Adefovir Dipivoxil

Class: Nucleosides and Nucleotides
VA Class: AM800
Chemical Name: [[[2-(6-Amino-9-H-purin-9-yl)ethoxy]methyl]phosphinylidene]bis(oxymethylene) ester 2,2-dimethyl propanoic acid
Molecular Formula: C₂₀H₃₂N₅O₈P
CAS Number: 142340-99-6
Brands: Hepsera

• 
  

  Severe acute exacerbations of hepatitis may occur in patients who discontinue adefovir.¹ (See Exacerbations of Hepatitis under Cautions.) Closely monitor hepatic function in such patients.¹

  
  


• 
  

  In patients at risk of or having underlying renal dysfunction, chronic administration of adefovir may result in nephrotoxicity.¹ Closely monitor renal function in such patients; dosage adjustments may be required.¹

  
  


• 
  

  HIV resistance may emerge in chronic HBV patients who have unrecognized or untreated HIV infection.¹ (See Individuals Coinfected with HBV and HIV under Cautions.)

  
  


• 
  

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

  
  

Introduction

Antiviral; acyclic nucleotide.¹

Uses for Adefovir Dipivoxil

Chronic Hepatitis B Virus (HBV) Infection

Treatment of chronic HBV infection in adults and adolescents ≥12 years of age with evidence of active HBV replication and either persistent elevations in serum aminotransferases (ALT or AST) or histologic evidence of active disease.¹ The relationship between treatment response (histologic, virologic, biochemical, serologic) to adefovir and long-term outcomes such as hepatocellular carcinoma or decompensated cirrhosis is not known.¹

May be effective in HBeAg-positive patients;^{1 3 23} HBeAg-negative (anti-HBe- and HBV-DNA-positive) patients;^{1 4 11 16} and pre- and post-liver transplantation patients.^{1 11 16 21}

May be effective in patients with lamivudine-resistant HBV.^{1 8 11 18}

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.⁹

Adefovir Dipivoxil Dosage and Administration

Administration

Oral Administration

Administer orally without regard to food.¹

Dosage

Available as adefovir dipivoxil; dosage expressed in terms adefovir dipivoxil.¹

Pediatric Patients

Chronic Hepatitis B Virus (HBV) Infection

Oral

Adolescents 12–17 years of age: 10 mg once daily.¹

Optimal duration of treatment unknown.^{1 9} Has been continued for up to 5 years in adults in controlled clinical studies.^{1 12 17}

Adults

Chronic Hepatitis B Virus (HBV) Infection

Oral

10 mg once daily.¹

Optimal duration of treatment unknown.^{1 9} Has been continued for up to 5 years in adults in controlled clinical studies.^{1 12 17}

Special Populations

Hepatic Impairment

Dosage adjustments not necessary in hepatic impairment.^{1 5}

Renal Impairment

Decrease dosage in adults with baseline Cl_cr <50 mL/minute.¹

Dosage for Adults with Renal Impairment1

Clcr (mL/min)	Dosage
30–49	10 mg once every 48 hours
10–29	10 mg once every 72 hours
<10 (not undergoing hemodialysis)	Dosage recommendations not available
Hemodialysis patients	10 mg once every 7 days following dialysis

These dosage guidelines for adults with renal impairment have not been clinically evaluated.¹ In addition, these dosages were derived from data involving patients with preexisting renal impairment and may not be appropriate for those in whom renal impairment evolves during adefovir therapy.¹ Closely monitor clinical response and renal function.¹

Safety and efficacy not studied in adolescents with renal impairment.¹ Data insufficient to make dosage recommendations for adolescents 12–17 years of age with underlying renal impairment;¹ use caution and closely monitor renal function.¹

Cautions for Adefovir Dipivoxil

Contraindications

• 
  

  Known hypersensitivity to adefovir or any ingredient in the formulation.¹

  
  

Warnings/Precautions

Warnings

Exacerbations of Hepatitis

Clinical and laboratory evidence of severe acute exacerbations of hepatitis have occurred following discontinuance of HBV therapy, including adefovir therapy.¹

Exacerbations of hepatitis (ALT elevations at least 10 times the ULN) reported in up to 25% of patients following discontinuance of adefovir, usually within 12 weeks after discontinuance.¹ These exacerbations generally occurred in the absence of HBeAg seroconversion and presented as elevations in ALT and reemergence of viral replication.¹

Although these exacerbations may be self-limited or resolve with reinitiation of therapy, severe exacerbations (including fatalities) have been reported.¹

In patients with compensated liver function, exacerbations have not generally been accompanied by hepatic decompensation.¹ However, patients with advanced liver disease or cirrhosis may be at higher risk for hepatic decompensation than those with compensated liver function.¹

Closely monitor hepatic function at repeated intervals with both clinical and laboratory follow-up for several months or longer after adefovir is discontinued.¹ If appropriate, resumption of anti-HBV therapy may be warranted.¹

Nephrotoxicity

Nephrotoxicity, characterized by a delayed onset, is the principal dose-limiting toxicity of adefovir and also may occur in patients receiving chronic (long-term) therapy with recommended dosage of the drug.¹

Delayed onset of gradual increases in serum creatinine and decreases in serum phosphorus were the treatment-limiting toxicities of adefovir in clinical studies evaluating use of high dosages for treatment of HIV infection† (60 or 120 mg daily) or use of high dosages for treatment of chronic HBV infection (30 mg daily).¹

Long-term administration in dosages recommended for the treatment of HBV infection (10 mg daily) also may result in delayed nephrotoxicity.¹ By week 96 or week 240, 2 or 3% of patients who received adefovir had serum creatinine increases of ≥0.5 mg/dL from baseline (by Kaplan Meier estimates), respectively.¹

In pre- or post-liver transplantation patients receiving the usually recommended dosage (10 mg daily), most of whom had some degree of baseline renal insufficiency, 37 or 32% had increases in serum creatinine concentrations of 0.3 mg/dL or greater from baseline by week 48, respectively, and 53 or 51% had serum creatinine increases of 0.3 mg/dL or greater from baseline by week 96, respectively.¹

Although overall risk of nephrotoxicity is low in patients with adequate renal function, consider possibility of nephrotoxicity in patients at risk of or having underlying renal dysfunction and in those receiving concomitant therapy with nephrotoxic agents.¹ (See Nephrotoxic Drugs or Drugs Eliminated by Renal Excretion under Interactions.)

