Thymoglobulin

Generic Name: Antithymocyte Globulin (Rabbit)
Class: Immunosuppressive Agents
ATC Class: L04AA04
VA Class: IM600

• 
  

  Should be used only by clinicians experienced in immunosuppressive therapy for the management of renal transplant patients.^b

  
  

Introduction

Antithymocyte globulin (rabbit) (ATG [rabbit]); rabbit-derived polyclonal antibody preparation; immunosuppressive agent.^{2 8 a b g}

Uses for Thymoglobulin

Renal Allotransplantation

Treatment of acute rejection of renal allografts in conjunction with other immunosuppressive agents.^{2 8 a b e g}

ATG (rabbit) found to be more effective than ATG (equine) in reversing acute rejection episodes (88% compared with 76%) and preventing recurrent rejection episodes in renal transplant recipients.^{2 b}

Has also been used successfully as induction therapy in conjunction with maintenance immunosuppressive therapy for the prevention of renal allograft rejection†.^{4 5 a d g m n o p q r s u w x}

Hepatic Allotransplantation

Induction therapy to prevent hepatic allograft rejection and minimize maintenance immunosuppression† in pediatric patients (designated an orphan drug by FDA for this use)^{j t} and in adults.^v

Myelodysplastic Syndrome and Aplastic Anemia

Has been used for the treatment of myelodysplastic syndrome† (designated an orphan drug by FDA for this use).^{j k}

Has been used for the treatment of aplastic anemia†, usually in conjunction with cyclosporine.^{7 9 a l}

Thymoglobulin Dosage and Administration

General

• 
  

  To reduce the incidence and intensity of infusion-related adverse effects, the manufacturer and some clinicians recommend premedication with corticosteroids, acetaminophen, and/or an antihistamine (e.g., diphenhydramine) 1 hour prior to each infusion.^{2 9 a b q u} (See Infusion-related Effects under Cautions.)

  
  


• 
  

  The manufacturer recommends prophylactic antiviral therapy (e.g., acyclovir, ganciclovir, valganciclovir) during ATG (rabbit) therapy.^{9 a b m} (See Infectious Complications under Cautions.)

  
  

Administration

IV Administration

For drug compatibility information, see Compatibility under Stability.

ATG (rabbit) is administered by IV infusion.^{1 a b g} The manufacturer states that ATG (rabbit) should be infused through an inline 0.22-μm filter into a high-flow vein.^{a b g} Has also been administered via a peripheral vein† in some patients, but safety not fully established and may increase risk of thrombophlebitis and DVT.^{g h i}

Administer in conjunction with other immunosuppressive agents.^b

Reconstitution

Allow vial to reach room temperature before reconstituting.^{a b} Reconstitute vial containing 25 mg of the drug with 5 mL of sterile water for injection to provide a solution containing 5 mg/mL.^{a b} Gently rotate vial until powder is completely dissolved.^{a b} Use reconstituted solution immediately.^b (See Storage under Stability.)

Dilution

Dilute appropriate dosage of reconstituted ATG (rabbit) in 0.9% sodium chloride or 5% dextrose injection.^{a b} Each reconstituted vial should be diluted in 50 mL of infusion solution; total volume of infusion solution required generally is 50–500 mL.^{a b} Recommended final concentration approximately 0.5 mg/mL.^{9 a} Mix diluted solution by gently inverting infusion bag only once or twice.^{a b}

Rate of Administration

Administer initial dose over ≥6 hours and subsequent doses over ≥4 hours.^{b g} Slowing infusion rate may help prevent or ameliorate acute infusion reactions.^{9 a b} (See Infusion-related Effects under Cautions.)

Dosage

Appropriate dosage for Thymoglobulin differs from dosages for other antithymocyte globulin (ATG) preparations since protein composition and concentrations vary depending on source of ATG used.^b Exercise care to ensure prescribed dose is appropriate for the ATG preparation being administered.^b

Reduce ATG (rabbit) dosage by 50% if WBC is ≥2000 but ≤3000/mm³ or platelet count is ≥50,000 but ≤75,000/m³.^b Consider drug discontinuance if WBC <2000/mm³ or platelet count <50,000/mm³.^b (See Hematologic Effects and Clinical/Laboratory Monitoring under Cautions.)

Pediatric Patients

Renal Allotransplantation

Prevention of Renal Allograft Rejection (Induction Therapy)†

IV Infusion

Optimum dosage not established; 1.5–2.5 mg/kg once daily for 5–10 days has been given.^{4 9 10 m n p q}

Adults

Renal Allotransplantation

Treatment of Allograft Rejection

IV Infusion

1.5 mg/kg once daily for 7–14 days.^{2 a b r} Usually continue other immunosuppressive agents used for treatment of acute renal transplant rejection (e.g., azathioprine, corticosteroids, cyclosporine) during therapy.^{2 a b r} (See Interactions.)

