse effects (e.g., cardiovascular effects)²⁶³ ²⁷⁶	Concomitant use contraindicated²⁶³
Digoxin	Increased plasma concentrations of digoxin reported; causative relationship unclear²⁶³	Closely monitor digoxin concentrations in patients receiving ketoconazole²⁶³
Histamine H₂-receptor antagonists (e.g., cimetidine, ranitidine)	Because gastric acidity is necessary for dissolution and absorption of ketoconazole, concomitant administration of histamine H₂-receptor antagonists may decrease absorption of the antifungal ²⁶³	Administer H₂-receptor antagonist at least 2 hours after ketoconazole²⁶³
Immunosuppressive agents (cyclosporine, methylprednisolone, prednisone, tacrolimus)	Cyclosporine or tacrolimus: Increased concentrations of the immunosuppressive agent¹⁴² ¹⁴³ ¹⁴⁴ ²⁶³ ³⁷² Methylprednisolone or prednisone: Increased concentrations of the corticosteroid and possible enhanced adrenal suppression²²⁷ ²²⁸ ²³² ²³³	Cyclosporine or tacrolimus: Use with caution and monitor concentrations of the immunosuppressive agent if possible; adjust cyclosporine or tacrolimus dosage if needed when ketoconazole is initiated or discontinued¹⁴⁶ ²⁶³ Methylprednisolone or prednisolone: Adjust dosage of the corticosteroid as needed²²⁷ ²²⁸ ²⁶³
Paclitaxel	In vitro evidence that ketoconazole can inhibit metabolism of paclitaxel²⁶⁹	Clinical importance unclear; use concomitantly with caution²⁶⁹
Sucralfate	Possible decreased absorption of ketoconazole³⁶²	Administer sucralfate at least 2 hours after ketoconazole³⁶²
Theophylline	Conflicting data;¹⁴⁷ ¹⁵⁰ possible decreased theophylline concentrations¹⁴⁷	Pending further accumulation of data, monitor serum theophylline concentrations and adjust theophylline dosage if necessary when ketoconazole is initiated or discontinued in patients receiving theophylline¹⁴⁷

Ketoconazole Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed from GI tract;¹⁶² ¹⁶³ peak plasma concentrations attained within 1–2 hours.¹⁴⁹ ¹⁶² ²⁶³

Ketoconazole must be dissolved in gastric secretions and converted to the hydrochloride salt prior to absorption from the stomach.^a Bioavailability depends on the pH of the gastric contents in the stomach; an increase in pH results in decreased absorption of the drug.^a (See Absorption: Special Populations.)

Food

Effect of food on rate and extent of GI absorption of ketoconazole has not been clearly determined.¹⁶²

Plasma Concentrations

Considerable interindividual variations in peak plasma concentrations and AUCs have been reported.^a

Special Populations

Oral bioavailability may be decreased in patients with achlorhydria,^a including those with HIV-associated gastric hypochlorhydria.¹⁹⁸ ²⁰⁰ Concomitant administration of dilute hydrochloric acid solution usually normalizes absorption of the drug in these patients.¹⁹⁸ Concomitant administration of an acidic beverage may increase bioavailability in some individuals.²⁷³ (See Oral Administration under Dosage and Administration.)

Distribution

Extent

Distributed into urine, bile, saliva, sebum, cerumen, and synovial fluid.^a

May be distributed into CSF following oral administration, but CNS penetration is unpredictable and has generally been considered to be minimal.^a

Not known whether crosses the placenta in humans; crosses the placenta in rats.^a Distributed into milk of dogs; probably distributed into human milk.^a

Plasma Protein Binding

84–99% bound to plasma proteins, primarily albumin.²⁶³ ^a

Elimination

Metabolism

Partially metabolized in the liver to several inactive metabolites by oxidation and degradation of the imidazole and piperazine rings, by oxidative O-dealkylation, and by aromatic hydroxylation.^a

Elimination Route

Major route of elimination of ketoconazole and its metabolites appears to be excretion into the feces via the bile.^a

In fasting adults with normal renal function, approximately 57% of a single 200-mg oral dose is excreted in feces within 4 days (20–65% of this is unchanged drug); approximately 13% of the dose is excreted in urine within 4 days (2–4% of this is unchanged drug).^a

Half-life

Plasma concentrations appear to decline in a biphasic manner with a half-life of approximately 2 hours in the initial phase and 8 hours in the terminal phase.²⁶³

Special Populations

Plasma concentrations and half-life not substantially affected by renal or hepatic

Thursday, August 30, 2012

Tropicamide

Pronunciation: TROP-ik-ah-mide
Generic Name: Tropicamide
Brand Name: Examples include Mydral and Mydriacyl

Tropicamide is used for:

Dilating the pupil and paralyzing certain muscles in the eye for diagnostic tests. It may also be used for other conditions as determined by your doctor.

Tropicamide is an anticholinergic. It works by relaxing the muscles of the eye to cause the pupil to dilate or widen (mydriasis).

Do NOT use Tropicamide if:

you are allergic to any ingredient in Tropicamide

you have angle-closure glaucoma

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

Before using Tropicamide:

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

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

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

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

if you have glaucoma or you are at risk for glaucoma

Some MEDICINES MAY INTERACT with Tropicamide. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

Carbachol, ophthalmic cholinesterase inhibitors (eg, echothiophate), or pilocarpine because their effectiveness may be decreased by Tropicamide

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

How to use Tropicamide:

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

Remove contact lenses before using Tropicamide.

First, wash your hands. Tilt your head back. Using your index finger, pull the lower eyelid away from the eye to form a pouch. Drop the medicine into the pouch and gently close your eyes. Immediately use your finger to apply pressure to the inside corner of the eye for 2 or 3 minutes after using the medicine. Do not blink. Keep your eyes closed for 2 or 3 minutes. Remove excess medicine around your eye with a clean tissue, being careful not to touch your eye. Wash your hands to remove any medicine that may be on them.

To prevent germs from contaminating your medicine, do not touch the applicator tip to any surface, including your eye. Keep the container tightly closed.

Use Tropicamide only in the eye. Do not get Tropicamide in your mouth or nose.

Wash your hands after using Tropicamide. If the patient is a child, wash the child's hands as well.

If you miss a dose of Tropicamide, contact your doctor for instructions.

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

Important safety information:

Tropicamide may cause blurred vision or sensitivity to sunlight. Wear sunglasses if you are outside in the bright sunlight. Do not drive, operate machinery, or do anything else that could be dangerous unless you can see clearly.

If you have an appointment for an eye examination and your doctor has told you that you will receive Tropicamide, be sure to make arrangements to have someone drive you home in case your vision is blurry.

Tropicamide may be harmful if swallowed. If you may have taken Tropicamide by mouth, contact your local poison control center or emergency room immediately.

Pupil dilation usually reverses within 4 to 8 hours after use, but may last as long as 24 hours.

Caution is advised when using Tropicamide in CHILDREN because they may be more sensitive to its effects, especially mental or mood changes.

PREGNANCY and BREAST-FEEDING: If you become pregnant, discuss with your doctor the benefits and risks of using Tropicamide during pregnancy. It is unknown if Tropicamide is excreted in breast milk. If you are or will be breast-feeding while you are using Tropicamide, check with your doctor or pharmacist to discuss the risks to your baby.

Possible side effects of Tropicamide:

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

Blurred vision; burning; dry mouth; headache; nausea; sensitivity to sunlight; temporary stinging.

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

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); behavioral changes, especially in children; eye pain; irregular or rapid heartbeat; mental or mood changes, especially in children; paleness or flushing of the skin; rigid muscles; shortness of breath; vomiting.

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

See also: Tropicamide side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.

Proper storage of Tropicamide:

Store Tropicamide at room temperature, between 46 and 80 degrees F (8 and 27 degrees C). Store away from heat, moisture, and light. Do not refrigerate. Do not store in the bathroom. Keep Tropicamide out of the reach of children and away from pets.

