Entecavir

Class: Nucleosides and Nucleotides
VA Class: AM800
Chemical Name: 6H-purin-6-one, 2- amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-monohydrate.
Molecular Formula: C₁₂H₁₅N₅O₃•H2O
CAS Number: 209216-23-9
Brands: Baraclude

• 
  

  Severe acute exacerbations of hepatitis reported in patients who have discontinued anti-hepatitis B virus (HBV) therapy, including entecavir.¹ (See Exacerbations of Hepatitis under Cautions.) Closely monitor hepatic function in patients who discontinue anti-HBV therapy; if appropriate, resumption of therapy may be warranted.¹

  
  


• 
  

  Lactic acidosis and severe hepatomegaly with steatosis (including some fatalities) reported in patients receiving nucleoside analogs alone or in conjunction with antiretroviral agents.¹ (See Lactic Acidosis and Severe Hepatomegaly with Steatosis under Cautions.)

  
  


• 
  

  Because of possible risk of emergence of HIV resistant to nucleoside reverse transcriptase inhibitors (NRTIs), entecavir should not be used for treatment of HBV in HIV-infected patients who are not receiving antiretroviral therapy.^{1 29 31} (See Individuals Coinfected with HBV and HIV under Cautions.)

  
  

Introduction

Antiviral; purine nucleoside analog derived from guanine.^{1 2 3 4 5 6 13 15}

Uses for Entecavir

Chronic Hepatitis B Virus (HBV) Infection

Management of chronic HBV infection in adults and adolescents ≥16 years of age with evidence of active HBV replication and either persistent elevations in serum aminotransaminases (ALT or AST) or histologic evidence of active disease.^{1 3 5 18 25 26 27} Relationship between treatment response and long-term outcomes such as hepatocellular carcinoma or decompensated cirrhosis not known.¹

Has been effective for HBeAg-positive or -negative chronic HBV infection with compensated liver disease in patients who were nucleoside-naive (had not previously received treatment with nucleoside antivirals) or had lamivudine-refractory HBV (history of HBV viremia while receiving lamivudine or HBV strains known to have mutations associated with lamivudine resistance).^{1 5 25 26 27}

Has been effective for treatment of chronic HBV infection in patients coinfected with both HBV and HIV who had recurrence of HBV viremia while receiving a lamivudine-containing antiretroviral regimen.^{1 2}

Should not be used for treatment of HBV infection in HIV-infected patients who are not receiving antiretroviral therapy.^{1 29 30 31 33} Limited clinical experience in such patients suggests a potential for development of HIV resistance.^{1 29 30 31 33} (See Individuals Coinfected with HBV and HIV under Cautions.)

Safety and efficacy not established for treatment of chronic HBV infection in liver transplant patients.¹ (See Liver Transplant Recipients under Cautions.)

Treatment of chronic HBV infection is complex and rapidly evolving and should be directed by clinicians familiar with the disease; consult a specialist to obtain the most up-to-date information.^{5 13 14 22}

Entecavir Dosage and Administration

Administration

Oral Administration

Administer orally, on an empty stomach at least 2 hours before or 2 hours after meals.¹

Administer oral solution using oral dosing spoon according to manufacturer’s instructions.¹

Oral solution should not be diluted or mixed with water or any other liquid.¹

Dosage

Optimal duration of treatment for chronic HBV infection unknown.¹

Pediatric Patients

Chronic Hepatitis B Virus (HBV) Infection

Nucleoside-naive Individuals

Oral

Adolescents ≥16 years of age: 0.5 mg once daily.¹

Lamivudine-refractory HBV or known lamivudine- or telbivudine-associated resistance mutations

Oral

Adolescents ≥16 years of age: 1 mg once daily.¹

Adults

Chronic Hepatitis B Virus (HBV) Infection

Nucleoside-naive Individuals

Oral

0.5 mg once daily.¹

Lamivudine-refractory HBV or known lamivudine- or telbivudine-associated resistance mutations

Oral

1 mg once daily.¹

Special Populations

Hepatic Impairment

Dosage adjustment not required.¹

Renal Impairment

Decrease dosage in those with Cl_cr <50 mL/minute, including those undergoing hemodialysis or CAPD.¹ Manufacturer states once-daily regimen is preferred.¹

Dosage for Treatment of Chronic HBV Infection in Patients with Renal Impairment

Clcr(mL/min)	Nucleoside-naive Individuals	Lamivudine-refractory HBV
30–<50	0.25 mg once daily or 0.5 mg every 48 hours1	0.5 mg once daily or 1 mg every 48 hours1
10–<30	0.15 mg once daily or 0.5 mg every 72 hours1	0.3 mg once daily or 1 mg every 72 hours1
<10	0.05 mg once daily or 0.5 mg every 7 days1	0.1 mg once daily or 1 mg every 7 days1
Hemodialysis or CAPD Patients	0.05 mg once daily or 0.5 mg every 7 days;1 10 give dose after hemodialysis1 10	0.1 mg once daily or 1 mg every 7 days;1 10 give dose after hemodialysis1 10

Cautions for Entecavir

Contraindications

• 
  

  None known.¹

  
  

Warnings/Precautions

Warnings

Exacerbations of Hepatitis

Clinical and laboratory evidence of severe acute exacerbations of hepatitis may occur following discontinuance of HBV therapy, including entecavir.¹ Exacerbations of hepatitis or ALT flare (e.g. ALT elevations ≥10 times ULN and ≥2 times baseline) reported in 2, 8, or 12% of nucleoside-naive HBeAg-positive patients, nucleoside-naive HBeAg-negative patients, or lamivudine-refractory patients, respectively, following discontinuance of entecavir.¹ The median time to exacerbations of hepatitis was 23 weeks.¹

Exacerbations of hepatitis also reported during entecavir treatment, but generally resolved with continued therapy.¹

Closely monitor hepatic function clinically and with laboratory studies at repeated intervals for at least several months after entecavir discontinued.¹ If appropriate, resumption of anti-HBV therapy may be warranted.¹

Individuals Coinfected with HBV and HIV

Use of entecavir for treatment of chronic HBV infection in patients with unrecognized or untreated HIV infection may result in emergence of HIV isolates resistant to NRTIs.^{1 23 30 31 32 33} HIV testing should be offered to all patients prior to entecavir therapy.¹

Entecavir has some activity against HIV and has suppressed HIV-1 RNA levels in at least 3 patients coinfected with HBV and HIV who were receiving entecavir for treatment of HBV infection but were not receiving antiretroviral therapy.^{23 30} HIV-1 resistance (M184V mutation) was reported in at least 1 of these patients following 6 months of entecavir therapy; this mutation was not present at baseline.^{23 30}

Has not been systematically evaluated in HIV-infected patients with HBV who were not receiving concomitant antiretroviral therapy.²³

Because of possible risk of emergence of NRTI-resistant HIV, entecavir should not be used for treatment of HBV in HIV-infected patients who are not receiving antiretroviral therapy.^{1 29 31 33}

Has not been systematically evaluated for treatment of HIV infection and such use is not recommended.¹

Lactic Acidosis and Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis (including some fatalities) reported in patients receiving nucleoside analogs alone or in conjunction with antiretrovirals.¹ Most reported cases have involved women; obesity and long-term therapy with nucleoside reverse transcriptase inhibitors (NRTIs) also may be risk factors.¹

Nucleoside analogs should be used with particular caution in patients with known risk factors for liver disease; however, lactic acidosis and severe hepatomegaly with steatosis have been reported in patients with no known risk factors.¹

Discontinue entecavir in any patient with clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).¹

General Precautions

Liver Transplant Recipients

Safety and efficacy in liver transplant recipients not evaluated.¹ If entecavir considered necessary in liver transplant recipients who have received or are receiving an immunosuppressive agent that may affect renal function (e.g., cyclosporine, tacrolimus), monitor renal function prior to and during entecavir treatment.¹ (See Interactions.)

Specific Populations

Pregnancy

Category C.¹

Pregnancy registry at 800-258-4263.¹ Data not available regarding effect of entecavir therapy on transmission of HBV to the infant; infants born to HBV-infected women should receive HBV vaccine according to the recommended childhood immunization schedule to prevent neonatal acquisition of HBV.^{1 8 9}

Lactation

Distributed into milk in rats; not known whether distributed into human milk.¹ Discontinue nursing or the drug, taking into account the importance of the drug to the women.¹

Pediatric Use

Safety and efficacy not established in children <16 years of age.¹

Geriatric Use

Experience in those ≥65 years of age insufficient to determine whether they respond differently than younger adults.¹

Use with caution.¹ Because of age-related decreases in renal function, select dosage based on degree of renal impairment; monitor renal function in such patients.¹ (See Renal Impairment under Dosage and Administration.)