Prevention of Renal Allograft Rejection (Induction Therapy)†

IV Infusion

Optimum dosage not established; 1.5 mg/kg once daily for 5–14 days or 3 mg/kg once daily on day 1 then 1.5 mg/kg once daily on days 2 and 3 has been given.^{5 9 g r u} Intermittent dosage regimens based on CD3⁺ lymphocyte counts^w and regimens in which the first dose is administered intraoperatively also have been given.^{5 r s u}

Myelodysplastic Syndrome† and Aplastic Anemia†

Myelodysplastic Syndrome†

IV Infusion

Optimum dosage not established; 3.75 mg/kg once daily for 5 days has been given.^k

Aplastic Anemia†

IV Infusion

Optimum dosage not established; 3.5 mg/kg once daily for 5 days has been given.^{7 a l}

Special Populations

No special population dosage recommendations at this time.^b

Cautions for Thymoglobulin

Contraindications

• 
  

  Known hypersensitivity to rabbit proteins^{a b} or any ingredient in the formulation;^{a 9} history of anaphylaxis following ATG (rabbit) administration.^{a b}

  
  


• 
  

  Active or acute infections that contraindicate any additional immunosuppression.^b

  
  

Warnings/Precautions

Warnings

See Boxed Warning.

Close medical supervision required during and after IV infusion of ATG (rabbit).^{a b}

Cytokine Release Syndrome

Severe cytokine release syndrome (CRS), an immune-mediated reaction, reported.^b Severe, acute CRS may cause serious cardiorespiratory effects and/or death.^b

Infectious Complications

Possible increased risk of infections (bacterial, fungal, viral, and protozoal), reactivation of infections (particularly cytomegalovirus [CMV]), and sepsis when ATG (rabbit) is used in combination with multiple immunosuppressive agents.^{2 5 b m n r u} Severe, acute infections may be fatal.^b The manufacturer recommends careful patient monitoring and appropriate anti-infective prophylaxis.^b

Sensitivity Reactions

Anaphylaxis

Serious and fatal anaphylactic reactions reported.^{a b}

If anaphylaxis or other severe hypersensitivity reaction occurs, discontinue ATG (rabbit) infusion immediately and institute appropriate therapy as indicated (e.g., epinephrine, corticosteroids, maintenance of an adequate airway, oxygen, IV fluids, antihistamines, maintenance of BP).^{a b}

Patients with a history of anaphylaxis to ATG (rabbit) should not receive the drug again.^b

General Precautions

Malignancies

Possible increased risk of malignancies with immunosuppressive therapy, including rabbit ATG (e.g., lymphoma, posttransplant lymphoproliferative disease [PTLD]).^{9 a b m n r u}

Hematologic Effects and Clinical/Laboratory Monitoring

T cells decrease during ATG (rabbit) therapy.^b Monitor lymphocyte counts (i.e., total lymphocytes and/or T-cell subsets) to assess level of T-cell depletion in patients receiving the drug.^b

Thrombocytopenia and/or leukopenia (including lymphopenia and neutropenia) commonly reported.^{2 5 a b g r u} Monitor WBC and platelet count; reduce dosage and/or consider drug discontinuance in patients who develop leukopenia and/or thrombocytopenia.^b (See Dosage under Dosage and Administration.)

Antibody Formation

Anti-rabbit antibodies developed in 68% of renal transplant patients who received ATG (rabbit) for 7–14 days for treatment of acute rejection; these antibodies were still present in 24% of patients at 90 days.^{6 a b} Presence of anti-rabbit antibodies not correlated with treatment success or failure in these patients;^{6 a} possible effects of these antibodies on drug's efficacy during subsequent use not evaluated.^b

Infusion-related Effects

Risk of infusion-related effects (e.g., fever, chills and/or rigors, dyspnea, nausea and/or vomiting, diarrhea, hypotension or hypertension, malaise, rash, and/or headache); may occur as soon as first or second infusion during a single course of treatment.^{a b}

May minimize or prevent infusion-related effects by administering initial ATG (rabbit) infusions over ≥6 hours, administering a pretreatment regimen (corticosteroid, acetaminophen, and/or an antihistamine) 1 hour prior to each ATG (rabbit) infusion, and/or slowing the infusion rate.^{2 9 a b q u} (See General and see Administration under Dosage and Administration.)