General information:

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

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

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

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

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

Issue Date: February 1, 2012

Database Edition 12.1.1.002

More Tropicamide resources

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

Mydral Ophthalmic Advanced Consumer (Micromedex) - Includes Dosage Information

Mydriacyl Prescribing Information (FDA)

Mydriacyl Concise Consumer Information (Cerner Multum)

Ocu-Tropic Advanced Consumer (Micromedex) - Includes Dosage Information

Tropicacyl Prescribing Information (FDA)

Compare Tropicamide with other medications

Organophosphate Poisoning
Pupillary Dilation
Refraction, Assessment

Wednesday, August 22, 2012

Konsyl

Generic Name: psyllium (SIL ee um)

Brand Names: Fiberall, Hydrocil, Konsyl, Konsyl Orange Sugar-free, Konsyl-D, Konsyl-Orange, Laxmar, Laxmar Orange, Laxmar Sugar Free, Metamucil, Metamucil Berry Burst Smooth Texture Sugar Free, Metamucil Orange Coarse Milled Original Texture, Metamucil Orange Smooth Texture, Metamucil Orange Smooth Texture Sugar Free, Metamucil Original Texture Regular, Metamucil Pink Lemonade Smooth Texture Sugar-Free, Metamucil Unflavored Coarse Milled Original Texture, Metamucil Unflavored Smooth Texture Sugar Free, Natural Fiber Therapy, Perdiem Fiber Powder, Reguloid

What is Konsyl (psyllium)?

Psyllium is a bulk-forming fiber laxative. Psyllium works by absorbing liquid in the intestines and swelling to create a softer, bulky stool that is easier to pass.

Psyllium is used to treat occasional constipation or bowel irregularity. Psyllium may also be used to treat diarrhea and may help lower cholesterol when used together with a diet low in cholesterol and saturated fat.

Psyllium may also be used for purposes not listed in this product guide.

What is the most important information I should know about Konsyl (psyllium)?

Laxatives may be habit-forming if they are used too often or for too long. This can lead to damage of intestinal nerves or muscle tissues. Do not take psyllium for longer than directed on the label or prescribed by your doctor. You should not take this product if you are allergic to psyllium, or if you have trouble swallowing, a sudden change in bowel habits that lasts longer than 2 weeks, severe nausea, vomiting, or stomach pain, or if you have ever had a skin rash while taking psyllium.

Also talk with your doctor before using psyllium if you have a colostomy or ileostomy, rectal bleeding, or a blockage in your intestines.

Stop using psyllium and call your doctor at once if you have choking or trouble swallowing, severe stomach pain or cramping, nausea or vomiting, constipation that lasts longer than 7 days, rectal bleeding, or itchy skin rash. Do not take psyllium for longer than 7 days in a row unless your doctor has told you to.

What should I discuss with my healthcare provider before taking Konsyl (psyllium)?

trouble swallowing;

a sudden change in bowel habits that lasts longer than 2 weeks;

severe nausea, vomiting, or stomach pain; or

if you have ever had a skin rash while taking psyllium.

Ask a doctor or pharmacist if it is safe for you to take this medicine if you have:

a colostomy or ileostomy;

rectal bleeding; or

a blockage in your intestines.

Psyllium products may contain sugar, sodium, or artificial sweeteners. This may be of concern to you if you have diabetes, high blood pressure, or phenylketonuria (PKU). Check the product label if you have any of these conditions.

Psyllium is not expected to be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. It is not known whether psyllium passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I take Konsyl (psyllium)?

Use exactly as directed on the label, or as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended.

Take psyllium with a full glass (at least 8 ounces) of water or another liquid. Taking psyllium without enough liquid may cause it to swell in your throat and cause choking. Drinking plenty of fluids each day while you are taking psyllium will also help improve bowel regularity.

The psyllium wafer must be chewed before you swallow it.

Do not swallow psyllium powder dry. It must be mixed with liquid. Place the psyllium powder into an empty glass and add at least 8 ounces of water or other liquid such as fruit juice. Stir this mixture and drink all of it right away.

If the powder and liquid mixture is too thick, add more liquid. After drinking the entire mixture, add a little more liquid to the same glass, swirl gently and drink right away to make sure you get the entire dose of psyllium.

Psyllium may be only part of a complete program of treatment that also includes diet, exercise, and weight control. Follow your diet, medication, and exercise routines very closely.

It may take up to 3 days of using this medicine before your symptoms improve. For best results, keep using the medication as directed. Talk with your doctor if your symptoms do not improve after 2 or 3 days of treatment.

Do not take psyllium for longer than 7 days in a row unless your doctor has told you to. Store at room temperature away from moisture and heat.

What happens if I miss a dose?

Since psyllium is used as needed, it does not have a daily dosing schedule. Call your doctor promptly if your symptoms do not improve after using psyllium.

What happens if I overdose?

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

Overdose symptoms may include nausea, vomiting, and stomach pain. Using a laxative too often or for too long may cause severe medical problems involving your intestines.

What should I avoid while taking Konsyl (psyllium)?

Avoid taking other oral (by mouth) medications within 2 hours before or after you take psyllium. Bulk-forming laxatives can make it harder for your body to absorb other medications, possibly making them less effective.

Avoid breathing in the dust from psyllium powder when mixing. Inhaling psyllium dust may cause an allergic reaction.

If you take psyllium as part of a cholesterol-lowering treatment plan, avoid eating foods that are high in fat or cholesterol. Your treatment will not be as effective in lowering your cholesterol if you do not follow a cholesterol-lowering diet plan.

Konsyl (psyllium) side effects

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

choking or trouble swallowing;

severe stomach pain, cramping, nausea or vomiting;

constipation that lasts longer than 7 days;

rectal bleeding; or

itchy skin rash.

Less serious side effects may include:

bloating; or

minor change in your bowel habits.

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

What other drugs will affect Konsyl (psyllium)?

Tell your doctor about all other medications you use, especially:

a blood thinner such as warfarin (Coumadin, Jantoven); or

demeclocycline (Declomycin), doxycycline (Adoxa, Doryx, Oracea, Vibramycin), minocycline (Dynacin, Minocin, Solodyn, Vectrin), or tetracycline (Brodspec, Panmycin, Sumycin, Tetracap).

This list is not complete and other drugs may interact with psyllium. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More Konsyl resources

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

Konsyl Powder MedFacts Consumer Leaflet (Wolters Kluwer)

Metamucil MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Konsyl with other medications

Constipation
Dietary Fiber Supplementation
Irritable Bowel Syndrome

Where can I get more information?

Your pharmacist can provide more information about psyllium.

See also: Konsyl side effects (in more detail)

Saturday, August 18, 2012

Ticarcillin/Clavulanate

Pronunciation: TYE-kar-SIL-in/KLAV-ue-la-nate
Generic Name: Ticarcillin/Clavulanate
Brand Name: Timentin

Ticarcillin/Clavulanate is used for:

Treating infections caused by certain bacteria.

Ticarcillin/Clavulanate is a penicillin antibiotic. It works by blocking the growth of the bacteria's cell wall, resulting in the death of the bacteria.