Closely monitor renal function in all patients receiving adefovir, especially those with preexisting renal impairment or other risks for renal impairment.¹ Dosage adjustments may be necessary.¹ (See Renal Impairment under Dosage and Administration.)

Individuals Coinfected with HBV and HIV

Use of adefovir for the treatment of chronic HBV infection in patients with unrecognized or untreated HIV infection may result in emergence of HIV resistance.¹ Although adefovir has in vitro activity against HIV,²² dosage of the drug used for treatment of HBV infection (10 mg daily) has not been shown to suppress HIV RNA levels in HIV-infected patients.^{1 14 16}

Offer HIV antibody testing to all patients prior to initiating adefovir.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 adefovir 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

Clinical Resistance

Resistance to adefovir may result in viral load rebound of HBV, which may lead to exacerbation of HBV infection; if the patient has impaired hepatic function, this may lead to liver decompensation and death.¹

To reduce risk of clinical resistance in patients with lamivudine-resistant HBV, use adefovir in conjunction with lamivudine; do not use adefovir monotherapy^{1 9}

Patients with serum HBV DNA levels >1000 copies/mL after 48 weeks of adefovir treatment are at greater risk of developing clinical resistance.¹ To reduce risk of clinical resistance in patients receiving monotherapy with the drug, consider treatment modification if serum HBV DNA levels remain >1000 copies/mL with continued treatment.¹

Specific Populations

Pregnancy

Category C.¹

Pregnancy registry at 800-258-4263.¹

Data not available regarding the effect of adefovir therapy during pregnancy on transmission of HBV to the infant;¹ such infants should receive HBV vaccine according to the usual childhood immunization schedule to prevent neonatal acquisition of HBV.¹

Lactation

Not known whether adefovir is distributed into milk.¹ Discontinue nursing or drug, taking into account the importance of the drug to the woman.¹

Pediatric Use

Safety and efficacy not established in children <12 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 because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.¹

Renal Impairment

Dosage adjustments recommended for adults if Cl_cr <50 mL/minute.^{1 5} (See Renal Impairment under Dosage and Administration.)

Has not been evaluated in adolescents 12–17 years of age with renal impairment.¹ Use caution in such adolescents and monitor renal function closely.¹

Common Adverse Effects

Asthenia, headache, abdominal pain, nausea, flatulence, diarrhea, dyspepsia.¹

Interactions for Adefovir Dipivoxil

Adefovir does not inhibit CYP isoenzymes, including CYP1A2, 2C9, 2C19, 2D6, and 3A4.¹ Adefovir is not a substrate for CYP isoenzymes; potential of the drug to induce these enzymes is unknown.¹

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions with drugs affecting or metabolized by CYP isoenzymes unlikely.¹

Nephrotoxic Drugs or Drugs Eliminated by Renal Excretion

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

Specific Drugs

Drug	Interaction	Comments
Acetaminophen	No pharmacokinetic interaction1
Co-trimoxazole	No pharmacokinetic interaction1
Didanosine	No pharmacokinetic interaction with didanosine delayed-release capsules containing enteric-coated pellets1
Entecavir	No pharmacokinetic interaction24
Ibuprofen	No effect on pharmacokinetics of ibuprofen;1 increased adefovir plasma concentrations and AUC;1 may occur because of increased oral bioavailability of adefovir;1	Clinical importance unknown1
Immunosuppressive agents (cyclosporine, tacrolimus)	Cyclosporine: Effect on adefovir concentrations unknown1 Tacrolimus: No pharmacokinetic interaction1
Lamivudine	No pharmacokinetic interaction1 Additive antiviral effects against HBV1
Telbivudine	No pharmacokinetic interaction25 In vitro evidence of additive antiviral effects against HBV25
Tenofovir	No pharmacokinetic interaction1	Should not be used concomitantly for treatment of chronic HBV infection20

Adefovir Dipivoxil Pharmacokinetics

Absorption

Bioavailability

Following oral administration of adefovir dipivoxil, approximate bioavailability of adefovir is 59%.¹ Peak plasma concentration of adefovir attained within 0.58–4 hours.¹

Food

Food does not affect AUC of adefovir.¹

Special Populations

Adolescents 12–17 years of age with compensated liver disease: Peak plasma concentrations and AUC similar to those reported in adults.¹

Distribution

Extent

Not known whether adefovir distributed into human milk.¹

Plasma Protein Binding

≤4%.¹

Elimination

Metabolism

Following oral administration, adefovir dipivoxil is converted to the active adefovir.¹

Adefovir is not metabolized by CYP isoenzymes.¹

Elimination Route

Adefovir is excreted in urine by glomerular filtration and active tubular secretion.¹

Following oral administration of adefovir dipivoxil, 45% of dose eliminated in urine as adefovir over 24 hours at steady-state.¹

Removed by hemodialysis; effect of peritoneal dialysis unknown.¹

Half-life

Terminal elimination half-life of adefovir: 7.48 hours.¹

Special Populations

In adults with nonchronic HBV infection and hepatic impairment, no substantial differences in pharmacokinetics in those with moderate to severe hepatic impairment compared with those without hepatic impairment.¹

In adults with moderate to severe renal impairment or end-stage renal disease requiring hemodialysis, clearance decreased and half-life prolonged.¹

Pharmacokinetics not studied in geriatric adults.¹

Pharmacokinetics not studied in adolescents 12–17 years of age with renal impairment.¹

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).¹

Actions and SpectrumActions

• 
  

  Adefovir available as adefovir dipivoxil, a diester prodrug that is inactive until converted in vivo to adefovir and phosphorylated to adefovir diphosphate.¹