Renal Impairment

Dosage adjustment recommended in patients with Cl_cr <50 mL/minute, including those undergoing hemodialysis or CAPD.¹ (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Headache, fatigue, dizziness, nausea.^{1 10} Elevated ALT concentrations, hyperbilirubinemia, elevated lipase concentrations, hematuria, glycosuria, hyperglycemia, elevated creatinine concentrations.^{1 10}

Interactions for Entecavir

Entecavir is not a substrate for CYP isoenzymes.¹ It does not inhibit or induce CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 3A4, or 2B6 and does not inhibit 3A5 or induce 2E1.¹

Pharmacokinetic interactions with drugs metabolized by CYP isoenzymes unlikely.¹

Drugs Affecting or Eliminated by Renal Excretion

Concomitant use with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of entecavir and/or the other drug.¹ Monitor closely for adverse effects if used concomitantly with drugs excreted renally or with drugs known to affect renal function.¹

Specific Drugs

Drug	Interaction	Comments
Adefovir	No evidence of pharmacokinetic interaction1
Immunosuppressive agents (cyclosporine, tacrolimus)	Possible increased entecavir concentrations due to altered renal function1	Monitor renal function prior to and during entecavir treatment in patients receiving immunosuppressive agents that may affect renal function1
Nucleoside reverse transcriptase inhibitors (NRTIs) (abacavir, didanosine, lamivudine, stavudine, zidovudine)	No in vitro evidence of reduced antiviral efficacy of entecavir against HBV or reduced antiretroviral activity of NRTIs 1 Lamivudine: No evidence of pharmacokinetic interaction1
Tenofovir	No evidence of pharmacokinetic interaction 1 No in vitro evidence of reduced antiviral efficacy of entecavir against HBV or reduced antiretroviral activity of tenofovir 1

Entecavir Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration.¹

Peak plasma concentrations attained within 0.5–1.5 hours after a dose.¹ Steady-state concentrations achieved after 6–10 days of once-daily administration with approximately 2-fold accumulation.¹

Commercially available tablets and oral solution are bioequivalent.¹

Food

Food delays absorption, decreases peak plasma concentrations, and decreases AUC.¹

Distribution

Extent

Extensively distributed into tissues.¹

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

Plasma Protein Binding

Approximately 13% in vitro.¹

Elimination

Metabolism

Undergoes phosphorylation by cellular enzymes to form active metabolite, entecavir triphosphate.^{1 3 4 5 6}

Partially metabolized to glucuronide and sulfate conjugates.¹

Elimination Route

Excreted principally in urine by both glomerular filtration and tubular secretion.^{1 5} Approximately 62–73% of an oral dose eliminated unchanged in urine.¹

Hemodialysis removes approximately 13% of a dose in 4 hours;¹ CAPD removes approximately 0.3% of a dose over 7 days.¹

Half-life

Biphasic; terminal half-life approximately 128–149 hours.¹

Special Populations

Impaired hepatic function: Pharmacokinetics not affected.¹

Impaired renal function: Decreased clearance and increased plasma concentrations and AUC.¹

Geriatric adults: Increased AUC compared with younger adults, possibly as the result of age-related changes in renal function.¹

Stability

Storage

Oral

Solution

Store in outer carton at 25°C (may be exposed to 15–30°C).¹ Protect from light.¹ After opening, discard by expiration date noted on bottle.¹

Tablets

Tight container at 25°C (may be exposed to 15–30°C).¹

Actions and SpectrumActions

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  Synthetic purine nucleoside analog antiviral agent active in vivo and in vitro against HBV, including some strains of lamivudine-resistant HBV.^{1 2 3 4 5 6 13 15 17 19 20}

  
  


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  Active metabolite, entecavir triphosphate, inhibits activities of HBV DNA polymerase (reverse transcriptase).^{1 3 4 5 6 13 15}

  
  


• 
  

  Has some activity against HIV-1.^{1 17}

  
  


• 
  

  HBV with reduced susceptibility to entecavir can develop slowly in some patients during long-term use.^{1 22 28} At week 96, viral rebound due to entecavir resistance reported in <1% of patients who were nucleoside-naive prior to entecavir therapy.^{1 28} Viral rebound due to entecavir resistance reported in 1% of lamivudine-refractory patients after 1 year of entecavir therapy and in 9% during the second year of therapy.²⁸

  
  


• 
  

  Cross-resistance may occur among some nucleoside analogs active against HBV.¹ Lamivudine- and telbivudine-resistant HBV with reduced susceptibility to entecavir has been reported.^{1 5 20} Adefovir-resistant HBV with changes in susceptibility to entecavir reported; efficacy of entecavir against such HBV not established.¹ HBV strains resistant to entecavir and lamivudine may retain susceptibility to adefovir.^{1 13 15 18}

  
  

Advice to Patients

• 
  

  Importance of providing a copy of the manufacturer’s patient information.¹

  
  


• 
  

  Importance of taking entecavir exactly as prescribed and not discontinuing or interrupting therapy unless instructed by a clinician; importance of regular medical follow-up.¹

  
  


• 
  

  Advise patients that deterioration of liver disease has occurred when entecavir therapy is discontinued and that any change in treatment should be discussed with the clinician.¹

  
  


• 
  

  Importance of taking entecavir once daily on an empty stomach (at least 2 hours before or 2 hours after meals), preferably at the same time each day.¹

  
  


• 
  

  Importance of protecting oral solution from light.¹ When using the oral solution, importance of using the calibrated dosing spoon provided, holding the spoon in a vertical position and filling it gradually to the mark corresponding to the prescribed dose, and rinsing it well after each use.¹

  
  


• 
  

  Importance of liver function test monitoring and immediate reporting of potential exacerbations of hepatitis following discontinuance of entecavir therapy.¹

  
  


• 
  

  Importance of immediately reporting to clinicians any signs or symptoms of lactic acidosis (e.g., weakness/fatigue, unusual muscle pain, trouble breathing, stomach pain with nausea and vomiting, feeling cold especially in arms and legs, dizziness or feeling light-headed, fast or irregular heart beat) or hepatotoxicity (e.g., jaundice, dark urine, bowel movements light in color, anorexia, nausea, stomach pain) or any other new symptoms.¹

  
  


• 
  

  Importance of HBV therapy compliance.¹ Entecavir is not a cure for HBV infection.¹ HBV transmission via sexual contact, sharing needles, or blood contamination is not prevented by entecavir therapy.¹

  
  


• 
  

  Patients should be advised of available measures to prevent spread of HBV infection to close contacts.¹

  
  


• 
  

  Importance of testing for HIV prior to initiation of entecavir therapy.¹ Advise patients that if they have HIV infection and are not receiving effective HIV treatment, entecavir may increase the risk of HIV resistance.¹

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, and any concomitant illnesses (e.g., renal disease).¹

  
  


• 
  

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

  
  


• 
  

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

  
  

Preparations

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

Entecavir

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Solution	0.05 mg/mL	Baraclude (with parabens; available with calibrated measuring spoon)	Bristol-Myers Squibb
Oral	Tablets, film-coated	0.5 mg	Baraclude (with povidone)	Bristol-Myers Squibb
		1 mg	Baraclude (with povidone)	Bristol-Myers Squibb

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Baraclude 0.5MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$874.43 or 90/$2443.84

Baraclude 1MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$863.15 or 90/$2533.57

Disclaimer

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

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

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions November 2009. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Bristol-Myers Squibb Company. Baraclude (entecavir) tablets and oral solution prescribing information. Princeton, NJ; 2009 Jan.

2. Rivkina A, Rybalov S. Chronic hepatitis B: current and future treatment options. Pharmacotherapy. 2002; 22: 721-37. [IDIS 482368] [PubMed 12066963]

3. Honkoop P, de Man RA. Entecavir: a potent new antiviral drug for hepatitis B. Expert Opin Investig Drugs. 2003; 12:683-8. [PubMed 12665423]

4. Wolters LM, Niesters HG, de Man RA. Nucleoside analogues for chronic hepatitis B. Eur J Gastroenterol Hepatol. 2001; 13:1499-506. [PubMed 11742201]

5. Shaw T, Locarnini S. Entecavir for the treatment of chronic hepatitis B. Expert Rev Anti Infect Ther. 2004; 2:853-71. [PubMed 15566330]

6. Billich A. Entecavir (Bristol-Myers Squibb). Curr Opin Investig Drugs. 2001; 2:617-21. [PubMed 11569933]

7. Gilead Sciences, Inc. Hepsera (adefovir dipivoxil) tablets prescribing information. Foster City, CA; 2004 Aug.

8. Committee on Infectious Diseases, American Academy of Pediatrics. Red book: 2006 report of the Committee on Infectious Diseases. 27th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2006.