Do NOT use Ticarcillin/Clavulanate if:

you are allergic to any ingredient in Ticarcillin/Clavulanate or to penicillin antibiotics (eg, amoxicillin)

you are taking a tetracycline antibiotic (eg, doxycycline)

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

Before using Ticarcillin/Clavulanate:

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

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

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

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

if you have had a severe allergic reaction (eg, severe rash, hives, difficulty breathing, dizziness) to a cephalosporin (eg, cephalexin) or other beta-lactam antibiotic (eg, imipenem)

if you have kidney problems, bleeding or clotting problems, heart failure, or abnormal blood electrolyte levels, or if you are dehydrated

if you are on a low-salt diet

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

Anticoagulants (eg, warfarin) because their effectiveness may be decreased or the risk of their side effects may be increased by Ticarcillin/Clavulanate

Probenecid because it may increase the amount of Ticarcillin/Clavulanate in your blood

Tetracyclines (eg, doxycycline) because they may decrease Ticarcillin/Clavulanate's effectiveness

Heparin or methotrexate because the risk of their side effects may be increased by Ticarcillin/Clavulanate

Aminoglycosides (eg, gentamicin) or oral contraceptives (eg, birth control pills) because their effectiveness may be decreased by Ticarcillin/Clavulanate

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

How to use Ticarcillin/Clavulanate:

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

Ticarcillin/Clavulanate is usually given as an injection at your doctor's office, hospital, or clinic. If you will be using Ticarcillin/Clavulanate at home, a health care provider will teach you how to use it. Be sure you understand how to use Ticarcillin/Clavulanate. Follow the procedures you are taught when you use a dose. Contact your health care provider if you have any questions.

Do not use Ticarcillin/Clavulanate if it contains particles, is cloudy or discolored, or if the vial is cracked or damaged.

To clear up your infection completely, use Ticarcillin/Clavulanate for the full course of treatment. Keep taking it even if you feel better in a few days.

Keep this product, as well as syringes and needles, out of the reach of children and pets. Do not reuse needles, syringes, or other materials. Ask your health care provider how to dispose of these materials after use. Follow all local rules for disposal.

If you miss a dose of Ticarcillin/Clavulanate, use it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not use 2 doses at once.

Ask your health care provider any questions you may have about how to use Ticarcillin/Clavulanate.

Important safety information:

Ticarcillin/Clavulanate only works against bacteria; it does not treat viral infections (eg, the common cold).

Be sure to use Ticarcillin/Clavulanate for the full course of treatment. If you do not, the medicine may not clear up your infection completely. The bacteria could also become less sensitive to this or other medicines. This could make the infection harder to treat in the future.

Long-term or repeated use of Ticarcillin/Clavulanate may cause a second infection. Tell your doctor if signs of a second infection occur. Your medicine may need to be changed to treat this.

Mild diarrhea is common with antibiotic use. However, a more serious form of diarrhea (pseudomembranous colitis) may rarely occur. This may develop while you use the antibiotic or within several months after you stop using it. Contact your doctor right away if stomach pain or cramps, severe diarrhea, or bloody stools occur. Do not treat diarrhea without first checking with your doctor.

Ticarcillin/Clavulanate may reduce the number of clot-forming cells (platelets) in your blood. Avoid activities that may cause bruising or injury. Tell your doctor if you have unusual bruising or bleeding. Tell your doctor if you have dark, tarry, or bloody stools.

Tell your doctor or dentist that you take Ticarcillin/Clavulanate before you receive any medical or dental care, emergency care, or surgery.

Hormonal birth control (eg, birth control pills) may not work as well while you are using Ticarcillin/Clavulanate. To prevent pregnancy, use an extra form of birth control (eg, condoms).

Ticarcillin/Clavulanate may interfere with certain lab tests. Be sure your doctor and lab personnel know you are using Ticarcillin/Clavulanate.

Lab tests, including kidney or liver function tests, complete blood cell counts, or blood electrolyte levels, may be performed while you use Ticarcillin/Clavulanate. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.

Use Ticarcillin/Clavulanate with caution in the ELDERLY; they may be more sensitive to its effects.

Ticarcillin/Clavulanate should be used with extreme caution in CHILDREN younger than 3 months old; safety and effectiveness in these children have not been confirmed.

Use Ticarcillin/Clavulanate with extreme caution in CHILDREN younger than 10 years old who have diarrhea or an infection of the stomach or bowel.

PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Ticarcillin/Clavulanate while you are pregnant. It is not known if Ticarcillin/Clavulanate is found in breast milk. If you are or will be breast-feeding while you use Ticarcillin/Clavulanate, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Ticarcillin/Clavulanate:

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

Changes in taste and smell; diarrhea; gas; giddiness; headache; nausea; pain, swelling, or redness at the injection site; stomach pain; vomiting.

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

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); bloody stools; chest pain; dark or bloody urine; fever, chills, or sore throat; joint or muscle pain; persistent painful urination; red, swollen, or blistered skin; seizures; severe diarrhea; severe stomach pain/cramps; swelling in the mouth; unusual bruising or bleeding; vaginal irritation or discharge; vein swelling or tenderness; yellowing of the eyes or skin.

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include agitation; confusion; hallucinations; seizures; severe excitability; tremor; unconsciousness.

Proper storage of Ticarcillin/Clavulanate:

Ticarcillin/Clavulanate is usually handled and stored by a health care provider. If you are using Ticarcillin/Clavulanate at home, store Ticarcillin/Clavulanate as directed by your pharmacist or health care provider. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Ticarcillin/Clavulanate out of the reach of children and away from pets.

General information:

If you have any questions about Ticarcillin/Clavulanate, please talk with your doctor, pharmacist, or other health care provider.

Ticarcillin/Clavulanate is to be used only by the patient for whom it is prescribed. Do not share it with other people.

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

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

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

Issue Date: February 1, 2012

Database Edition 12.1.1.002

More Ticarcillin/Clavulanate resources

Ticarcillin/Clavulanate Use in Pregnancy & Breastfeeding
Ticarcillin/Clavulanate Drug Interactions
Ticarcillin/Clavulanate Support Group
0 Reviews for Ticarcillin/Clavulanate - Add your own review/rating

Compare Ticarcillin/Clavulanate with other medications

Aspiration Pneumonia
Bacteremia
Bacterial Infection
Bone infection
Deep Neck Infection
Endometritis
Febrile Neutropenia
Intraabdominal Infection
Joint Infection
Kidney Infections
Pelvic Inflammatory Disease
Peritonitis
Pneumonia
Pneumonia with Cystic Fibrosis
Septicemia
Skin Infection
Urinary Tract Infection

Perio Med

Generic Name: fluoride topical (FLOR ide TOP i kal)

Brand Names: ACT Fluoride Rinse, ACT Kids Fluoride Rinse, ACT Restoring Mouthwash Cinnamon, ACT Restoring Mouthwash Mint, ACT Restoring Mouthwash Spearmint, ACT Restoring Mouthwash Vanilla Mint, Control Rx, Denta 5000 Plus, Dentagel, Ethedent, Fluoridex, Fluoridex Daily Defense, Fluoridex Daily Defense Enhanced Whitening, Fluorigard, Fluorinse, Gel-Kam, Gel-Kam Dental Therapy Pak, Gel-Kam Dentinbloc, Gel-Kam Sensitivity Therapy, NaFrinse Daily/Acidulated, NaFrinse Daily/Neutral, Nafrinse Solution, NaFrinse Weekly, Neutracare Gel, Neutragard, Neutragard Advanced, Neutral Sodium Fluoride Rinse, Omnii Gel, Omnii Gel Just For Kids, Oral B Anti-Cavity, Perfect Choice, Perio Med, Phos-Flur, Prevident, Prevident 500 Plus Boost, PreviDent 5000 Booster, Prevident 5000 Dry Mouth, Prevident 5000 Plus, Prevident 5000 Sensitive, Prevident Dental Rinse, SF, SF 5000 Plus, Stop, Thera-Flur-N

What is Perio Med (fluoride topical)?

Fluoride is a substance that strengthens tooth enamel. This helps to prevent dental cavities.

Fluoride topical is used as a medication to prevent tooth decay in patients that have a low level of fluoride topical in their drinking water. Fluoride topical is also used to prevent tooth decay in patients who undergo radiation of the head and/or neck, which may cause dryness of the mouth and an increased incidence of tooth decay.

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

What is the most important information I should know about Perio Med (fluoride topical)?

Fluoride topical should not be used if the level of fluoride in the drinking water is greater than 0.7 parts per million (ppm).

Before using fluoride topical, tell your dentist and doctor if you are on a low salt or a salt free diet. You may not be able to use fluoride topical, or you may need special tests while you are using it.