  
  


• 
  

  An acyclic nucleotide antiviral.¹

  
  


• 
  

  Active in vitro and in vivo against HBV.^{1 2}

  
  


• 
  

  Also has some in vitro activity against herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), HIV-1 and HIV-2, human papillomavirus (HPV), Epstein-Barr virus, and varicella zoster virus, but has not been shown to be effective in clinical infections caused by these viruses.^{2 15 22}

  
  


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  HBV with reduced susceptibility to adefovir can develop in some patients during long-term use.^{1 9 12 16 17}

  
  


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  Cross-resistance can occur among the nucleoside antivirals used for treatment of HBV.^{26 28}

  
  


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  Some strains of HBV may be cross-resistant to both adefovir and lamivudine,^{26 27 28} but some lamivudine-resistant HBV may be susceptible to adefovir and some adefovir-resistant isolates may be susceptible to lamivudine.^{1 9 16 19 21 26}

  
  


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  In vitro studies indicate that some HBV with mutations associated with adefovir resistance may have decreased susceptibility to entecavir.²⁴

  
  

Advice to Patients

• 
  

  Advise patient of the risks and benefits of adefovir and other alternatives for treatment of HBV infection and importance of reading the adefovir patient package insert before starting treatment.¹

  
  


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  Importance of remaining under the care of a clinician while taking adefovir and not discontinuing the drug without first informing a clinician.¹

  
  


• 
  

  Importance of following a regular dosage schedule and avoiding missed doses.¹

  
  


• 
  

  Risk of exacerbations of hepatitis when adefovir is discontinued and importance of close monitoring of liver function and HBV levels for several months or longer after the drug is stopped.¹

  
  


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  Risk of nephrotoxicity and importance of monitoring renal function during treatment, especially in those with preexisting renal impairment or other risks for renal impairment.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, cold intolerance especially in the arms and legs, dizziness or feeling light-headed, fast or irregular heart beat) or any signs or symptoms of hepatotoxicity (e.g., jaundice, dark urine, bowel movements light in color, anorexia, nausea, stomach pain).¹ Importance of reporting any other unusual symptoms or if any known symptom persists or worsens.¹

  
  


• 
  

  Risk of emergence of HIV resistance in patients with unrecognized or untreated HIV infection; importance of HIV antibody testing prior to initiation of adefovir therapy and anytime during therapy if possible exposure to HIV occurs.¹

  
  


• 
  

  Advise patients with lamivudine-resistant HBV that they should receive adefovir in conjunction with lamivudine and should not receive adefovir monotherapy.¹

  
  


• 
  

  Advise patients that it is not known whether adefovir will prevent transmission of HBV to others and that appropriate measures should be taken to prevent sexual or other transmission of the virus.¹

  
  


• 
  

  Advise patients that the optimal duration of treatment and the relationship between treatment response and long-term outcomes (hepatocellular carcinoma, decompensated cirrhosis) are not known.¹

  
  


• 
  

  Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, and any concomitant illnesses.¹

  
  


• 
  

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

  
  


• 
  

  Importance of advising patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

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

Adefovir Dipivoxil

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	10 mg	Hepsera	Gilead

Comparative Pricing

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

Hepsera 10MG Tablets (GILEAD SCIENCES): 30/$1013.97 or 90/$2931.05

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 April 01, 2009. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Gilead Sciences, Inc. Hepsera (adefovir dipivoxil) tablet prescribing information. Foster City, CA; 2008 May.

2. Dusheiko G. Adefovir dipivoxil for the treatment of HBeAg-positive chronic hepatitis B. Paper presented at the European Association for the Study of the Liver (EASL) international consensus conference on hepatitis B. Geneva, Switzerland, 2002 Sep 13-14. From the EASL website. Accessed 2003 Jan.

3. Marcellin P, Chung TT, Lim SG et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med. 2003; 348:808-16. [IDIS 494875] [PubMed 12606735]

4. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med. 2003; 348:800-7. [IDIS 494874] [PubMed 12606734]

5. Knight W, Hayashi S, Behnhamou Y et al. Dosing guidelines for adefovir dipivoxil in the treatment of chronic hepatitis B patients with renal or hepatic impairment. In: Posters of the 37th Annual Meeting of the European Association for the Study of the Liver (EASL), Madrid, Spain, 2002 Apr 17–21. Poster #308.

7. Anon. Gilead adefovir hep B resistance potential shows need for combo trials. FDC Rep. 2002; (Aug 12):5-6.

8. Perrillo R, Schiff E, Yoshida E et al. Adefovir dipivoxil for the treatment of lamivudine-resistant hepatitis B mutants. Hepatology. 2000; 32:129-34. [PubMed 10869300]

9. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007; 45:507-39. [PubMed 17256718]

10. Anon. FDA approves new treatment for chronic hepatitis B. FDA Talk Paper. Rockville, MD: Food and Drug Administration; 2002 Sep 20.

11. Hadziyannis SJ. Papatheodoridis GV. Treatment of HBeAg negative chronic hepatitis B: treatment with new drugs (adefovir and others). Paper presented at the European Association for the Study of the Liver (EASL) international consensus conference on hepatitis B. Geneva, Switzerland, 2002 Sep 13-14. From the EASL website. Accessed 2003 Jan.

12. Marcellin P, Chang TT, Lim SG et al. Long-term efficacy and safety of adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. Hepatology. 2008; 48:750-8. [PubMed 18752330]

14. Fisher EJ, Chaloner K, Cohn DL et al. The safety and efficacy of adefovir dipivoxil in patients with advanced HIV disease: a randomized, placebo-controlled trial. AIDS. 2001; 15:1695-700. [PubMed 11546945]

15. Kamp W, Schokker J, Cambridge E et al. Effect of weekly adefovir (PMEA) infusions on HIV-1 virus load: results of a phase I/II study. Antivir Ther. 1999; 4:101-7. [PubMed 10682155]

16. Gilead Sciences, Inc, Foster City, CA: Personal communication.

17. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years. Gastroenterology. 2006; 131:1743-51. [PubMed 17087951]

18. Peters MG, Hann Hw H, Martin P et al. Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology. 2004; 126:91-101. [PubMed 14699491]

19. Xiong S, Yang H, Westland C et al. Resistance surveillance of HBeAg negative chronic hepatitis B patients treated for two years with adefovir dipivoxil. Presented at the 11th international symposium on viral hepatitis and liver disease, 2003. Sydney, Australia, 2003 Apr 6-10.