9. Centers for Disease Control and Prevention Advisory Committee on Immunization Practices, American Academy of Pediatrics, and American Academy of Family Physicians. Recommended childhood and adolescent immunization schedule—United States, 2005. Pediatrics. 2005; 115.

10. Bristol-Myers Squibb. Princeton, NJ: Personal communication.

11. Peters MG. Managing hepatitis B coinfection in HIV-infected patients. Curr HIV/AIDS Rep. 2005; 2:122-6. [PubMed 16091258]

12. Nunez M, Soriano V. Management of patients co-infected with hepatitis B virus and HIV. Lancet Infect Dis.2005; 5:374-82.

13. Perrillo RP. Current treatment of chronic hepatitis B: benefits and limitations.Semin Liver Dis. 2005; 25 (Suppl 1):20-8. [PubMed 16103978]

14. Lok ASF, McMahon BJ. Chronic hepatitis B. Hepatology. 2001; 34:1225-41. [PubMed 11732013]

15. Gish RG. Clinical trial results of new therapies for HBV: implications for treatment guidelines. Semin Liver Dis. 2005; 25 (Suppl 1):29-39. [PubMed 16103979]

16. Lai CL, Rosmawati M, Lao J, Van Vlierberghe H et al. Entecavir is superior to lamivudine in reducing hepatitis B virus DNA in patients with chronic hepatitis B infection. Gastroenterology. 2002; 123:1831-8. [IDIS 492287] [PubMed 12454840]

17. Innaimo SF, Seifer M, Bisacchi GS et al. Identification of BMS-200475 as a potent and selective inhibitor of hepatitis B virus.Antimicrob Agents Chemother. 1997; 41:1444-8. [PubMed 9210663]

18. Anon. Entecavir (Baraclude) for chronic hepatitis B. Med Lett Drugs Ther. 2005; 47:47-8.

19. Yamanaka G, Wilson T, Innaimo S, Bisacchi GS et al. Metabolic studies on BMS-200475, a new antiviral compound active against hepatitis B virus. Antimicrob Agents Chemother. 1999; 43:190-3. [PubMed 9869593]

20. Buti M, Esteban R. Drugs in development for hepatitis B. Drugs. 2005; 65:1451-60. [PubMed 16033287]

21. Tenney DJ, Levine SM, Rose RE et al. Clinical emergence of entecavir-resistant hepatitis B virus requires additional substitutions in virus already resistant to lamivudine. Antimicrob Agents Chemother. 2004; 48:3498-507. [PubMed 15328117]

22. Lok ASF, McMahon BJ. Chronic hepatitis B. AASLD practice guidelines. Hepatology. 2007; 45:507-39. [PubMed 17256718]

23. Lewis-Hall FC. Dear health care provider letter pertaining to important information regarding Baraclude (entecavir) in patients co-infected with HIV and HBV. Bristol-Myers Squibb February 2007.

24. Soriano V, Puoti M, Bonacini M et al. Care of patients with chronic hepatitis B and HIV co-infection: recommendations from an HIV-HBV international panel. AIDS. 2005; 19:221-40. [PubMed 15718833]

25. Chang TT, Gish RG, de Man R et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med. 2006; 354:1001-10. [PubMed 16525137]

26. Lai CL, Shouval D, Lok AS et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2006; 354:1011-20. [PubMed 16525138]

27. Sherman M, Yurdaydin C, Sollano J et al. Entecavir for treatment of lamivudine-refractory, HBeAg-positive chronic hepatitis B. Gastroenterology. 2006; 130:2039-49. [PubMed 16762627]

28. Tenney DJ, Rose RE, Baldick CJ et al. Two-year assessment of entecavir resistance in lamivudine-refractory hepatitis B virus patients reveals different clinical outcomes depending on the resistance substitutions present. Antimicrob Agents Chemother. 2007; 51:902-11. [PubMed 17178796]

29. Panel on Clinical Practices for Treatment of HIV infection of the Department of Health and Human Services (DHHS). Supplement to the guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (April 30, 2007). From the US Department of Health and Human Services HIV/AIDS Information Services (AIDSinfo) website.

30. McMahon MA, Jilek BL, Brennan TP et al. The HBV drug entecavir–effects on HIV-1 replication and resistance. N Engl J Med. 2007; 356:2614-21. [PubMed 17582071]

31. Lewis-Hall FC. Dear healthcare professional letter pertaining to important information regarding Baraclude (entecavir) in patients co-infected with HIV and HBV. Bristol-Myers Squibb. August 2007.

32. Lok ASF, McMahon BJ. Corrections to AASLD guidelines on chronic hepatitis B. Hepatology. 2007; 45:1347. Letter.

33. Kaplan JE, Benson C, Holmes KH et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep. 2009; 58 (RR-4):1-207.

More Entecavir resources

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

• Entecavir MedFacts Consumer Leaflet (Wolters Kluwer)


• Entecavir Professional Patient Advice (Wolters Kluwer)


• entecavir Advanced Consumer (Micromedex) - Includes Dosage Information


• Baraclude Prescribing Information (FDA)


• Baraclude Consumer Overview

Compare Entecavir with other medications

• Hepatitis B

Zantac 75

Pronunciation: ra-NI-ti-deen
Generic Name: Ranitidine
Brand Name: Zantac 75

Zantac 75 is used for:

Treating or preventing heartburn, acid indigestion, and sour stomach caused by certain foods and drinks. It may also be used for other conditions as determined by your doctor.

Zantac 75 is a histamine H₂-receptor antagonist. It works by blocking the action of histamine in the stomach. This reduces the amount of acid the stomach makes, which helps to relieve symptoms of heartburn, acid indigestion, and sour stomach.

Do NOT use Zantac 75 if:

• you are allergic to any ingredient in Zantac 75 or other H₂-receptor antagonists (eg, famotidine)


• you have a history of the blood disease porphyria


• you have trouble swallowing


• you are taking dasatinib

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

Before using Zantac 75:

Some medical conditions may interact with Zantac 75. 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 a history of kidney or liver problems


• if you have frequent wheezing or chest pain; chest or shoulder pain with shortness of breath; pain spreading to your arm, neck, or shoulder; lightheadedness; nausea or vomiting; or sudden increased sweating


• if you have painful swallowing, vomit with blood, black or bloody stools, or severe or persistent heartburn

Some MEDICINES MAY INTERACT with Zantac 75. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Certain benzodiazepines (eg, midazolam, triazolam), glipizide, procainamide, or warfarin because the risk of their side effects may be increased by Zantac 75


• Dasatinib, delavirdine, gefitinib, certain HIV protease inhibitors (eg, atazanavir), itraconazole, or ketoconazole because their effectiveness may be decreased by Zantac 75

This may not be a complete list of all interactions that may occur. Ask your health care provider if Zantac 75 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 Zantac 75:

Use Zantac 75 as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• If you are using Zantac 75 to treat symptoms, take it by mouth with or without food.


• If you are using Zantac 75 to prevent symptoms, take it by mouth 30 to 60 minutes before eating food or drinking beverages that cause your symptoms.


• Take Zantac 75 with a full glass of water (8 oz/240 mL).


• If you also take itraconazole or ketoconazole, ask your doctor or pharmacist how to take it with Zantac 75.


• Do not take other antacids while you are using Zantac 75 without first checking with your doctor.


• Continue to take Zantac 75 even if you feel well. Do not miss any doses.


• If you miss a dose of Zantac 75, take 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 take 2 doses at once.

Ask your health care provider any questions you may have about how to use Zantac 75.

Important safety information:

• Zantac 75 may rarely cause drowsiness, dizziness, or blurred vision. These effects may be worse if you take it with alcohol or certain medicines. Use Zantac 75 with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Do NOT take more than the recommended dose or use for longer than 14 days without checking with your doctor.


• If your stomach pain does not get better or if it gets worse, check with your doctor.


• Zantac 75 may interfere with certain lab tests, including urine protein tests. Be sure your doctor and lab personnel know you are taking Zantac 75.