Do not eat, drink, or rinse your mouth for 30 minutes after using a fluoride topical. Do not swallow fluoride topical. Spit it out after use. Do not allow a child to swallow fluoride topical or serious overdose symptoms could result.

Overdose symptoms may result if you swallow large amounts of fluoride while using it.

What should I discuss with my healthcare provider before using Perio Med (fluoride topical)?

Fluoride topical should not be used if the level of fluoride in the drinking water is greater than 0.7 parts per million (ppm).

If you have gum disease, some forms of fluoride topical may be irritating to your gums. Talk to your dentist or doctor if you have bothersome mouth irritation while using fluoride topical.

Talk to your doctor and dentist before using fluoride topical if you are pregnant. Talk to your doctor and dentist before using fluoride topical if you are breast-feeding. The use of fluoride is particularly important in children to protect against tooth decay. The American Dental Association's Council on Dental Therapeutics recommends the use of fluoride by children up to 13 years of age. The American Academy of Pediatrics recommends fluoride supplementation in children until the age of 16 years old. Do not allow a child to swallow fluoride topical or serious overdose symptoms could result.

How should I use Perio Med (fluoride topical)?

Use this medication exactly as directed on the label, or as it was prescribed by your dentist or doctor. Do not use it in larger amounts or for longer than recommended. Follow the directions on your prescription label.

Fluoride topical should be used immediately after brushing or flossing your teeth. For best results, use the medication just before bedtime, unless your doctor tells you otherwise.

Swish this medication in your mouth without swallowing. Then spit it out.

Do not eat, drink, or rinse your mouth for 30 minutes after using fluoride topical. Store fluoride topical at room temperature away from moisture and heat.

What happens if I miss a dose?

Use the missed dose as soon as you remember. If it is almost time for your next dose, wait until then to use the medicine and skip the missed dose. Do not use extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine.

Overdose symptoms may include nausea, vomiting, stomach pain, diarrhea, drooling, numbness or tingling, loss of feeling anywhere in your body, muscle stiffness, or seizure (convulsions).

Overdose symptoms may result if you swallow large amounts of fluoride while using it.

What should I avoid while using Perio Med (fluoride topical)?

Do not swallow fluoride topical. Spit it out after use.

Perio Med (fluoride topical) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor if you have any of the following side effects:

discolored teeth;

weakened tooth enamel; or

any changes in the appearance of your teeth.

Less serious side effects may include:

stomach upset;

headache; or

weakness.

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

What other drugs will affect Perio Med (fluoride topical)?

It is not likely that other drugs you take orally or inject will have an effect on topically applied fluoride. But many drugs can interact with each other. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.

More Perio Med resources

Perio Med Side Effects (in more detail)
Perio Med Use in Pregnancy & Breastfeeding
Perio Med Support Group
0 Reviews for Perio Med - Add your own review/rating

Perio Med Rinse MedFacts Consumer Leaflet (Wolters Kluwer)

APF Gel Advanced Consumer (Micromedex) - Includes Dosage Information

EtheDent Chewable Tablets MedFacts Consumer Leaflet (Wolters Kluwer)

Phos-Flur Cream MedFacts Consumer Leaflet (Wolters Kluwer)

PreviDent 5000 Sensitive MedFacts Consumer Leaflet (Wolters Kluwer)

Prevident 5000 Booster Prescribing Information (FDA)

Prevident 5000 Dry Mouth Prescribing Information (FDA)

Prevident 5000 Enamel Protect Prescribing Information (FDA)

Prevident 5000 Sensitive Prescribing Information (FDA)

Compare Perio Med with other medications

Prevention of Dental Caries

Where can I get more information?

Your pharmacist can provide more information about fluoride topical.

See also: Perio Med side effects (in more detail)

Friday, August 17, 2012

Thyrogen

thyrotropin alfa

Dosage Form: injection, powder, for solution

Thyrogen Description

Thyrogen® (thyrotropin alfa for injection) contains a highly purified recombinant form of human thyroid stimulating hormone (TSH), a glycoprotein which is produced by recombinant DNA technology. Thyrotropin alfa is synthesized in a genetically modified Chinese hamster ovary cell line.

Thyrotropin alfa is a heterodimeric glycoprotein comprised of two non-covalently linked subunits, an alpha subunit of 92 amino acid residues containing two N-linked glycosylation sites and a beta subunit of 118 residues containing one N-linked glycosylation site. The amino acid sequence of thyrotropin alfa is identical to that of human pituitary thyroid stimulating hormone.

Both thyrotropin alfa and naturally occurring human pituitary thyroid stimulating hormone are synthesized as a mixture of glycosylation variants. Unlike pituitary TSH, which is secreted as a mixture of sialylated and sulfated forms, thyrotropin alfa is sialylated but not sulfated. The biological activity of thyrotropin alfa is determined by a cell-based bioassay. In this assay, cells expressing a functional TSH receptor and a cAMP-responsive element coupled to a heterologous reporter gene, luciferase, enable the measurement of rhTSH activity by measuring the luciferase response. The specific activity of thyrotropin alfa is determined relative to an internal Genzyme reference standard that was calibrated against the World Health Organization (WHO) human TSH reference standard.

Thyrogen is supplied as a sterile, non-pyrogenic, white to off-white lyophilized product, intended for intramuscular (IM) administration after reconstitution with Sterile Water for Injection, USP. Each vial of Thyrogen contains 1.1 mg thyrotropin alfa, 36 mg Mannitol, 5.1 mg Sodium Phosphate, and 2.4 mg Sodium Chloride.

After reconstitution with 1.2 mL of Sterile Water for Injection, USP, the thyrotropin alfa concentration is 0.9 mg/mL. The pH of the reconstituted solution is approximately 7.0.

Thyrogen - Clinical Pharmacology

Pharmacodynamics

Thyrotropin alfa (recombinant human thyroid stimulating hormone) is a heterodimeric glycoprotein produced by recombinant DNA technology. It has comparable biochemical properties to the human pituitary TSH. Binding of thyrotropin alfa to TSH receptors on normal thyroid epithelial cells or on well-differentiated thyroid cancer tissue stimulates iodine uptake and organification, and synthesis and secretion of thyroglobulin (Tg), triiodothyronine (T3) and thyroxine (T4).

In patients with thyroid cancer, a near-total or total thyroidectomy is usually performed. Thyroidectomy is usually followed by radioiodine treatment to remove any remnant of normal thyroid tissue and microscopic residues of malignant tissue. Prior to radioiodine remnant ablation, serum TSH elevation is necessary to promote uptake of radioiodine by thyroid cells or thyroid cancer cells. Elevation of TSH may be achieved by withholding of synthetic thyroid hormone medication after thyroidectomy, with subsequent rise of endogenous pituitary thyroid stimulating hormone; or by administration of thyrotropin in the setting of synthetic thyroid hormone administration. After remnant ablation, patients are placed on synthetic thyroid hormone supplements to replace endogenous hormone and to suppress serum levels of TSH in order to avoid TSH-stimulated tumor growth. Thereafter, patients are followed for the presence of remnants, or of residual or recurrent cancer, by thyroglobulin (Tg) testing, usually with radioiodine imaging. This follow-up testing is most effective when conducted under TSH stimulation, achieved either by thyroid hormone withdrawal or administration of thyrotropin. Thyroid hormone withdrawal results in hypothyroidism with subsequent elevation of endogenous pituitary TSH; when thyrotropin is used, patients remain on thyroid hormone suppressive therapy and are euthyroid.

Pharmacokinetics

The pharmacokinetics of Thyrogen were studied in 16 patients with well-differentiated thyroid cancer given a single 0.9 mg IM dose. Mean peak concentrations of 116 ± 38 mU/L were reached between 3 and 24 hours after injection (median of 10 hours). The mean apparent elimination half-life was 25 ± 10 hours. The organ(s) of TSH clearance in man have not been identified, but studies of pituitary-derived TSH suggest the involvement of the liver and kidneys.