20. Gilead Sciences. Viread (tenofovir disoproxil fumarate) tablets prescribing information. Foster City, CA; 2008 Aug.

21. Schiff E, Lai CL, Hadziyannis S et al. Adefovir dipivoxil for wait-listed and post-liver transplantation patients with lamivudine-resistant hepatitis B: final long-term results. Liver Transpl. 2007; 13:349-60. [PubMed 17326221]

22. Balzarini J, Schols D, Laethem KV et al. Pronounced in vitro and in vivo antiretroviral activity of 5-substituted 2,4-diamino-6-[2-(phosphonomethoxy)ethyoxy] pyrimidines. J Antimicrob Chemother. 2007; 59:80-6. [PubMed 17124193]

23. Jonas MM, Kelly D, Pollack H et al. Safety, efficacy, and pharmacokinetics of adefovir dipivoxil in children and adolescents (age 2 to <18 years) with chronic hepatitis B. Hepatology. 2008; 47:1863-71. [PubMed 18433023]

24. Bristol-Myers Squibb Company. Baraclude (entecavir) tablets and oral solution prescribing information. Princeton, NJ; 2008 Feb.

25. Idenix Pharmaceuticals. Tyzeka (telbivudine) tablets prescribing information. Cambridge, MA; 2006 Oct.

26. Gerolami R, Bourliere M, Colson P et al. Unusual selection of rtA181V HBV mutants cross-resistant to adefovir following prolonged lamivudine monotherapy: report of two cases. Antivir Ther. 2006; 11:1103-6. [PubMed 17302381]

27. Karatayli E, Karayalçin S, Karaaslan H et al. A novel mutation pattern emerging during lamivudine treatment shows cross-resistance to adefovir dipivoxil treatment. Antivir Ther. 2007; 12:761-8. [PubMed 17713159]

28. Villet S, Pichoud C, Billioud G et al. Impact of hepatitis B virus rtA181V/T mutants on hepatitis B treatment failure. J Hepatol. 2008; 48:747-55. [PubMed 18331765]

More Adefovir Dipivoxil resources

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Compare Adefovir Dipivoxil with other medications

• Hepatitis B

Paraplatin

carboplatin

Dosage Form: injection

Warning

Paraplatin (carboplatin aqueous solution) INJECTION should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate treatment facilities are readily available.

Bone marrow suppression is dose related and may be severe, resulting in infection and/or bleeding. Anemia may be cumulative and may require transfusion support. Vomiting is another frequent drug-related side effect.

Anaphylactic-like reactions to carboplatin have been reported and may occur within minutes of Paraplatin administration. Epinephrine, corticosteroids, and antihistamines have been employed to alleviate symptoms.

Paraplatin Description

Paraplatin® (carboplatin aqueous solution) INJECTION is supplied as a sterile, pyrogen-free, 10 mg/mL aqueous solution of carboplatin. Carboplatin is a platinum coordination compound. The chemical name for carboplatin is platinum, diammine[1,1-cyclobutanedicarboxylato(2-)-O,O′]-, (SP-4-2), and carboplatin has the following structural formula:

Carboplatin is a crystalline powder with the molecular formula of C6H12N2O4Pt and a molecular weight of 371.25. It is soluble in water at a rate of approximately 14 mg/mL, and the pH of a 1% solution is 5 to 7. It is virtually insoluble in ethanol, acetone, and dimethylacetamide.

Paraplatin - Clinical Pharmacology

Carboplatin, like cisplatin, produces predominantly interstrand DNA cross-links rather than DNA-protein cross-links. This effect is apparently cell-cycle nonspecific. The aquation of carboplatin, which is thought to produce the active species, occurs at a slower rate than in the case of cisplatin. Despite this difference, it appears that both carboplatin and cisplatin induce equal numbers of drug-DNA cross-links, causing equivalent lesions and biological effects. The differences in potencies for carboplatin and cisplatin appear to be directly related to the difference in aquation rates.

In patients with creatinine clearances of about 60 mL/min or greater, plasma levels of intact carboplatin decay in a biphasic manner after a 30-minute intravenous infusion of 300 mg/m2 to 500 mg/m2 of carboplatin. The initial plasma half-life (alpha) was found to be 1.1 to 2 hours (n=6), and the postdistribution plasma half-life (beta) was found to be 2.6 to 5.9 hours (n=6). The total body clearance, apparent volume of distribution and mean residence time for carboplatin are 4.4 L/hour, 16 L and 3.5 hours, respectively. The Cmax values and areas under the plasma concentration versus time curves from 0 to infinity (AUC inf) increase linearly with dose, although the increase was slightly more than dose proportional. Carboplatin, therefore, exhibits linear pharmacokinetics over the dosing range studied (300 mg/m2 to 500 mg/m2).

Carboplatin is not bound to plasma proteins. No significant quantities of protein-free, ultrafilterable platinum-containing species other than carboplatin are present in plasma. However, platinum from carboplatin becomes irreversibly bound to plasma proteins and is slowly eliminated with a minimum half-life of 5 days.

The major route of elimination of carboplatin is renal excretion. Patients with creatinine clearances of approximately 60 mL/min or greater excrete 65% of the dose in the urine within 12 hours and 71% of the dose within 24 hours. All of the platinum in the 24-hour urine is present as carboplatin. Only 3% to 5% of the administered platinum is excreted in the urine between 24 and 96 hours. There are insufficient data to determine whether biliary excretion occurs.