• Zantac 75 should not be used in CHILDREN younger than 12 years old without first checking with the child's doctor; safety and effectiveness in these children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Zantac 75 while you are pregnant. Zantac 75 is found in breast milk. If you are or will be breast-feeding while you use Zantac 75, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Zantac 75:

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:

Constipation; diarrhea; headache; nausea; stomach upset.

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; unusual hoarseness); change in the amount of urine produced; confusion; dark urine; depression; fast, slow, or irregular heartbeat; fever, chills, or sore throat; hallucinations; severe or persistent headache or stomach pain; unusual bruising or bleeding; yellowing of the eyes or skin.

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: Zantac 75 side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include dizziness; trouble walking.

Proper storage of Zantac 75:

Store Zantac 75 at room temperature, between 68 and 77 degrees (20 and 25 degrees C), in a tightly closed container. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Zantac 75 out of the reach of children and away from pets.

General information:

• If you have any questions about Zantac 75, please talk with your doctor, pharmacist, or other health care provider.


• Zantac 75 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 Zantac 75. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

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Pacerone

Dosage Form: tablet
Pacerone®

(Amiodarone HCl) Tablets, 100 mg and 200 mg

Rx only

Pacerone Description

Pacerone®(Amiodarone HCl) Tablets are a member of a class of antiarrhythmic drugs with predominantly Class III (Vaughan Williams' classification) effects, available for oral administration in 100 mg and 200 mg strengths of amiodarone hydrochloride. Both strengths of Pacerone® Tablets contain the following inactive ingredients: lactose monohydrate, magnesium stearate, povidone, pregelatinized corn starch, sodium starch glycolate, stearic acid, FD&C Red 40 (200 mg only) and FD&C Yellow 6.

Amiodarone hydrochloride, the active ingredient in Pacerone® Tablets, is a benzofuran derivative: 2-butyl-3-benzofuranyl 4-[2-(diethylamino)-ethoxy]-3,5-diiodophenyl ketone hydrochloride.

The structural formula is as follows:

Amiodarone HCl is a white to cream-colored crystalline powder. It is slightly soluble in water, soluble in alcohol and freely soluble in chloroform. It contains 37.3% iodine by weight.

Pacerone - Clinical Pharmacology

Electrophysiology/Mechanisms of Action

In animals, amiodarone HCl is effective in the prevention or suppression of experimentally induced arrhythmias. The antiarrhythmic effect of amiodarone may be due to at least two major properties:

1. a prolongation of the myocardial cell-action potential duration and refractory period and


2. noncompetitive α- and β -adrenergic inhibition.

Amiodarone prolongs the duration of the action potential of all cardiac fibers while causing minimal reduction of dV/dt (maximal upstroke velocity of the action potential). The refractory period is prolonged in all cardiac tissues. Amiodarone increases the cardiac refractory period without influencing resting membrane potential, except in automatic cells where the slope of the prepotential is reduced, generally reducing automaticity. These electrophysiologic effects are reflected in a decreased sinus rate of 15 to 20%, increased PR and QT intervals of about 10%, the development of U-waves and changes in T-wave contour. These changes should not require discontinuation of Pacerone® Tablets as they are evidence of its pharmacological action, although amiodarone can cause marked sinus bradycardia or sinus arrest and heart block. On rare occasions, QT prolongation has been associated with worsening of arrhythmia (see "WARNINGS").

Hemodynamics

In animal studies and after intravenous administration in man, amiodarone relaxes vascular smooth muscle, reduces peripheral vascular resistance (afterload), and slightly increases cardiac index. After oral dosing, however, amiodarone produces no significant change in left ventricular ejection fraction (LVEF), even in patients with depressed LVEF. After acute intravenous dosing in man, amiodarone may have a mild negative inotropic effect.

Pharmacokinetics

Following oral administration in man, amiodarone is slowly and variably absorbed. The bioavailability of amiodarone is approximately 50%, but has varied between 35 and 65% in various studies. Maximum plasma concentrations are attained 3 to 7 hours after a single dose. Despite this, the onset of action may occur in 2 to 3 days, but more commonly takes 1 to 3 weeks, even with loading doses. Plasma concentrations with chronic dosing at 100 to 600 mg/day are approximately dose proportional, with a mean 0.5 mg/L increase for each 100 mg/day. These means, however, include considerable individual variability. Food increases the rate and extent of absorption of amiodarone. The effects of food upon the bioavailability of amiodarone have been studied in 30 healthy subjects who received a single 600-mg dose immediately after consuming a high-fat meal and following an overnight fast. The area under the plasma concentration-time curve (AUC) and the peak plasma concentration (Cmax) of amiodarone increased by 2.3 (range 1.7 to 3.6) and 3.8 (range 2.7 to 4.4) times, respectively, in the presence of food. Food also increased the rate of absorption of amiodarone, decreasing the time to peak plasma concentration (Tmax) by 37%. The mean AUC and mean Cmax of desethylamiodarone increased by 55% (range 58 to 101%) and 32% (range 4 to 84%), respectively, but there was no change in the Tmax in the presence of food.

Amiodarone has a very large but variable volume of distribution, averaging about 60 L/kg, because of extensive accumulation in various sites, especially adipose tissue and highly perfused organs, such as the liver, lung and spleen. One major metabolite of amiodarone, desethylamiodarone (DEA), has been identified in man; it accumulates to an even greater extent in almost all tissues. No data are available on the activity of DEA in humans, but in animals, it has significant electrophysiologic and antiarrhythmic effects generally similar to amiodarone itself. DEA's precise role and contribution to the antiarrhythmic activity of oral amiodarone are not certain. The development of maximal ventricular Class III effects after oral amiodarone administration in humans correlates more closely with DEA accumulation over time than with amiodarone accumulation.

Amiodarone is metabolized to desethylamiodarone by the cytochrome P450 (CYP450) enzyme group, specifically cytochrome P450 3A4 (CYP3A4) and CYP2C8. The CYP3A4 isoenzyme is present in both the liver and intestines.

Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion and there is negligible excretion of amiodarone or DEA in urine. Neither amiodarone nor DEA is dialyzable.

In clinical studies of 2 to 7 days, clearance of amiodarone after intravenous administration in patients with VT and VF ranged between 220 and 440 mL/hr/kg. Age, sex, renal disease and hepatic disease (cirrhosis) do not have marked effects on the disposition of amiodarone or DEA. Renal impairment does not influence the pharmacokinetics of amiodarone. After a single dose of intravenous amiodarone in cirrhotic patients, significantly lower Cmax and average concentration values are seen for DEA, but mean amiodarone levels are unchanged. Normal subjects over 65 years of age show lower clearances (about 100 mL/hr/kg) than younger subjects (about 150 mL/hr/kg) and an increase in t½ from about 20 to 47 days. In patients with severe left ventricular dysfunction, the pharmacokinetics of amiodarone are not significantly altered but the terminal disposition t½ of DEA is prolonged. Although no dosage adjustment for patients with renal, hepatic or cardiac abnormalities has been defined during chronic treatment with amiodarone, close clinical monitoring is prudent for elderly patients and those with severe left ventricular dysfunction.

Following single dose administration in 12 healthy subjects, amiodarone exhibited multi-compartmental pharmacokinetics with a mean apparent plasma terminal elimination half-life of 58 days (range 15 to 142 days) for amiodarone and 36 days (range 14 to 75 days) for the active metabolite (DEA). In patients, following discontinuation of chronic oral therapy, amiodarone has been shown to have a biphasic elimination with an initial one-half reduction of plasma levels after 2.5 to 10 days. A much slower terminal plasma-elimination phase shows a half-life of the parent compound ranging from 26 to 107 days, with a mean of approximately 53 days and most patients in the 40- to 55-day range. In the absence of a loading-dose period, steady-state plasma concentrations, at constant oral dosing, would therefore be reached between 130 and 535 days, with an average of 265 days. For the metabolite, the mean plasma-elimination half-life was approximately 61 days. These data probably reflect an initial elimination of drug from well-perfused tissue (the 2.5- to 10-day half-life phase), followed by a terminal phase representing extremely slow elimination from poorly perfused tissue compartments such as fat.

The considerable intersubject variation in both phases of elimination, as well as uncertainty as to what compartment is critical to drug effect, requires attention to individual responses once arrhythmia control is achieved with loading doses because the correct maintenance dose is determined, in part, by the elimination rates. Daily maintenance doses of Pacerone® Tablets should be based on individual patient requirements (see "DOSAGE AND ADMINISTRATION").