Clinical Trials

Clinical Trials of Thyrogen as an Adjunctive Diagnostic Tool:

Two phase 3 clinical trials were conducted in 358 evaluable patients with well-differentiated thyroid cancer to compare 48-hour radioiodine (131I) whole body scans obtained after Thyrogen to whole body scans after thyroid hormone withdrawal. One of these trials also compared Tg levels obtained after Thyrogen to those on thyroid hormone suppressive therapy, and to those after thyroid hormone withdrawal. All Tg testing was performed in a central laboratory using a radioimmunoassay (RIA) with a functional sensitivity of 2.5 ng/mL. Only successfully ablated patients (defined as patients who have undergone total or near-total thyroidectomy with or without radioiodine ablation, and with < 1% uptake in the thyroid bed on a scan after thyroid hormone withdrawal) without detectable anti-thyroglobulin antibodies were included in the Tg data analysis. The maximum Thyrogen Tg value was obtained 72 hours after the final Thyrogen injection, and this value was used in the analysis (see DOSAGE AND ADMINISTRATION).

Diagnostic Radioiodine Whole Body Scan Results

Table 1 summarizes the scan data in patients with positive scans after withdrawal of thyroid hormone from the diagnostic phase 3 studies:

Table 1: Scan Data in Patients with Positive Scans
	# scan pairs by disease category	#(%) scan pairs in which Thyrogen® scan detected disease seen on withdrawal scan	#(%) scan pairs in which Thyrogen® scan did not detect disease seen on withdrawal scan
* Across all studies, uptake was detected on the Thyrogen scan but not observed on the scan after thyroid hormone withdrawal in 5 patients with remnant or cancer in the thyroid bed.
First Phase 3 Study (0.9 mg IM qd x 2)
positive for remnant or cancer in thyroid bed	48	39(81)	9(19)
metastatic disease	15	11(73)	4(27)
total positive withdrawal scans*	63	50(79)	13(21)

Second Phase 3 Study (0.9 mg IM qd x 2)
positive for remnant or cancer in thyroid bed	35	30(86)	5(14)
metastatic disease	9	6(67)	3(33)
total positive withdrawal scans*	44	36(82)	8(18)

Second Phase 3 Study (0.9 mg IM q 72 hrs x 3)
positive for remnant or cancer in thyroid bed	41	35(85)	6(15)
metastatic disease	14	12(86)	2(14)
total positive withdrawal scans*	55	47(85)	8(15)

Across the two clinical studies, the Thyrogen scan failed to detect remnant and/or cancer localized to the thyroid bed in 16% (20/124) of patients in whom it was detected by a scan after thyroid hormone withdrawal. In addition, the Thyrogen scan failed to detect metastatic disease in 24% (9/38) of patients in whom it was detected by a scan after thyroid hormone withdrawal.

Thyroglobulin (Tg) Results:

Thyrogen Tg Testing Alone and in Combination with Diagnostic Whole Body Scanning: Comparison with Results after Thyroid Hormone Withdrawal:

In Tg antibody negative patients with a thyroid remnant or cancer as defined by a withdrawal Tg ≥ 2.5 ng/mL or a positive scan (after thyroid hormone withdrawal or after radioiodine therapy), the Thyrogen Tg was ≥ 2.5 ng/mL in 69% (40/58) of patients after 2 doses of Thyrogen, and in 80% (53/66) of patients after 3 doses of Thyrogen. Across both dosage groups, 45% had a Tg ≥ 2.5 ng/mL on thyroid hormone suppressive therapy.

In these same patients, adding the whole body scan increased the detection rate of thyroid remnant or cancer to 84% (49/58) of patients after 2 doses of Thyrogen and 94% (62/66) of patients after 3 doses of Thyrogen.

Thyrogen Tg Testing Alone and in Combination with Diagnostic Whole Body Scanning in Patients with Confirmed Metastatic Disease:

Metastatic disease was confirmed by a post-treatment scan or by lymph node biopsy in 35 patients. Thyrogen Tg was ≥ 2.5 ng/mL in all 35 patients while Tg on thyroid hormone suppressive therapy was ≥ 2.5 ng/mL in 79% of these patients.

In this same cohort of 35 patients with confirmed metastatic disease, the Thyrogen Tg levels were below 10 ng/mL in 27% (3/11) of patients after 2 doses of Thyrogen and in 13% (3/24) of patients after 3 doses of Thyrogen. The corresponding thyroid hormone withdrawal Tg levels in these 6 patients were 15.6 – 137 ng/mL. The Thyrogen scan detected metastatic disease in 1 of these 6 patients (see INDICATIONS AND USAGE, Considerations in the Use of Thyrogen).

As with thyroid hormone withdrawal, the intra-patient reproducibility of Thyrogen testing with regard to both Tg stimulation and radioiodine imaging has not been studied.

Clinical Trials of Thyrogen as an Adjunct to Radioiodine Therapy to Achieve Thyroid Remnant Ablation:
A randomized prospective clinical trial comparing the rates of thyroid remnant ablation achieved after preparation of patients either with hypothyroidism or Thyrogen has been performed. Patients (n = 63) with low-risk well-differentiated thyroid cancer underwent near-total thyroidectomy, then were equally randomized to the Hypothyroid group (serum TSH > 25 µU/mL) or thyroxine replacement (Euthyroid group; serum TSH < 5 µU/mL). Patients in the Euthyroid group then received Thyrogen 0.9 mg IM daily on two consecutive days, and then radioiodine 24 hours after the second dose of Thyrogen. All patients received 100 mCi 131I ± 10% with the intent to ablate any thyroid remnant tissue. The primary endpoint of the study, which was the success of ablation, was assessed 8 months later by a Thyrogen-stimulated radioiodine scan. Patients were considered successfully ablated if there was no visible thyroid bed uptake on the scan, or if visible, uptake was less than 0.1%. Table 2 summarizes the results of this evaluation.

Table 2: Results from the Remnant Ablation Clinical Trial
Group*	Mean Age (Yr)	Gender (F:M)	Cancer Type (Pap:Fol)	Ablation Criterion (Measure at 8 Months)
* 60 per protocol patients with interpretable scan data. 95% CI for difference in ablation rates, rTSH minus THW, = -6.9% to 27.1%. † Interpretation by 2 of 3 reviewers. 95% CI for difference in ablation rates, rTSH minus THW, = -30.5% to 9.1%. Abbreviations: fol = follicular, pap = papillary, THW = thyroid hormone withdrawal
				Thyroid Bed Activity ‹0.1%	No Visible Thyroid Bed Activity†
THW (N=28)	43	24:6	29:1	28/28 (100)	24/28 (86)
rTSH (N=32)	44	26:7	30:3	32/32 (100)	24/32 (75)

The mean radiation dose to blood was 0.266±0.061 mGy/MBq in the Euthyroid group and 0.395±0.135 mGy/MBq in the Hypothyroid group (p<0.0001). Radioiodine residence time in remnant tissue was 0.9±1.3 hours in the Euthyroid group and 1.4±1.5 hours in the Hypothyroid group. It is not known whether this difference in radiation exposure would convey a clinical benefit.

A follow-up study was conducted on patients who previously completed the initial study. The main objective of the follow-up study was to confirm the status of thyroid remnant ablation by using Thyrogen-stimulated radioiodine static neck imaging after a median follow-up of 3.7 years (range 3.4 to 4.4 years) following radioiodine ablation. Thyroglobulin testing was also performed.

Sixty-one male and female thyroidectomized patients who participated in the original study (Table 2) were planned for inclusion in this follow-up study. Fifty-one patients were enrolled in this study; 48 received Thyrogen for remnant neck/whole body imaging and/or Tg testing (three patients underwent the collection of medical history portion of the study but did not undergo stimulated neck/WB scanning or testing). Patients were still considered to be successfully ablated if there was no visible thyroid bed uptake on the scan, or if visible, uptake was less than 0.1% (Table 3).