In patients with creatinine clearances below 60 mL/min, the total body and renal clearances of carboplatin decrease as the creatinine clearance decreases. Paraplatin dosages should therefore be reduced in these patients (see DOSAGE AND ADMINISTRATION).

The primary determinant of Paraplatin clearance is glomerular filtration rate (GFR) and this parameter of renal function is often decreased in elderly patients. Dosing formulas incorporating estimates of GFR (see DOSAGE AND ADMINISTRATION) to provide predictable Paraplatin plasma AUCs should be used in elderly patients to minimize the risk of toxicity.

Clinical Studies

Use with Cyclophosphamide for Initial Treatment of Ovarian Cancer

In two prospectively randomized, controlled studies conducted by the National Cancer Institute of Canada, Clinical Trials Group (NCIC), and the Southwest Oncology Group (SWOG), 789 chemotherapy naive patients with advanced ovarian cancer were treated with carboplatin or cisplatin, both in combination with cyclophosphamide every 28 days for 6 courses before surgical reevaluation. The following results were obtained from both studies:

Comparative Efficacy

Overview of Pivotal Trials

	NCIC	SWOG
Number of patients randomized	447	342
Median age (years)	60	62
Dose of cisplatin	75 mg/m2	100 mg/m2
Dose of carboplatin	300 mg/m2	300 mg/m2
Dose of cyclophosphamide	600 mg/m2	600 mg/m2
Residual tumor <2 cm (number of patients)	39% (174/447)	14% (49/342)

Clinical Response in Measurable Disease Patients

	NCIC	SWOG
Carboplatin (number of patients)	60% (48/80)	58% (48/83)
Cisplatin (number of patients)	58% (49/85)	43% (33/76)
95% CI of difference (Carboplatin-Cisplatin)	(−13.9%, 18.6%)	(−2.3%, 31.1%)

Pathologic Complete Response*

	NCIC	SWOG
* 114 Carboplatin and 109 Cisplatin patients did not undergo second look surgery in NCIC study.    90 Carboplatin and 106 Cisplatin patients did not undergo second look surgery in SWOG study.
Carboplatin (number of patients)	11% (24/224)	10% (17/171)
Cisplatin (number of patients)	15% (33/223)	10% (17/171)
95% CI of difference (Carboplatin-Cisplatin)	(−10.7%, 2.5%)	(−6.9%, 6.9%)

Progression-Free Survival (PFS)

	NCIC	SWOG
*  Kaplan-Meier Estimates Unrelated deaths occurring in the absence of progression were counted as events (progression) in this analysis.
** Analysis adjusted for factors found to be of prognostic significance were consistent with unadjusted analysis.
Median
Carboplatin	59 weeks	49 weeks
Cisplatin	61 weeks	47 weeks
2-year PFS*
Carboplatin	31%	21%
Cisplatin	31%	21%
95% CI of difference (Carboplatin-Cisplatin)	(−9.3, 8.7)	(−9.0, 9.4)
3-year PFS*
Carboplatin	19%	8%
Cisplatin	23%	14%
95% CI of difference (Carboplatin-Cisplatin)	(−11.5, 4.5)	(−14.1, 0.3)
Hazard Ratio**	1.10	1.02
95% CI (Carboplatin-Cisplatin)	(0.89, 1.35)	(0.81, 1.29)

Survival

	NCIC	SWOG
*  Kaplan-Meier Estimates
** Analysis adjusted for factors found to be of prognostic significance were consistent with unadjusted analysis.
Median
Carboplatin	110 weeks	86 weeks
Cisplatin	99 weeks	79 weeks
2-year Survival*
Carboplatin	51.9%	40.2%
Cisplatin	48.4%	39.0%
95% CI of difference (Carboplatin-Cisplatin)	(−6.2, 13.2)	(−9.8, 12.2)
3-year Survival*
Carboplatin	34.6%	18.3%
Cisplatin	33.1%	24.9%
95% CI of difference (Carboplatin-Cisplatin)	(−7.7, 10.7)	(−15.9, 2.7)
Hazard Ratio**	0.98	1.01
95% CI (Carboplatin-Cisplatin)	(0.78, 1.23)	(0.78, 1.30)

Comparative Toxicity

The pattern of toxicity exerted by the carboplatin-containing regimen was significantly different from that of the cisplatin-containing combinations. Differences between the two studies may be explained by different cisplatin dosages and by different supportive care.

The carboplatin-containing regimen induced significantly more thrombocytopenia and, in one study, significantly more leukopenia and more need for transfusional support. The cisplatin-containing regimen produced significantly more anemia in one study. However, no significant differences occurred in incidences of infections and hemorrhagic episodes.

Non-hematologic toxicities (emesis, neurotoxicity, ototoxicity, renal toxicity, hypomagnesemia, and alopecia) were significantly more frequent in the cisplatin-containing arms.

ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN CANCER NCIC STUDY

		Carboplatin Arm Percent*	Cisplatin Arm Percent*	P-Values**
*  Values are in percent of evaluable patients.
** ns=not significant, p>0.05.
+  May have been affected by cyclophosphamide dosage delivered.
Bone Marrow
Thrombocytopenia	<100,000/mm3	70	29	<0.001
	<50,000/mm3	41	6	<0.001
Neutropenia	<2000 cells/mm3	97	96	ns
	<1000 cells/mm3	81	79	ns
Leukopenia	<4000 cells/mm3	98	97	ns
	<2000 cells/mm3	68	52	0.001
Anemia	<11 g/dL	91	91	ns
	<8 g/dL	18	12	ns
Infections		14	12	ns
Bleeding		10	4	ns
Transfusions		42	31	0.018
Gastrointestinal
Nausea and vomiting		93	98	0.010
Vomiting		84	97	<0.001
Other GI side effects		50	62	0.013
Neurologic
Peripheral neuropathies		16	42	<0.001
Ototoxicity		13	33	<0.001
Other sensory side effects		6	10	ns
Central neurotoxicity		28	40	0.009
Renal
Serum creatinine elevations		5	13	0.006
Blood urea elevations		17	31	<0.001
Hepatic
Bilirubin elevations		5	3	ns
SGOT elevations		17	13	ns
Alkaline phosphatase elevations		-	-	-
Electrolytes loss
Sodium		10	20	0.005
Potassium		16	22	ns
Calcium		16	19	ns
Magnesium		63	88	<0.001
Other side effects
Pain		36	37	ns
Asthenia		40	33	ns
Cardiovascular		15	19	ns
Respiratory		8	9	ns
Allergic		12	9	ns
Genitourinary		10	10	ns
Alopecia +		50	62	0.017
Mucositis		10	9	ns

ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN CANCER SWOG STUDY

		Carboplatin Arm Percent*	Cisplatin Arm Percent*	P-Values**
*  Values are in percent of evaluable patients.
** ns=not significant, p>0.05.
+  May have been affected by cyclophosphamide dosage delivered.
Bone Marrow
Thrombocytopenia	<100,000/mm3	59	35	<0.001
	<50,000/mm3	22	11	0.006
Neutropenia	<2000 cells/mm3	95	97	ns
	<1000 cells/mm3	84	78	ns
Leukopenia	<4000 cells/mm3	97	97	ns
	<2000 cells/mm3	76	67	ns
Anemia	<11 g/dL	88	87	ns
	<8 g/dL	8	24	<0.001
Infections		18	21	ns
Bleeding		6	4	ns
Transfusions		25	33	ns
Gastrointestinal
Nausea and vomiting		94	96	ns
Vomiting		82	91	0.007
Other GI side effects		40	48	ns
Neurologic
Peripheral neuropathies		13	28	0.001
Ototoxicity		12	30	<0.001
Other sensory side effects		4	6	ns
Central neurotoxicity		23	29	ns
Renal
Serum creatinine elevations		7	38	<0.001
Blood urea elevations		-	-	-
Hepatic
Bilirubin elevations		5	3	ns
SGOT elevations		23	16	ns
Alkaline phosphatase elevations		29	20	ns
Electrolytes loss
Sodium		-	-	-
Potassium		-	-	-
Calcium		-	-	-
Magnesium		58	77	<0.001
Other side effects
Pain		54	52	ns
Asthenia		43	46	ns
Cardiovascular		23	30	ns
Respiratory		12	11	ns
Allergic		10	11	ns
Genitourinary		11	13	ns
Alopecia +		43	57	0.009
Mucositis		6	11	ns

Use as a Single Agent for Secondary Treatment of Advanced Ovarian Cancer

In two prospective, randomized controlled studies in patients with advanced ovarian cancer previously treated with chemotherapy, carboplatin achieved 6 clinical complete responses in 47 patients. The duration of these responses ranged from 45 to 71+ weeks.

INDICATIONS

Initial Treatment of Advanced Ovarian Carcinoma

Paraplatin (carboplatin aqueous solution) INJECTION is indicated for the initial treatment of advanced ovarian carcinoma in established combination with other approved chemotherapeutic agents. One established combination regimen consists of Paraplatin and cyclophosphamide. Two randomized controlled studies conducted by the NCIC and SWOG with carboplatin versus cisplatin, both in combination with cyclophosphamide, have demonstrated equivalent overall survival between the two groups (see CLINICAL STUDIES).

There is limited statistical power to demonstrate equivalence in overall pathologic complete response rates and long-term survival (≥3 years) because of the small number of patients with these outcomes: the small number of patients with residual tumor <2 cm after initial surgery also limits the statistical power to demonstrate equivalence in this subgroup.

Secondary Treatment of Advanced Ovarian Carcinoma

Paraplatin is indicated for the palliative treatment of patients with ovarian carcinoma recurrent after prior chemotherapy, including patients who have been previously treated with cisplatin.

Within the group of patients previously treated with cisplatin, those who have developed progressive disease while receiving cisplatin therapy may have a decreased response rate.

Contraindications

Paraplatin (carboplatin aqueous solution) INJECTION is contraindicated in patients with a history of severe allergic reactions to cisplatin or other platinum-containing compounds.

Paraplatin should not be employed in patients with severe bone marrow depression or significant bleeding.

Warnings

Bone marrow suppression (leukopenia, neutropenia, and thrombocytopenia) is dose-dependent and is also the dose-limiting toxicity. Peripheral blood counts should be frequently monitored during Paraplatin treatment and, when appropriate, until recovery is achieved. Median nadir occurs at day 21 in patients receiving single-agent carboplatin. In general, single intermittent courses of Paraplatin should not be repeated until leukocyte, neutrophil, and platelet counts have recovered.

Since anemia is cumulative, transfusions may be needed during treatment with Paraplatin, particularly in patients receiving prolonged therapy.

Bone marrow suppression is increased in patients who have received prior therapy, especially regimens including cisplatin. Marrow suppression is also increased in patients with impaired kidney function. Initial Paraplatin dosages in these patients should be appropriately reduced (see DOSAGE AND ADMINISTRATION) and blood counts should be carefully monitored between courses. The use of Paraplatin in combination with other bone marrow suppressing therapies must be carefully managed with respect to dosage and timing in order to minimize additive effects.

Carboplatin has limited nephrotoxic potential, but concomitant treatment with aminoglycosides has resulted in increased renal and/or audiologic toxicity, and caution must be exercised when a patient receives both drugs. Clinically significant hearing loss has been reported to occur in pediatric patients when carboplatin was administered at higher than recommended doses in combination with other ototoxic agents.

Paraplatin can induce emesis, which can be more severe in patients previously receiving emetogenic therapy. The incidence and intensity of emesis have been reduced by using premedication with antiemetics. Although no conclusive efficacy data exist with the following schedules of Paraplatin, lengthening the duration of single intravenous administration to 24 hours or dividing the total dose over 5 consecutive daily pulse doses has resulted in reduced emesis.

Although peripheral neurotoxicity is infrequent, its incidence is increased in patients older than 65 years and in patients previously treated with cisplatin. Pre-existing cisplatin-induced neurotoxicity does not worsen in about 70% of the patients receiving carboplatin as secondary treatment.