Amiodarone and its metabolite have a limited transplacental transfer of approximately 10 to 50%. The parent drug and its metabolite have been detected in breast milk.

Amiodarone is highly protein-bound (approximately 96%).

Although electrophysiologic effects, such as prolongation of QTc, can be seen within hours after a parenteral dose of amiodarone, effects on abnormal rhythms are not seen before 2 to 3 days and usually require 1 to 3 weeks, even when a loading dose is used. There may be a continued increase in effect for longer periods still. There is evidence that the time to effect is shorter when a loading-dose regimen is used.

Consistent with the slow rate of elimination, antiarrhythmic effects persist for weeks or months after Pacerone® Tablets are discontinued, but the time of recurrence is variable and unpredictable. In general, when the drug is resumed after recurrence of the arrhythmia, control is established relatively rapidly compared to the initial response, presumably because tissue stores were not wholly depleted at the time of recurrence.

Pharmacodynamics

There is no well-established relationship of plasma concentration to effectiveness, but it does appear that concentrations much below 1 mg/L are often ineffective and that levels above 2.5 mg/L are generally not needed. Within individuals, dose reductions and ensuing decreased plasma concentrations can result in loss of arrhythmia control. Plasma-concentration measurements can be used to identify patients whose levels are unusually low, and who might benefit from a dose increase, or unusually high, and who might have dosage reduction in the hope of minimizing side effects. Some observations have suggested a plasma concentration, dose or dose/duration relationship for side effects such as pulmonary fibrosis, liver-enzyme elevations, corneal deposits and facial pigmentation, peripheral neuropathy, gastrointestinal and central nervous system effects.

Monitoring Effectiveness

Predicting the effectiveness of any antiarrhythmic agent in long-term prevention of recurrent ventricular tachycardia and ventricular fibrillation is difficult and controversial, with highly qualified investigators recommending use of ambulatory monitoring, programmed electrical stimulation with various stimulation regimens, or a combination of these, to assess response. There is no present consensus on many aspects of how best to assess effectiveness, but there is a reasonable consensus on some aspects:

1. If a patient with a history of cardiac arrest does not manifest a hemodynamically unstable arrhythmia during electrocardiographic monitoring prior to treatment, assessment of the effectiveness of amiodarone requires some provocative approach, either exercise or programmed electrical stimulation (PES).


2. Whether provocation is also needed in patients who do manifest their life-threatening arrhythmia spontaneously is not settled, but there are reasons to consider PES or other provocation in such patients. In the fraction of patients whose PES-inducible arrhythmia can be made noninducible by amiodarone (a fraction that has varied widely in various series from less than 10% to almost 40%, perhaps due to different stimulation criteria), the prognosis has been almost uniformly excellent, with very low recurrence (ventricular tachycardia or sudden death) rates. More controversial is the meaning of continued inducibility. There has been an impression that continued inducibility in amiodarone patients may not foretell a poor prognosis but, in fact, many observers have found greater recurrence rates in patients who remain inducible than in those who do not. A number of criteria have been proposed, however, for identifying patients who remain inducible but who seem likely nonetheless to do well on Pacerone® Tablets. These criteria include increased difficulty of induction (more stimuli or more rapid stimuli), which has been reported to predict a lower rate of recurrence, and ability to tolerate the induced ventricular tachycardia without severe symptoms, a finding that has been reported to correlate with better survival but not with lower recurrence rates. While these criteria require confirmation and further study in general, easier inducibility or poorer tolerance of the induced arrhythmia should suggest consideration of a need to revise treatment.

Several predictors of success not based on PES have also been suggested, including complete elimination of all nonsustained ventricular tachycardia on ambulatory monitoring and very low premature ventricular-beat rates (less than 1 VPB/1,000 normal beats).

While these issues remain unsettled for amiodarone, as for other agents, the prescriber of Pacerone® Tablets should have access to (direct or through referral), and familiarity with, the full range of evaluatory procedures used in the care of patients with life-threatening arrhythmias.

It is difficult to describe the effectiveness rates of Pacerone® Tablets, as these depend on the specific arrhythmia treated, the success criteria used, the underlying cardiac disease of the patient, the number of drugs tried before resorting to Pacerone® Tablets, the duration of follow-up, the dose of amiodarone HCl, the use of additional antiarrhythmic agents and many other factors. As amiodarone has been studied principally in patients with refractory life-threatening ventricular arrhythmias, in whom drug therapy must be selected on the basis of response and cannot be assigned arbitrarily, randomized comparisons with other agents or placebo have not been possible. Reports of series of treated patients with a history of cardiac arrest and mean follow-up of one year or more have given mortality (due to arrhythmia) rates that were highly variable, ranging from less than 5% to over 30%, with most series in the range of 10 to 15%. Overall arrhythmia-recurrence rates (fatal and nonfatal) also were highly variable (and, as noted above, depended on response to PES and other measures), and depend on whether patients who do not seem to respond initially are included. In most cases, considering only patients who seemed to respond well enough to be placed on long-term treatment, recurrence rates have ranged from 20 to 40% in series with a mean follow-up of a year or more.

Indications and Usage for Pacerone

Because of its life-threatening side effects and the substantial management difficulties associated with amiodarone use (see "WARNINGS" below), Pacerone® (Amiodarone HCl) Tablets are indicated only for the treatment of the following documented, life-threatening recurrent ventricular arrhythmias when these have not responded to documented adequate doses of other available antiarrhythmics or when alternative agents could not be tolerated.

1. Recurrent ventricular fibrillation.


2. Recurrent hemodynamically unstable ventricular tachycardia.

As is the case for other antiarrhythmic agents, there is no evidence from controlled trials that the use of amiodarone HCl tablets favorably affects survival.

Pacerone® (Amiodarone HCl) Tablets should be used only by physicians familiar with and with access to (directly or through referral) the use of all available modalities for treating recurrent life-threatening ventricular arrhythmias, and who have access to appropriate monitoring facilities, including in-hospital and ambulatory continuous electrocardiographic monitoring and electrophysiologic techniques. Because of the life-threatening nature of the arrhythmias treated, potential interactions with prior therapy and potential exacerbation of the arrhythmia, initiation of therapy with Pacerone® (Amiodarone HCl) Tablets should be carried out in the hospital.

Contraindications

Pacerone® (Amiodarone HCl) Tablets are contraindicated in patients with cardiogenic shock; severe sinus-node dysfunction, causing marked sinus bradycardia; second- or third-degree atrioventricular block; and when episodes of bradycardia have caused syncope (except when used in conjunction with a pacemaker).

Pacerone® (Amiodarone HCl) Tablets are contraindicated in patients with a known hypersensitivity to the drug or to any of its components, including iodine.

Warnings

Pacerone® (Amiodarone HCl) Tablets are intended for use only in patients with the indicated life-threatening arrhythmias because amiodarone use is accompanied by substantial toxicity.

Amiodarone has several potentially fatal toxicities, the most important of which is pulmonary toxicity (hypersensitivity pneumonitis or interstitial/alveolar pneumonitis) that has resulted in clinically manifest disease at rates as high as 10 to 17% in some series of patients with ventricular arrhythmias given doses around 400 mg/day, and as abnormal diffusion capacity without symptoms in a much higher percentage of patients. Pulmonary toxicity has been fatal about 10% of the time. Liver injury is common with amiodarone, but is usually mild and evidenced only by abnormal liver enzymes. Overt liver disease can occur, however, and has been fatal in a few cases. Like other antiarrhythmics, amiodarone can exacerbate the arrhythmia, e.g., by making the arrhythmia less well tolerated or more difficult to reverse. This has occurred in 2 to 5% of patients in various series, and significant heart block or sinus bradycardia has been seen in 2 to 5%. All of these events should be manageable in the proper clinical setting in most cases. Although the frequency of such proarrhythmic events does not appear greater with amiodarone than with many other agents used in this population, the effects are prolonged when they occur.

Even in patients at high risk of arrhythmic death, in whom the toxicity of amiodarone is an acceptable risk, Pacerone® Tablets pose major management problems that could be life-threatening in a population at risk of sudden death, so that every effort should be made to utilize alternative agents first.