Table 3: Summary of Thyroid Remnant Ablation During the 3.7-Year Follow-Up of Patients Treated in the Initial Study
Uptake in Thyroid Bed	Former THW* Group (n=18) N (%)	Former rTSH Group (n=25) N (%)
* THW = Thyroid Hormone Withdrawal
No Visibile Uptake in Thyroid Bed or Uptake ‹ 0.1%	18 (100)	25 (100)

Of note, 9 patients (distributed similarly in both treatment groups: 5 former Hypothyroid and 4 former Euthyroid patients) received 131I (approximately 100 mCi (3.7 GBq) or more) during the period between the end of the initial study and the initiation of this follow-up study. When considering only the patients who did not receive radioiodine during the period between studies, 100% of patients in both treatment subgroups (15 former Hypothyroid and 22 former Euthyroid patients) were successfully ablated according to the predefined study criteria.

Successful ablation also can be inferred when the Thyrogen-stimulated serum Tg level is < 2 ng/mL, although a lower Tg level might also be used as a criterion by some experts. The presence of antithyroglobulin antibodies can render results of thyroglobulin assays uninterpretable. A total of 17 patients in the former Hypothyroid group and 20 patients in the former Euthyroid group had antithyroglobulin antibody levels <5 units/mL. Of these patients, 16/17 (94%) of patients in the former Hypothyroid group and 19/20 (95%) of patients in the former Euthyroid group had stimulated serum thyroglobulin levels of <2 ng/mL.

No patient had a definitive cancer recurrence during the 3.7 years of follow-up. Overall, 48/51 patients (94%) had no evidence of cancer recurrence, 1 patient had possible cancer recurrence (although it was not clear whether this patient had a true recurrence or persistent tumor from the regional disease noted at the start of the initial study), and 2 patients could not be assessed.

In summary, in this study and its follow-up study, Thyrogen was noninferior to thyroid hormone withholding for elevation of TSH levels as adjunctive therapy to radioiodine for post-surgical ablation of remnant thyroid tissue.

Several publications describe studies or series of patients in which Thyrogen was used as an adjunct to radioiodine for the ablation of thyroid remnant tissue. Some publications1-4 found comparable rates of remnant ablation whether patients were prepared using hypothyroidism or Thyrogen, whereas another publication5 found that hypothyroidism had a better rate of success than Thyrogen, although in that study the radioiodine was administered 48 hours rather than 24 hours after the second dose of Thyrogen. Follow-up for 2.5 years of patients undergoing ablation at Memorial Sloan-Kettering has shown that use of Thyrogen results in a low rate of tumor recurrence that is comparable to the rate seen after use of withdrawal from thyroxine.6

Quality of Life:

Quality of Life (QOL) was measured during both the diagnostic study and the ablation of thyroid remnant study, using the SF-36 Health Survey, a standardized, patient-administered instrument assessing QOL across eight domains measuring both physical and mental functioning. In the diagnostic study and in the remnant ablation study, following Thyrogen administration, little change from baseline was observed in any of the eight QOL domains of the SF-36. Following thyroid hormone withdrawal in the diagnostic study, statistically significant negative changes were noted in all eight QOL domains of the SF-36. The difference between treatment groups was statistically significant (p<0.0001) for all eight QOL domains, favoring Thyrogen over thyroid hormone withdrawal (Figure 1). In the remnant ablation study, following thyroid hormone withdrawal, statistically significant negative changes were noted in five of the eight QOL domains (physical functioning, role physical, vitality, social functioning and mental health). The difference between treatment groups was statistically significant (p<0.05), favoring Thyrogen over thyroid hormone withdrawal.

FIGURE 1 – SF-36 HEALTH SURVEY RESULTS

QUALITY OF LIFE DOMAINS

DIAGNOSTIC INDICATION

Hypothyroid Signs and Symptoms - Diagnostic Indication:

Thyrogen administration was not associated with the signs and symptoms of hypothyroidism that accompanied thyroid hormone withdrawal as measured by the Billewicz scale. Statistically significant worsening in all signs and symptoms were observed during the hypothyroid phase (p<0.01) (Figure 2).

FIGURE 2 - HYPOTHYROID SYMPTOM ASSESSMENT BILLEWICZ SCALE

DIAGNOSTIC INDICATION

0.9 mg Thyrogen® q 24 hours x 2 doses

Indications and Usage for Thyrogen

Thyrogen (thyrotropin alfa for injection) is indicated for use as an adjunctive diagnostic tool for serum thyroglobulin (Tg) testing with or without radioiodine imaging in the follow-up of patients with well-differentiated thyroid cancer.

Thyrogen (thyrotropin alfa for injection) is indicated for use as an adjunctive treatment for radioiodine ablation of thyroid tissue remnants in patients who have undergone a near-total or total thyroidectomy for well-differentiated thyroid cancer and who do not have evidence of metastatic thyroid cancer.

Potential Clinical Uses:

Thyrogen Tg testing may be used in patients with an undetectable Tg on thyroid hormone suppressive therapy to exclude the diagnosis of residual or recurrent thyroid cancer (see CLINICAL PHARMACOLOGY, Clinical Trials, Thyroglobulin (Tg) Results).

Thyrogen treatment may be used in combination with radioiodine (131I) to ablate thyroid remnants following near-total thyroidectomy in patients without evidence of metastatic disease.

Thyrogen testing may be used in patients requiring serum Tg testing and radioiodine imaging who are unwilling to undergo thyroid hormone withdrawal testing and whose treating physician believes that use of a less sensitive test is justified.

Thyrogen treatment and testing may be used in patients who are either unable to mount an adequate endogenous TSH response to thyroid hormone withdrawal or in whom withdrawal is medically contraindicated.

Considerations in the Use of Thyrogen®:

Even when Thyrogen-stimulated Tg testing is performed in combination with radioiodine imaging, there remains a meaningful risk of missing a diagnosis of thyroid cancer or of underestimating the extent of disease. Therefore, thyroid hormone withdrawal Tg testing with radioiodine imaging remains the standard diagnostic modality to assess the presence, location and extent of thyroid cancer.

Although Thyrogen appeared noninferior to thyroid hormone withholding in a study of postsurgical thyroid remnant ablation, long-term clinical outcome data are limited. Due to the relatively small clinical experience with Thyrogen in remnant ablation, it is not possible to conclude whether long-term thyroid cancer outcomes would be equivalent after use of Thyrogen or use of thyroid hormone withholding for TSH elevation prior to remnant ablation.

Clinicians employ a wide range of 131I activities to achieve remnant ablation in patients who have been prepared by withholding of thyroid hormone. The primary study of Thyrogen for remnant ablation employed 100 mCi ± 10% in all patients. Data are inadequate to determine if a lower dose of radioiodine would be effective when Thyrogen is used as an adjunct to radioiodine in postsurgical thyroid remnant ablation.

Thyrogen Tg levels are generally lower than, and do not correlate with Tg levels after thyroid hormone withdrawal (see CLINICAL PHARMACOLOGY, Thyroglobulin (Tg) Results).

A newly detectable Tg level or a Tg level rising over time after Thyrogen, or a high index of suspicion of metastatic disease, even in the setting of a negative or low-stage Thyrogen radioiodine scan, should prompt further evaluation such as thyroid hormone withdrawal to definitively establish the location and extent of thyroid cancer. On the other hand, none of the 31 patients studied with undetectable Thyrogen Tg levels (< 2.5 ng/mL) had metastatic disease. Therefore, an undetectable Thyrogen Tg level suggests the absence of clinically significant disease (see CLINICAL PHARMACOLOGY, Clinical Trials).

The decisions whether to perform a Thyrogen radioiodine scan in conjunction with a Thyrogen serum Tg test and whether and when to withdraw a patient from thyroid hormone are complex. Pertinent factors in these decisions include the sensitivity of the Tg assay used, the Thyrogen Tg level obtained, and the index of suspicion of recurrent or persistent local or metastatic disease. In the clinical trials, combination Tg and scan testing did enhance the diagnostic accuracy of Thyrogen in some cases (see CLINICAL PHARMACOLOGY, Clinical Trials).