Loss of vision, which can be complete for light and colors, has been reported after the use of carboplatin with doses higher than those recommended in the package insert. Vision appears to recover totally or to a significant extent within weeks of stopping these high doses.

As in the case of other platinum-coordination compounds, allergic reactions to carboplatin have been reported. These may occur within minutes of administration and should be managed with appropriate supportive therapy. There is increased risk of allergic reactions including anaphylaxis in patients previously exposed to platinum therapy. (See CONTRAINDICATIONS and ADVERSE REACTIONS: Allergic Reactions.)

High dosages of carboplatin (more than 4 times the recommended dose) have resulted in severe abnormalities of liver function tests.

Paraplatin (carboplatin aqueous solution) INJECTION may cause fetal harm when administered to a pregnant woman. Carboplatin has been shown to be embryotoxic and teratogenic in rats. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

Precautions

General

Needles or intravenous administration sets containing aluminum parts that may come in contact with Paraplatin (carboplatin aqueous solution) INJECTION should not be used for the preparation or administration of the drug. Aluminum can react with carboplatin causing precipitate formation and loss of potency.

Drug Interactions

The renal effects of nephrotoxic compounds may be potentiated by Paraplatin.

Carcinogensis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of carboplatin has not been studied, but compounds with similar mechanisms of action and mutagenicity profiles have been reported to be carcinogenic. Carboplatin has been shown to be mutagenic both in vitro and in vivo. It has also been shown to be embryotoxic and teratogenic in rats receiving the drug during organogenesis. Secondary malignancies have been reported in association with multi-drug therapy.

Pregnancy

Pregnancy Category D

See WARNINGS.

Nursing Mothers

It is not known whether carboplatin is excreted in human milk. Because there is a possibility of toxicity in nursing infants secondary to Paraplatin treatment of the mother, it is recommended that breast feeding be discontinued if the mother is treated with Paraplatin (carboplatin aqueous solution) INJECTION.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established (see WARNINGS; “audiologic toxicity”).

Geriatric Use

Of the 789 patients in initial treatment combination therapy studies (NCIC and SWOG), 395 patients were treated with carboplatin in combination with cyclophosphamide. Of these, 141 were over 65 years of age and 22 were 75 years or older. In these trials, age was not a prognostic factor for survival. In terms of safety, elderly patients treated with carboplatin were more likely to develop severe thrombocytopenia than younger patients. In a combined database of 1,942 patients (414 were ≥65 years of age) that received single-agent carboplatin for different tumor types, a similar incidence of adverse events was seen in patients 65 years and older and in patients less than 65. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Because renal function is often decreased in the elderly, renal function should be considered in the selection of Paraplatin dosage (see DOSAGE AND ADMINISTRATION).

Adverse Reactions

For a comparison of toxicities when carboplatin or cisplatin was given in combination with cyclophosphamide, see CLINICAL STUDIES: Use with Cyclophosphamide for Initial Treatment of Ovarian Cancer: Comparative Toxicity.

ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN CANCER

		First Line Combination Therapy* Percent	Second Line Single-Agent Therapy** Percent
*  Use with Cyclophosphamide for Initial Treatment of Ovarian Cancer: Data are based on the experience of 393 patients with ovarian cancer (regardless of baseline status) who received initial combination therapy with carboplatin and cyclophosphamide in two randomized controlled studies conducted by SWOG and NCIC (see CLINICAL STUDIES). Combination with cyclophosphamide as well as duration of treatment may be responsible for the differences that can be noted in the adverse experience table.
** Single Agent Use for the Secondary Treatment of Ovarian Cancer: Data are based on the experience of 553 patients with previously treated ovarian carcinoma (regardless of baseline status) who received single-agent carboplatin.
Bone Marrow
Thrombocytopenia	<100,000/mm3	66	62
	<50,000/mm3	33	35
Neutropenia	<2000 cells/mm3	96	67
	<1000 cells/mm3	82	21
Leukopenia	<4000 cells/mm3	97	85
	<2000 cells/mm3	71	26
Anemia	<11 g/dL	90	90
	<8 g/dL	14	21
Infections		16	5
Bleeding		8	5
Transfusions		35	44
Gastrointestinal
Nausea and vomiting		93	92
Vomiting		83	81
Other GI side effects		46	21
Neurologic
Peripheral neuropathies		15	6
Ototoxicity		12	1
Other sensory side effects		5	1
Central neurotoxicity		26	5
Renal
Serum creatinine elevations		6	10
Blood urea elevations		17	22
Hepatic
Bilirubin elevations		5	5
SGOT elevations		20	19
Alkaline phosphatase elevations		29	37
Electrolytes loss
Sodium		10	47
Potassium		16	28
Calcium		16	31
Magnesium		61	43
Other side effects
Pain		44	23
Asthenia		41	11
Cardiovascular		19	6
Respiratory		10	6
Allergic		11	2
Genitourinary		10	2
Alopecia		49	2
Mucositis		8	1

In the narrative section that follows, the incidences of adverse events are based on data from 1,893 patients with various types of tumors who received carboplatin as single-agent therapy.

Hematologic Toxicity

Bone marrow suppression is the dose-limiting toxicity of Paraplatin. Thrombocytopenia with platelet counts below 50,000/mm3 occurs in 25% of the patients (35% of pretreated ovarian cancer patients); neutropenia with granulocyte counts below 1,000/mm3 occurs in 16% of the patients (21% of pretreated ovarian cancer patients); leukopenia with WBC counts below 2,000/mm3 occurs in 15% of the patients (26% of pretreated ovarian cancer patients). The nadir usually occurs about day 21 in patients receiving single-

Covonia Catarrh Relief Formula

1. Name Of The Medicinal Product

Covonia Catarrh Relief Formula

2. Qualitative And Quantitative Composition

Each 5ml contains:-

Liquid Extract Boneset (1:1 21% alcohol) 0.6ml

Liquid Extract Blue Flag (1:1 37% alcohol) 0.05ml

Liquid Extract Burdock Root (1:1 21% alcohol) 0.25ml

Liquid Extract Hyssop (1:1 21% alcohol) 0.35ml

3. Pharmaceutical Form

Oral Liquid

4. Clinical Particulars

4.1 Therapeutic Indications

A herbal remedy traditionally used for the symptomatic relief of nasal catarrh and catarrh of the throat.