The difficulty of using Pacerone® Tablets effectively and safely itself poses a significant risk to patients. Patients with the indicated arrhythmias must be hospitalized while the loading dose of Pacerone® Tablets is given, and a response generally requires at least one week, usually two or more. Because absorption and elimination are variable, maintenance-dose selection is difficult, and it is not unusual to require dosage decrease or discontinuation of treatment. In a retrospective survey of 192 patients with ventricular tachyarrhythmias, 84 required dose reduction and 18 required at least temporary discontinuation because of adverse effects, and several series have reported 15 to 20% overall frequencies of discontinuation due to adverse reactions. The time at which a previously controlled life-threatening arrhythmia will recur after discontinuation or dose adjustment is unpredictable, ranging from weeks to months. The patient is obviously at great risk during this time and may need prolonged hospitalization. Attempts to substitute other antiarrhythmic agents when Pacerone® Tablets must be stopped will be made difficult by the gradually, but unpredictably, changing amiodarone body burden. A similar problem exists when amiodarone is not effective; it still poses the risk of an interaction with whatever subsequent treatment is tried.

Mortality

In the National Heart, Lung and Blood Institute's Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multi-centered, randomized, double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias who had had myocardial infarctions more than six days but less than two years previously, an excessive mortality or non-fatal cardiac arrest rate was seen in patients treated with encainide or flecainide (56/730) compared with that seen in patients assigned to matched placebo-treated groups (22/725). The average duration of treatment with encainide or flecainide in this study was ten months.

Amiodarone therapy was evaluated in two multi-centered, randomized, double-blind, placebo-controlled trials involving 1202 (Canadian Amiodarone Myocardial Infarction Arrhythmia Trial; CAMIAT) and 1486 (European Myocardial Infarction Amiodarone Trial; EMIAT) post-MI patients followed for up to 2 years. Patients in CAMIAT qualified with ventricular arrhythmias, and those randomized to amiodarone received weight- and response-adjusted doses of 200 to 400 mg/day. Patients in EMIAT qualified with ejection fraction <40%, and those randomized to amiodarone received fixed doses of 200 mg/day. Both studies had weeks-long loading dose schedules. Intent-to-treat all-cause mortality results were as follows:

	Placebo		Amiodarone		Relative Risk
	N	Deaths	N	Deaths		95% CI
EMIAT	743	102	743	103	0.99	0.76-1.31
CAMIAT	596	68	606	57	0.88	0.58-1.16

These data are consistent with the results of a pooled analysis of smaller, controlled studies involving patients with structural heart disease (including myocardial infarction).

Pulmonary Toxicity

There have been post-marketing reports of acute-onset (days to weeks) pulmonary injury in patients treated with oral amiodarone with or without initial I.V. therapy. Findings have included pulmonary infiltrates and/or mass on X-ray, pulmonary alveolar hemorrhage, pleural effusion, bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, and hypoxia. Some cases have progressed to respiratory failure and/or death. Post-marketing reports describe cases of pulmonary toxicity in patients treated with low doses of amiodarone; however, reports suggest that the use of lower loading and maintenance doses of amiodarone are associated with a decreased incidence of amiodarone-induced pulmonary toxicity.

Amiodarone HCl Tablets may cause a clinical syndrome of cough and progressive dyspnea accompanied by functional, radiographic, gallium-scan, and pathological data consistent with pulmonary toxicity, the frequency of which varies from 2 to 7% in most published reports, but is as high as 10 to 17% in some reports. Therefore, when Pacerone® Tablets therapy is initiated, a baseline chest X-ray and pulmonary-function tests, including diffusion capacity, should be performed. The patient should return for a history, physical exam and chest X-ray every 3 to 6 months.

Pulmonary toxicity secondary to amiodarone seems to result from either indirect or direct toxicity as represented by hypersensitivity pneumonitis (including eosinophilic pneumonia) or interstitial/alveolar pneumonitis, respectively.

Patients with preexisting pulmonary disease have a poorer prognosis if pulmonary toxicity develops.

Hypersensitivity pneumonitis usually appears earlier in the course of therapy and rechallenging these patients with Pacerone® Tablets results in a more rapid recurrence of greater severity.

Bronchoalveolar lavage is the procedure of choice to confirm this diagnosis, which can be made when a T suppressor/cytotoxic (CD8-positive) lymphocytosis is noted. Steroid therapy should be instituted and Pacerone® Tablets therapy discontinued in these patients.

Interstitial/alveolar pneumonitis may result from the release of oxygen radicals and/or phospholipidosis and is characterized by findings of diffuse alveolar damage, interstitial pneumonitis or fibrosis in lung biopsy specimens. Phospholipidosis (foamy cells, foamy macrophages), due to inhibition of phospholipase, will be present in most cases of amiodarone-induced pulmonary toxicity; however, these changes also are present in approximately 50% of all patients on amiodarone therapy. These cells should be used as markers of therapy, but not as evidence of toxicity. A diagnosis of amiodarone-induced interstitial/alveolar pneumonitis should lead, at a minimum, to dose reduction or, preferably, to withdrawal of Pacerone® Tablets to establish reversibility, especially if other acceptable antiarrhythmic therapies are available. Where these measures have been instituted, a reduction in symptoms of amiodarone-induced pulmonary toxicity was usually noted within the first week, and a clinical improvement was greatest in the first two to three weeks. Chest X-ray changes usually resolve within two to four months. According to some experts, steroids may prove beneficial. Prednisone in doses of 40 to 60 mg/day or equivalent doses of other steroids have been given and tapered over the course of several weeks depending upon the condition of the patient. In some cases rechallenge with amiodarone at a lower dose has not resulted in return of toxicity.

In a patient receiving Pacerone® Tablets, any new respiratory symptoms should suggest the possibility of pulmonary toxicity, and the history, physical exam, chest X-ray and pulmonary-function tests (with diffusion capacity) should be repeated and evaluated. A 15% decrease in diffusion capacity has a high sensitivity but only a moderate specificity for pulmonary toxicity; as the decrease in diffusion capacity approaches 30%, the sensitivity decreases but the specificity increases. A gallium-scan also may be performed as part of the diagnostic workup.

Fatalities, secondary to pulmonary toxicity, have occurred in approximately 10% of cases. However, in patients with life-threatening arrhythmias, discontinuation of Pacerone® Tablets therapy due to suspected drug-induced pulmonary toxicity should be undertaken with caution, as the most common cause of death in these patients is sudden cardiac death. Therefore, every effort should be made to rule out other causes of respiratory impairment (i.e., congestive heart failure with Swan-Ganz catheterization if necessary, respiratory infection, pulmonary embolism, malignancy, etc.) before discontinuing Pacerone® Tablets in these patients. In addition, bronchoalveolar lavage, transbronchial lung biopsy and/or open lung biopsy may be necessary to confirm the diagnosis, especially in those cases where no acceptable alternative therapy is available.

If a diagnosis of amiodarone-induced hypersensitivity pneumonitis is made, Pacerone® Tablets should be discontinued, and treatment with steroids should be instituted. If a diagnosis of amiodarone-induced interstitial/alveolar pneumonitis is made, steroid therapy should be instituted and, preferably, Pacerone® Tablets discontinued or, at a minimum, reduced in dosage. Some cases of amiodarone-induced interstitial/alveolar pneumonitis may resolve following a reduction in Pacerone® Tablets dosage in conjunction with the administration of steroids. In some patients, rechallenge at a lower dose has not resulted in return of interstitial/alveolar pneumonitis; however, in some patients (perhaps because of severe alveolar damage) the pulmonary lesions have not been reversible.

Worsened Arrhythmia

Amiodarone, like other antiarrhythmics, can cause serious exacerbation of the presenting arrhythmia, a risk that may be enhanced by the presence of concomitant antiarrhythmics. Exacerbation has been reported in about 2 to 5% in most series, and has included new ventricular fibrillation, incessant ventricular tachycardia, increased resistance to cardioversion and polymorphic ventricular tachycardia associated with QTc prolongation (Torsade de Pointes [TdP]). In addition, amiodarone has caused symptomatic bradycardia or sinus arrest with suppression of escape foci in 2 to 4% of patients.

Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly. (See "Drug Interactions, Other reported interactions with amiodarone".)

The need to co-administer amiodarone with any other drug known to prolong the QTc interval must be based on a careful assessment of the potential risks and benefits of doing so for each patient.

A careful assessment of the potential risks and benefits of administering Pacerone® Tablets must be made in patients with thyroid dysfunction due to the possibility of arrhythmia breakthrough or exacerbation of arrhythmia in these patients.

Implantable Cardiac Devices

In patients with implanted defibrillators or pacemakers, chronic administration of antiarrhythmic drugs may affect pacing or defibrillating thresholds. Therefore, at the inception of and during amiodarone treatment, pacing and defibrillation thresholds should be assessed.