The signs and symptoms of hypothyroidism which accompany thyroid hormone withdrawal are avoided with Thyrogen (see CLINICAL PHARMACOLOGY, Clinical Trials, Quality of Life, Hypothyroid Signs and Symptoms).

Precautions

(see INDICATIONS AND USAGE, Considerations in the Use of Thyrogen)

General

The use of Thyrogen (thyrotropin alfa for injection) should be directed by physicians knowledgeable in the management of patients with thyroid cancer.

There have been reports of deaths in which events leading to death occurred within 24 hours after administration of Thyrogen. A 77 year-old non-thyroidectomized patient with a history of heart disease and spinal metastases who received 4 Thyrogen injections over 6 days in a special treatment protocol experienced a fatal MI 24 hours after he received the last Thyrogen injection. The event was likely related to Thyrogen-induced hyperthyroidism. In post-marketing experience, there have been rare reports of events leading to death that occurred within 24 hours of administration of Thyrogen in patients with multiple serious medical problems. For patients for whom Thyrogen-induced hyperthyroidism could have serious consequences, hospitalization for administration of Thyrogen and post-administration observation should be considered. Such patients might include those with known heart disease, extensive metastatic disease, or other known serious underlying illness.

Thyroglobulin (Tg) antibodies may confound the Tg assay and render Tg levels uninterpretable. Therefore, in such cases, even with a negative or low-stage Thyrogen radioiodine scan, consideration should be given to evaluating patients further with, for example, a confirmatory thyroid hormone withdrawal scan to determine the location and extent of thyroid cancer.

Thyrogen should be administered intramuscularly only. It should not be administered intravenously.

TSH antibodies have not been reported in patients treated with Thyrogen in the clinical trials, although only 27 patients received Thyrogen on more than one occasion.

Caution should be exercised when Thyrogen is administered to patients who have been previously treated with bovine TSH and, in particular, to those patients who have experienced hypersensitivity reactions to bovine TSH.

Thyrogen is known to cause a transient but significant rise in serum thyroid hormone concentration when given to patients who have substantial thyroid tissue still in situ. Therefore, caution should be exercised in patients with a known history of heart disease and with significant residual thyroid tissue (see ADVERSE REACTIONS).

It is recommended that pretreatment with glucocorticoids be considered for patients in whom local tumor expansion may compromise vital anatomic structures (such as trachea, central nervous system, or extensive macroscopic lung metastases) (see ADVERSE REACTIONS).

Careful evaluation of benefit risk relationships should be assessed for high risk elderly patients with functioning thyroid tumors undergoing Thyrogen administration. This may result in palpitations or cardiac rhythm disorder (see ADVERSE REACTIONS).

Elimination of Thyrogen is significantly slower in dialysis-dependent end stage renal disease (ESRD) patients, resulting in prolonged elevation of TSH levels (see ADVERSE REACTIONS).

Drug-Drug Interactions

Formal interaction studies between Thyrogen and other medicinal products have not been performed. In clinical trials, no interactions were observed between Thyrogen and the thyroid hormones triiodothyronine (T3) and thyroxine (T4) when administered concurrently.

The use of Thyrogen allows for radioiodine imaging while patients are euthyroid on triiodothyronine (T3) and/or thyroxine (T4). Data on radioiodine 131I kinetics indicate that the clearance of radioiodine is approximately 50% greater in euthyroid patients than in hypothyroid patients, who have decreased renal function. Thus radioiodine retention is less in euthyroid patients at the time of imaging and this factor should be considered when selecting the activity of radioiodine for use in radioiodine imaging.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term toxicity studies in animals have not been performed with Thyrogen to evaluate the carcinogenic potential of the drug. Thyrogen was not mutagenic in the bacterial reverse mutation assay. Studies have not been performed with Thyrogen to evaluate the effects on fertility.

Pregnancy Category C

Animal reproduction studies have not been conducted with Thyrogen.

It is also not known whether Thyrogen can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Thyrogen should be given to a pregnant woman only if clearly needed.

Nursing Mothers

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

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 16 years have not been established.

Geriatric Use

Results from controlled trials indicate no difference in the safety and efficacy of Thyrogen between adult patients less than 65 years and those greater than 65 years of age.

Adverse Reactions

Adverse reaction data were derived from post-marketing surveillance and clinical trials. The percentages in Table 4 below represent adverse reactions experienced by 481 thyroid cancer patients who participated in the clinical trials for Thyrogen. Most patients received 2 intramuscular injections, 0.9 mg of thyrotropin alfa per injection, 24 hours apart.

The safety profile of patients who received Thyrogen as adjunctive treatment for radioiodine ablation of thyroid tissue remnants who have undergone a thyroidectomy for well-differentiated thyroid cancer did not differ from that of patients who received Thyrogen for diagnostic purposes.

The most common adverse events (>5%) reported in clinical trials were nausea (11.9%) and headache (7.3%). Events reported in ≥ 1% of patients in the combined trials are summarized in Table 4. In some studies, an individual patient may have participated in both the Euthyroid Phase (Thyrogen) and Hypothyroid Phase (withdrawal).

Table 4: Summary of Adverse Events by Euthyroid Phase and Hypothyroid Phase in All Clinical Trials (≥1%)
Preferred Term	Euthyroid Phase 481 Patients n (%)	Hypothyroid Phase 418 Patients n (%)
Nausea	57 (11.9)	13 (3.1)
Headache	35 (7.3)	5 (1.2)
Fatigue	16 (3.3)	4 (1.0)
Hypercholesterolemia	0 (0.0)	13 (3.1)
Vomiting	14 (2.9)	3 (0.7)
Dizziness	12 (2.5)	0 (0.0)
Paraesthesia	8 (1.7)	0 (0.0)
Asthenia	7 (1.5)	0 (0.0)
Insomnia	7 (1.5)	0 (0.0)
Blood Cholesterol Abnormal	0 (0.0)	6 (1.4)
Diarrhea	6 (1.2)	0 (0.0)
Nasopharyngitis	5 (1.0)	0 (0.0)
Thyroglobulin Present	5 (1.0)	0 (0.0)

Post-marketing experience indicates that Thyrogen administration may cause transient (<48 hours) influenza-like symptoms [also called flu-like symptoms (FLS)], which may include fever (>100°F/38°C), chills/shivering, myalgia/arthralgia, fatigue/asthenia/malaise, headache (non-focal), and chills.

Very rare manifestations of hypersensitivity to Thyrogen have been reported in clinical trials, post-marketing settings and in a special treatment program involving patients with advanced disease: these are urticaria, rash, pruritus, flushing, and respiratory signs and symptoms.

In clinical trials no patients have developed antibodies to thyrotropin alfa, either after single or repeated (27 patients) use of the product.

Four patients out of 55 (7.3%) with CNS metastases who were followed in a special treatment protocol experienced acute hemiplegia, hemiparesis or pain one to three days after Thyrogen administration. The symptoms were attributed to local edema and/or focal hemorrhage at the site of the cerebral or spinal cord metastases. In addition, one case each of acute visual loss and of laryngeal edema with respiratory distress, requiring tracheotomy, with onset of symptoms within 24 hours after Thyrogen administration, have been reported in patients with metastases to the optic nerve and paratracheal areas, respectively. In addition, sudden, rapid and painful enlargement of locally recurring papillary carcinoma has been reported within 12-48 hours of Thyrogen administration. The enlargement was accompanied by dyspnea, stridor or dysphonia. Rapid clinical improvement occurred following glucocorticoid therapy. It is recommended that pretreatment with glucocorticoids be considered for patients in whom local tumor expansion may compromise vital anatomic structures.