4.2 Posology And Method Of Administration

Adults and the Elderly (only): One 5ml spoonful three times a day.

Children over 12: One 5ml spoonful morning and evening

Children under 12: Not recommended

4.3 Contraindications

Hypersensitivity to any of the ingredients.

4.4 Special Warnings And Precautions For Use

This medicinal product contains 11.5 vol% ethanol (alcohol), i.e. up to 453 mg per dose, equivalent to 12 ml beer, 5 ml wine per dose.

Harmful for those suffering from alcoholism.

To be taken into account in pregnant or breast-feeding women, children and high-risk groups such as patients with liver disease, or epilepsy.

Patients with rare glucose-galactose malabsorption should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Refer to 4.4

4.6 Pregnancy And Lactation

There are no adequate data from the use of Covonia Catarrh Relief Formula in pregnant women. Covonia Catarrh Relief Formula should not be used in pregnancy.

4.7 Effects On Ability To Drive And Use Machines

None

4.8 Undesirable Effects

None

4.9 Overdose

No cases known.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Boneset and Hyssop are specific herbal anticatarrhals. Boneset is also immune-stimulant.

5.2 Pharmacokinetic Properties

No information available.

5.3 Preclinical Safety Data

No information available.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Chloroform spirit (containing chloroform, ethanol and purified water), methyl parahydroxybenzoate (E218), tincture capsicum (containing capsicum oleoresin, ethanol and water), colour solution (containing nipagen m, caramel (E150), glycerol (E422), chloroform, water), viscarin SD 389 (contains dextrose/carageenan (E407)), menthol, sodium saccharin (E954), and purified water.

6.2 Incompatibilities

None.

6.3 Shelf Life

Three years unopened.

Once opened use within 28 days.

6.4 Special Precautions For Storage

Do not store above 25 degrees C.

6.5 Nature And Contents Of Container

100ml amber glass sirop bottle with 28mm polypropylene white tamper-evident cap with EPE/Aluminium/Melinex liner.

150ml amber glass bottle embossed “Covonia” with a 28mm polypropylene white tamper evident cap with EPE/Aluminium/Melinex liner.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Thornton & Ross Ltd

Linthwaite, Huddersfield

West Yorkshire HD7 5QH

United Kingdom

8. Marketing Authorisation Number(S)

PL 00240/0142

9. Date Of First Authorisation/Renewal Of The Authorisation

22/02/2006

10. Date Of Revision Of The Text

04/10/2010

Midamor

Pronunciation: a-MILL-oh-ride
Generic Name: Amiloride
Brand Name: Midamor

Amiloride may cause high blood potassium levels that can be fatal if not corrected. High blood potassium levels occur more commonly in patients with kidney problems, diabetes, elderly patients, those who are severely ill, or patients who are not taking an agent used to increase excretion of potassium. If you develop muscle weakness or irregular heartbeat, notify your doctor immediately.

Midamor is used for:

Preventing development of low blood potassium or helping to restore normal blood potassium in patients with high blood pressure or heart failure. It is usually used with other medicines. It may also be used for other conditions as determined by your doctor.

Midamor is a potassium-sparing diuretic. It works by making the kidneys eliminate sodium (salt) and water from the body while retaining potassium.

Do NOT use Midamor if:

• you are allergic to any ingredient in Midamor


• you are taking potassium supplements or potassium-sparing diuretics (eg, aldosterone, triamterene)


• you are unable to urinate


• you have high blood potassium levels or kidney problems due to diabetes or other severe kidney disease

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

Before using Midamor:

Some medical conditions may interact with Midamor. 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 heart problems, diabetes, kidney damage caused by diabetes, liver or kidney problems, low blood sodium levels, or a high acidity of body fluids, or you are dehydrated

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

• Angiotensin-converting enzyme (ACE) inhibitors (eg, enalapril), angiotensin II receptor antagonists (eg, valsartan), cyclosporine, other potassium-sparing diuretics (eg, aldosterone, triamterene) or potassium supplements because high blood potassium levels may occur and cause listlessness, confusion, abnormal skin sensations of the arms and legs, heaviness of the limbs, slow or irregular heartbeat, or stopping of the heart


• Nonsteroidal anti-inflammatory drugs (NSAIDs) (eg, indomethacin) because they may decrease Midamor's effectiveness and increase the risk of kidney problems and high blood potassium levels


• Lithium or quinidine because the risk of their side effects and toxicity may be increased by Midamor

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

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

• Take Midamor by mouth with food.


• Midamor may increase the amount of urine or cause you to urinate more often when you first start taking it. To keep this from disturbing your sleep, try to take your dose before 6 pm.


• If you miss a dose of Midamor, 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 Midamor.

Important safety information:

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


• Check with your doctor before you use a salt substitute or a product that has potassium in it.


• Lab tests, including electrolyte levels and blood pressure monitoring, may be performed while you use Midamor. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Use Midamor with caution in the ELDERLY; they may be more sensitive to its effects.


• Midamor should not be used in CHILDREN; safety and effectiveness in children have not been confirmed.


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

Possible side effects of Midamor:

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

Diarrhea; headache; loss of appetite; nausea; weakness.

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); dry mouth; excessive thirst; slowed heart rate; unusual muscle weakness; unusual tiredness; 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: Midamor 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 lightheadedness; nausea; vomiting; weakness.

Proper storage of Midamor:

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

General information:

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


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

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Midamor resources

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

• Midamor Prescribing Information (FDA)


• Midamor Advanced Consumer (Micromedex) - Includes Dosage Information


• Midamor Concise Consumer Information (Cerner Multum)


• Midamor Monograph (AHFS DI)


• Amiloride Prescribing Information (FDA)

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