Thyrotoxicosis

Amiodarone-induced hyperthyroidism may result in thyrotoxicosis and/or the possibility of arrhythmia breakthrough or aggravation. There have been reports of death associated with amiodarone-induced thyrotoxicosis. IF ANY NEW SIGNS OF ARRHYTHMIA APPEAR, THE POSSIBILITY OF HYPERTHYROIDISM SHOULD BE CONSIDERED (see "PRECAUTIONS, Thyroid Abnormalities").

Liver Injury

Elevations of hepatic enzyme levels are seen frequently in patients exposed to amiodarone and in most cases are asymptomatic. If the increase exceeds three times normal, or doubles in a patient with an elevated baseline, discontinuation of Pacerone® Tablets or dosage reduction should be considered. In a few cases in which biopsy has been done, the histology has resembled that of alcoholic hepatitis or cirrhosis. Hepatic failure has been a rare cause of death in patients treated with amiodarone.

Loss of Vision

Cases of optic neuropathy and/or optic neuritis, usually resulting in visual impairment, have been reported in patients treated with amiodarone. In some cases, visual impairment has progressed to permanent blindness. Optic neuropathy and/or neuritis may occur at any time following initiation of therapy. A causal relationship to the drug has not been clearly established. If symptoms of visual impairment appear, such as changes in visual acuity and decreases in peripheral vision, prompt ophthalmic examination is recommended. Appearance of optic neuropathy and/or neuritis calls for re-evaluation of Pacerone® Tablets therapy. The risks and complications of antiarrhythmic therapy with Pacerone® Tablets must be weighed against its benefits in patients whose lives are threatened by cardiac arrhythmias. Regular ophthalmic examination, including funduscopy and slit-lamp examination, is recommended during administration of Pacerone® Tablets (see "ADVERSE REACTIONS").

Neonatal Hypo- or Hyperthyroidism

Amiodarone can cause fetal harm when administered to a pregnant woman. Although amiodarone use during pregnancy is uncommon, there have been a small number of published reports of congenital goiter/hypothyroidism and hyperthyroidism. If Pacerone® (Amiodarone HCl) Tablets are used during pregnancy, or if the patient becomes pregnant while taking Pacerone® Tablets, the patient should be apprised of the potential hazard to the fetus.

In general, Pacerone® Tablets should be used during pregnancy only if the potential benefit to the mother justifies the unknown risk to the fetus.

In pregnant rats and rabbits, amiodarone HCl in doses of 25 mg/kg/day (approximately 0.4 and 0.9 times, respectively, the maximum recommended human maintenance dose*) had no adverse effects on the fetus. In the rabbit, 75 mg/kg/day (approximately 2.7 times the maximum recommended human maintenance dose*) caused abortions in greater than 90% of the animals. In the rat, doses of 50 mg/kg/day or more were associated with slight displacement of the testes and an increased incidence of incomplete ossification of some skull and digital bones; at 100 mg/kg/day or more, fetal body weights were reduced; at 200 mg/kg/day, there was an increased incidence of fetal resorption. (These doses in the rat are approximately 0.8, 1.6 and 3.2 times the maximum recommended human maintenance dose.*) Adverse effects on fetal growth and survival also were noted in one of two strains of mice at a dose of 5 mg/kg/day (approximately 0.04 times the maximum recommended human maintenance dose*).

*600 mg in a 50 kg patient (doses compared on a body surface area basis)

Precautions

Impairment of Vision

Optic Neuropathy and/or Neuritis

Cases of optic neuropathy and optic neuritis have been reported (see "WARNINGS").

Corneal Microdeposits

Corneal microdeposits appear in the majority of adults treated with amiodarone. They are usually discernible only by slit-lamp examination, but give rise to symptoms such as visual halos or blurred vision in as many as 10% of patients. Corneal microdeposits are reversible upon reduction of dose or termination of treatment. Asymptomatic microdeposits alone are not a reason to reduce dose or discontinue treatment (see "ADVERSE REACTIONS").

Neurologic

Chronic administration of oral amiodarone in rare instances may lead to the development of peripheral neuropathy that may resolve when amiodarone is discontinued, but this resolution has been slow and incomplete.

Photosensitivity

Amiodarone has induced photosensitization in about 10% of patients; some protection may be afforded by the use of sun-barrier creams or protective clothing. During long-term treatment, a blue-gray discoloration of the exposed skin may occur. The risk may be increased in patients of fair complexion or those with excessive sun exposure, and may be related to cumulative dose and duration of therapy.

Thyroid Abnormalities

Amiodarone inhibits peripheral conversion of thyroxine (T4) to triiodothyronine (T3) and may cause increased thyroxine levels, decreased T3 levels and increased levels of inactive reverse T3 (rT3) in clinically euthyroid patients. It is also a potential source of large amounts of inorganic iodine. Because of its release of inorganic iodine, or perhaps for other reasons, amiodarone can cause either hypothyroidism or hyperthyroidism. Thyroid function should be monitored prior to treatment and periodically thereafter, particularly in elderly patients, and in any patient with a history of thyroid nodules, goiter or other thyroid dysfunction. Because of the slow elimination of amiodarone and its metabolites, high plasma iodide levels, altered thyroid function and abnormal thyroid-function tests may persist for several weeks or even months following Pacerone® (Amiodarone HCl) Tablets withdrawal.

Hypothyroidism has been reported in 2 to 4% of patients in most series, but in 8 to 10% in some series. This condition may be identified by relevant clinical symptoms and particularly by elevated serum TSH levels. In some clinically hypothyroid amiodarone-treated patients, free thyroxine index values may be normal. Hypothyroidism is best managed by Pacerone® Tablets dose reduction and/or thyroid hormone supplement. However, therapy must be individualized, and it may be necessary to discontinue Pacerone® Tablets in some patients.

Hyperthyroidism occurs in about 2% of patients receiving amiodarone, but the incidence may be higher among patients with prior inadequate dietary iodine intake. Amiodarone-induced hyperthyroidism usually poses a greater hazard to the patient than hypothyroidism because of the possibility of thyrotoxicosis and/or arrhythmia breakthrough or aggravation, all of which may result in death. There have been reports of death associated with amiodarone-induced thyrotoxicosis. IF ANY NEW SIGNS OF ARRHYTHMIA APPEAR, THE POSSIBILITY OF HYPERTHYROIDISM SHOULD BE CONSIDERED.

Hyperthyroidism is best identified by relevant clinical symptoms and signs, accompanied usually by abnormally elevated levels of serum T3 RIA, and further elevations of serum T4, and a subnormal serum TSH level (using a sufficiently sensitive TSH assay). The finding of a flat TSH response to TRH is confirmatory of hyperthyroidism and may be sought in equivocal cases. Since arrhythmia breakthroughs may accompany amiodarone-induced hyperthyroidism, aggressive medical treatment is indicated, including, if possible, dose reduction or withdrawal of Pacerone® Tablets.

The institution of antithyroid drugs, β-adrenergic blockers and/or temporary corticosteroid therapy may be necessary. The action of antithyroid drugs may be especially delayed in amiodarone-induced thyrotoxicosis because of substantial quantities of preformed thyroid hormones stored in the gland. Radioactive iodine therapy is contraindicated because of the low radioiodine uptake associated with amiodarone-induced hyperthyroidism. Amiodarone-induced hyperthyroidism may be followed by a transient period of hypothyroidism (see "WARNINGS, Thyrotoxicosis").

When aggressive treatment of amiodarone-induced thyrotoxicosis has failed or amiodarone cannot be discontinued because it is the only drug effective against the resistant arrhythmia, surgical management may be an option. Experience with thyroidectomy as a treatment for amiodarone-induced thyrotoxicosis is limited, and this form of therapy could induce thyroid storm. Therefore, surgical and anesthetic management require careful planning.

There have been postmarketing reports of thyroid nodules/thyroid cancer in patients treated with amiodarone. In some instances hyperthyroidism was also present (see "WARNINGS" and "ADVERSE REACTIONS").

Surgery

Volatile Anesthetic Agents: Close perioperative monitoring is recommended in patients undergoing general anesthesia who are on amiodarone therapy as they may be more sensitive to the myocardial depressant and conduction effects of halogenated inhalational anesthetics.

Hypotension Postbypass: Rare occurrences of hypotension upon discontinuation of cardiopulmonary bypass during open-heart surgery in patients receiving amiodarone have been reported. The relationship of this event to Pacerone® Tablets therapy is unknown.