Information from post-marketing surveillance, as well as from the literature, suggests that elimination of Thyrogen is significantly slower in dialysis-dependent end stage renal disease (ESRD) patients, resulting in prolonged elevation of TSH levels. ESRD patients who receive Thyrogen may have markedly elevated TSH levels for several days after treatment, which may lead to increased risk of headache and nausea.

Post-marketing data include cases of atrial arrhythmias in elderly patients with pre-existing cardiac disease who received Thyrogen, and suggest that use of Thyrogen in this group should be considered carefully.

Overdosage

There has been no reported experience of overdose in humans. However, in clinical trials, three patients experienced symptoms after receiving Thyrogen doses higher than those recommended. Two patients had nausea after a 2.7 mg IM dose, and in one of these patients, the event was accompanied by weakness, dizziness and headache. Another patient experienced nausea, vomiting and hot flashes after a 3.6 mg IM dose.

In addition, one patient experienced symptoms after receiving Thyrogen intravenously. This patient received 0.3 mg Thyrogen as a single intravenous bolus and, 15 minutes later experienced severe nausea, vomiting, diaphoresis, hypotension (BP decreased from 115/66 mm Hg to 81/44 mm Hg) and tachycardia (pulse increased from 75 to 117 bpm).

Thyrogen Dosage and Administration

A two-injection regimen is recommended for Thyrogen administration.

The two-injection regimen is Thyrogen 0.9 mg intramuscularly (IM), followed by a second 0.9 mg IM injection 24 hours later.

After reconstitution with 1.2 mL Sterile Water for Injection, a 1.0 mL solution (0.9 mg thyrotropin alfa) is administered by intramuscular injection to the buttock.

For radioiodine imaging or remnant ablation, radioiodine administration should be given 24 hours following the final Thyrogen injection. Diagnostic scanning should be performed 48 hours after radioiodine administration, whereas post-therapy scanning may be delayed additional days to allow background activity to decline.

The following parameters utilized in the second Phase 3 study are recommended for diagnostic radioiodine scanning with Thyrogen:

A diagnostic activity of 4 mCi (148 MBq) 131I should be used.

Whole body images should be acquired for a minimum of 30 minutes and/or should contain a minimum of 140,000 counts.

Scanning times for single (spot) images of body regions should be 10-15 minutes or less if the minimum number of counts is reached sooner (i.e. 60,000 for a large field of view camera, 35,000 counts for a small field of view).

For radioiodine ablation of thyroid tissue remnants, the activity of 131I is carefully selected at the discretion of the nuclear medicine physician. Studies with Thyrogen were conducted using 100 mCi ± 10% of 131I. Data are inadequate to determine if a lower dose of radioiodine would be effective when Thyrogen is used as an adjunct to radioiodine in postsurgical thyroid remnant ablation.

For serum Tg testing, the serum sample should be obtained 72 hours after the final injection of Thyrogen.

INSTRUCTIONS FOR USE

Thyrogen (thyrotropin alfa for injection) is for intramuscular injection to the buttock. The powder should be reconstituted immediately prior to use with 1.2 mL of Sterile Water for Injection, USP. Each vial of Thyrogen and each vial of diluent, if provided, is intended for single use. Discard unused portion of the diluent.

Thyrogen should be stored at 2-8°C (36-46°F). Each vial, after reconstitution with 1.2 mL of the accompanying Sterile Water for Injection, USP, should be inspected visually for particulate matter or discoloration before use. Any vials exhibiting particulate matter or discoloration should not be used.

If necessary, the reconstituted solution can be stored for up to 24 hours at a temperature between 2°C and 8°C, while avoiding microbial contamination.

DO NOT USE Thyrogen after the expiration date on the vial. Protect from light.

How is Thyrogen Supplied

Thyrogen (thyrotropin alfa for injection) is supplied as a sterile, non-pyrogenic, lyophilized product. It is available either in a two-vial or a four-vial kit. The two-vial kit contains two 1.1 mg vials of Thyrogen (thyrotropin alfa for injection). The four-vial kit contains two 1.1 mg vials of Thyrogen, as well as two 10 mL vials of Sterile Water for Injection, USP.

            NDC 58468-1849-4 (4-vial kit)

            NDC 58468-0030-2 (2-vial kit)

            Store at 2-8°C.

Rx ONLY

Thyrogen® (thyrotropin alfa for injection)

REFERENCES

Robbins RJ, Tuttle RM, Sonenberg M, Shaha A, Sharaf R, Robbins H, Fleisher M, Larson SM. Radioiodine ablation of thyroid remnants after preparation with recombinant human thyrotropin. Thyroid 2001; 11:865-869.

Robbins RJ, Larson SM, Sinha N, Shaha A, Divgi C, Pentlow KS, Ghossein R, Tuttle RM. A retrospective review of the effectiveness of recombinant human TSH as a preparation for radioiodine thyroid remnant ablation. J Nucl Med 2002; 43:1482-1488.

Barbaro D, Boni G, Meucci G, Simi U, Lapi P, Orsini P, Pasquini C, Piazza F, Caciagli M, Mariani G. Radioiodine treatment with 30 mCi after recombinant human thyrotropin stimulation in thyroid cancer: Effectiveness for postsurgical remnants ablation and possible role of iodine content in L-thyroxine in the outcome of ablation. J Clin Endocrinol Metab 2003; 88:4110-4115.

Pacini F, Molinaro E, Castagna MG, Lippi F, Ceccarelli C, Agate L, Elisei R, Pinchera A. Ablation of thyroid residues with 30 mCi 131I: A comparison in thyroid cancer patients prepared with recombinant human TSH or thyroid hormone withdrawal. J Clin Endocrinol Metab 2002; 87:4063-4068.

Pacini F, Ladenson P, Schlumberger M, Driedger A, Luster M, Kloos RT, Sherman S, Haugen B, Corone C, Molinaro E, Elisei R, Ceccarelli C, Pinchera A, Wahl RL, Leboulleux S, Ricard M, Yoo J, Busaidy E, Delpassand E, Hanschied H, Felbinger R, Lassmann M, Reiner C. Radioiodine Ablation of Thyroid Remnants after Preparation with Recombinant Human Thyrotropin in Differentiated Thyroid Carcinoma: Results of an International, Randomized, Controlled Study. J Clin Endocrinol Metab 2006; 91:926-932.

Brokhin M, Robbins R, Omry G, Martorella A, Fleisher M, Tuttle RM. Recombinant human TSH (rhTSH)-assisted radioactive iodine remnant ablation (RRA) achieves very low short term clinical recurrence rates which are not significantly different than traditional thyroid hormone withdrawal (THW). Abstract # 232, American Thyroid Assn., 2006.

Genzyme Corporation

500 Kendall Street

Cambridge, MA 02142

(800) 745-4447

Thyrogen is a registered trademark of Genzyme Corporation.

Package Label - Principal Display Panel – 4 vial Carton

NDC 58468-1849-4

Thyrogen®

thyrotropin alfa for injection

0.9 mg/mL after reconstitution

For intramuscular injection only

Carton contains 2 vials of Thyrogen®

and 2 vials of diluent.

genzyme

Package Label - Principal Display Panel – 2 vial Carton

NDC 58468-0030-2

Thyrogen®

thyrotropin alfa for injection

0.9 mg/mL after reconstitution

For intramuscular injection only

Carton contains 2 vials of Thyrogen®

Dilute only with Sterile Water for Injection, USP.

genzyme

Thyrogen
thyrotropin alfa injection, powder, for solution

Product Information
Product Type	HUMAN PRESCRIPTION DRUG	NDC Product Code (Source)	58468-0030
Route of Administration	INTRAMUSCULAR	DEA Schedule

Active Ingredient/Active Moiety
Ingredient Name	Basis of Strength	Strength
THYROTROPIN ALFA (THYROTROPIN ALFA)	THYROTROPIN ALFA	0.9 mg in 1 mL

Inactive Ingredients
Ingredient Name	Strength
MANNITOL	30 mg in 1 mL