Adult Respiratory Distress Syndrome (ARDS): Postoperatively, occurrences of ARDS have been reported in patients receiving amiodarone therapy who have undergone either cardiac or noncardiac surgery. Although patients usually respond well to vigorous respiratory therapy, in rare instances the outcome has been fatal. Until further studies have been performed, it is recommended that FiO2 and the determinants of oxygen delivery to the tissues (e.g., SaO2, PaO2) be closely monitored in patients on amiodarone.

Corneal Refractive Laser Surgery

Patients should be advised that most manufacturers of corneal refractive laser surgery devices contraindicate that procedure in patients taking amiodarone.

Information for Patients

Patients should be instructed to read the accompanying Medication Guide each time they refill their prescription. The complete text of the Medication Guide is reprinted at the end of this document.

Laboratory Tests

Elevations in liver enzymes (SGOT and SGPT) can occur. Liver enzymes in patients on relatively high maintenance doses should be monitored on a regular basis. Persistent significant elevations in the liver enzymes or hepatomegaly should alert the physician to consider reducing the maintenance dose of Pacerone® Tablets or discontinuing therapy.

Amiodarone alters the results of thyroid-function tests, causing an increase in serum T4 and serum reverse T3, and a decline in serum T3 levels. Despite these biochemical changes, most patients remain clinically euthyroid.

Drug Interactions

Amiodarone is metabolized to desethylamiodarone by the cytochrome P450 (CYP450) enzyme group, specifically cytochrome P450 3A4 (CYP3A4) and CYP2C8. The CYP3A4 isoenzyme is present in both the liver and intestines (see "CLINICAL PHARMACOLOGY, Pharmacokinetics"). Amiodarone is an inhibitor of CYP3A4 and p-glycoprotein. Therefore, amiodarone has the potential for interactions with drugs or substances that may be substrates, inhibitors or inducers of CYP3A4 and substrates of p-glycoprotein. While only a limited number of in vivo drug-drug interactions with amiodarone have been reported, the potential for other interactions should be anticipated. This is especially important for drugs associated with serious toxicity, such as other antiarrhythmics. If such drugs are needed, their dose should be reassessed and, where appropriate, plasma concentration measured. In view of the long and variable half-life of amiodarone, potential for drug interactions exists, not only with concomitant medication, but also with drugs administered after discontinuation of amiodarone.

Since amiodarone is a substrate for CYP3A4 and CYP2C8, drugs/substances that inhibit CYP3A4 may decrease the metabolism and increase serum concentrations of amiodarone. Reported examples include the following:

Protease inhibitors:

Protease inhibitors are known to inhibit CYP3A4 to varying degrees. A case report of one patient taking amiodarone 200 mg and indinavir 800 mg three times a day resulted in increases in amiodarone concentrations from 0.9 mg/L to 1.3 mg/L. DEA concentrations were not affected. There was no evidence of toxicity. Monitoring for amiodarone toxicity and serial measurement of amiodarone serum concentration during concomitant protease inhibitor therapy should be considered.

Histamine H1 antagonists:

Loratadine, a non-sedating antihistaminic, is metabolized primarily by CYP3A4. QT interval prolongation and Torsade de Pointes have been reported with the co-administration of loratadine and amiodarone.

Histamine H2 antagonists:

Cimetidine inhibits CYP3A4 and can increase serum amiodarone levels.

Antidepressants:

Trazodone, an antidepressant, is metabolized primarily by CYP3A4. QT interval prolongation and Torsade de Pointes have been reported with the co-administration of trazodone and amiodarone.

Other substances:

Grapefruit juice given to healthy volunteers increased amiodarone AUC by 50% and Cmax by 84%, and decreased DEA to unquantifiable concentrations. Grapefruit juice inhibits CYP3A4-mediated metabolism of oral amiodarone in the intestinal mucosa, resulting in increased plasma levels of amiodarone; therefore, grapefruit juice should not be taken during treatment with oral amiodarone. This information should be considered when changing from intravenous amiodarone to oral amiodarone (see "DOSAGE AND ADMINISTRATION").

Amiodarone inhibits p-glycoprotein and certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6, and CYP3A4. This inhibition can result in unexpectedly high plasma levels of other drugs which are metabolized by those CYP450 enzymes or are substrates of p-glycoprotein. Reported examples of this interaction include the following:

Immunosuppressives:

Cyclosporine (CYP3A4 substrate) administered in combination with oral amiodarone has been reported to produce persistently elevated plasma concentrations of cyclosporine resulting in elevated creatinine, despite reduction in dose of cyclosporine.

HMG-CoA Reductase Inhibitors:

The use of HMG-CoA reductase inhibitors that are CYP3A4 substrates in combination with amiodarone has been associated with reports of myopathy/rhabdomyolysis.

Limit the dose of simvastatin in patients on amiodarone to 20 mg daily. Limit the daily dose of lovastatin to 40 mg. Lower starting and maintenance doses of other CYP3A4 substrates (e.g., atorvastatin) may be required as amiodarone may increase the plasma concentration of these drugs.

Cardiovasculars:

Cardiac glycosides: In patients receiving digoxin therapy, administration of oral amiodarone regularly results in an increase in the serum digoxin concentration that may reach toxic levels with resultant clinical toxicity. Amiodarone taken concomitantly with digoxin increases the serum digoxin concentration by 70% after one day. On initiation of oral amiodarone, the need for digitalis therapy should be reviewed and the dose reduced by approximately 50% or discontinued. If digitalis treatment is continued, serum levels should be closely monitored and patients observed for clinical evidence of toxicity. These precautions probably should apply to digitoxin administration as well.

Antiarrhythmics:

Other antiarrhythmic drugs, such as quinidine, procainamide, disopyramide and phenytoin, have been used concurrently with oral amiodarone.

There have been case reports of increased steady-state levels of quinidine, procainamide and phenytoin during concomitant therapy with amiodarone. Phenytoin decreases serum amiodarone levels. Amiodarone taken concomitantly with quinidine increases quinidine serum concentration by 33% after two days. Amiodarone taken concomitantly with procainamide for less than seven days increases plasma concentrations of procainamide and n-acetyl procainamide by 55% and 33%, respectively. Quinidine and procainamide doses should be reduced by one-third when either is administered with amiodarone. Pl

Water for Injections BP 2ml, 5ml, 10ml & 20ml

1. Name Of The Medicinal Product

Water for Injections B.P. 2ml, 5ml, 10ml & 20ml.

2. Qualitative And Quantitative Composition

Each 1ml of solution contains 1ml of Water for Injections B.P.

3. Pharmaceutical Form

Clear, colourless, odourless, sterile solution intended for parenteral administration to human beings.

4. Clinical Particulars

4.1 Therapeutic Indications

For the reconstitution, dilution and making-up of appropriate drugs where Water for Injections is the diluent of choice, and for use as an irrigant.

4.2 Posology And Method Of Administration

Route of administration: For S.C., I.M. or IV. injection, or as appropriate to the reconstituted drug.

Dosage: In accordance with the particular situation for which Water for Injections B.P. is being used.

4.3 Contraindications

None known.

4.4 Special Warnings And Precautions For Use

None.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

May be used during this period.

4.7 Effects On Ability To Drive And Use Machines

None.

4.8 Undesirable Effects

None known.

4.9 Overdose

No effects anticipated with the proposed use.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Not applicable.

5.2 Pharmacokinetic Properties

Not applicable.

5.3 Preclinical Safety Data

No further relevant information other than that which is included in other sections of the Summary of Product Characteristics.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Not applicable.

6.2 Incompatibilities

Water for Injections B.P. should not be mixed with any other agents unless their compatibility has been established.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

2ml, 5ml, 10ml and 20ml hermetically sealed translucent plastic ampoules, polypropylene Ph.Eur., packed in cardboard cartons to contain 10, 20, 50 and 100 ampoules.

6.6 Special Precautions For Disposal And Other Handling

For S/C, I/M or I/V Injection or as appropriate to the reconstituted drug.

If only part of an ampoule is used, discard the remaining solution.

Use as directed by the physician.

Keep out of reach of children.

7. Marketing Authorisation Holder

Antigen International Ltd.,

Roscrea,

Co. Tipperary,

Ireland.

8. Marketing Authorisation Number(S)

PL 2848/0152.

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorization : 10/10/91.

10. Date Of Revision Of The Text

August 2001