Immunization

Safety of attenuated live vaccine administration following ATG (rabbit) therapy not established.^b Manufacturer states that immunization with attenuated live vaccines not recommended in patients who recently received the drug.^b

Laboratory Test Interference

Potential interference with rabbit antibody-based immunoassays and with cross-match or panel-reactive antibody cytotoxicity assays.^{a b}

Specific Populations

Pregnancy

Category C.^b

Lactation

¹ Not known whether ATG (rabbit) is distributed into milk; however, other immunoglobulins are distributed into human milk.^b Discontinue nursing or the drug.^b

Pediatric Use

The manufacturer states that safety and efficacy not established in children <18 years of age in controlled trials.^{a 9 b} However, ATG (rabbit) has been used as induction therapy in conjunction with maintenance immunosuppressive therapy to prevent renal or hepatic allograft rejection† in pediatric patients 5 months–18 years of age.^{4 9 10 a m n o p q t} (See Hepatic Allotransplantation under Uses.)

Dosage, efficacy, and adverse effect profile in pediatric patients generally appear to be the same as in adults.^{b n p q t}

Common Adverse Effects

Infectious complications (including sepsis, urinary tract infections, and CMV infections),^{5 a b n r u} fever,^b chills,^b leukopenia,^{5 b u} lymphopenia,^{5 d g r} thrombocytopenia,^{b g u} cytokine release syndrome,^g abdominal pain,^b nausea,^b diarrhea,^b asthenia,^b dyspnea,^b headache,^b pain,^b hyperkalemia,^b hypertension,^b peripheral edema,^b tachycardia,^b dizziness,^b infusion site pain/swelling/erythema.^b

Interactions for Thymoglobulin

No formal drug interaction studies to date.^b

Specific Drugs

Drug	Interaction	Comments
Basiliximab		No increase in adverse effectsf
Daclizumab		Limited experiencec
Immunosuppressive agents	Risk of oversuppression of the immune system and associated susceptibility to infection and malignancies, including lymphomaa b	Consider decreasing maintenance immunosuppressive therapy during concurrent usea b
Vaccines	Safety data not available on the effects of immunization with live vaccines during ATG (rabbit) therapyb	Avoid use of live vaccines in patients who have recently received ATG (rabbit)b

Thymoglobulin Pharmacokinetics

Absorption

Onset

T-cell depletion usually observed within 1 day after initiating therapy.^{b g}

Plasma Concentrations

Average 21.5 and 87 mcg/mL 4–8 hours post-infusion after first and last IV doses, respectively, when given for 7–11 days.^b

Duration

Lymphopenia may persist ≥1–2 years after ATG (rabbit) administration.^{5 g r}

Distribution

Extent

Not known whether ATG (rabbit) distributes into human milk; however, other immunoglobulins are distributed into human milk.^{a b}

Elimination

Half-life

2–3 days after first dose;^b may increase after multiple-dose administration.^{2 y}

Stability

Storage

Parenteral

Powder for Injection

2–8°C; do not freeze.^b Protect from light.^b

Although reconstituted solutions are stable at room temperature for up to 24 hours, room temperature storage is not recommended by the manufacturer since the preparation contains no preservatives; use immediately.^b

Use diluted solutions immediately.^b

Discard any unused drug after infusion.^b

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Drug Compatibility^HID

Admixture Compatibility

Variable
Heparin sodium with hydrocortisone sodium succinate

Y-Site Compatibility

Compatible
Hydrocortisone sodium succinate
Variable
Heparin sodium

Incompatibility not observed with polyvinyl chloride bags or infusion sets.^{9 a z}

ActionsActions

• 
  

  Rabbit-derived polyclonal antibody; immunosuppressive agent.^{2 8 a b g}

  
  


• 
  

  Exact mechanism of immunosuppressive action not fully elucidated; appears to involve clearance of peripheral antigen-reactive T lymphocytes (T cells) and modulation of T-cell activation, homing, and cytotoxicity.^{8 a b g}

  
  


• 
  

  ATG (rabbit) contains antibodies that bind T-cell surface receptors, including CD2, CD3, CD4, CD8, CD11a, CD18, CD25, CD44, CD45, HLA-DR, HLA class I heavy chains, and β₂-microglobulin.^{8 a b g}

  
  


• 
  

  Induces profound depletion of CD2, CD3, CD4, CD8, CD16, CD25, and CD45 lymphocytes within 24 hours of first dose administration.^{b g}

  
  


• 
  

  Not effective for treating antibody-mediated (humoral) transplant rejections.^b

  
  

Advice to Patients

• 
  

  Importance of informing patients about the potential benefits of ATG (rabbit) and attendant risks of immunosuppressive therapy.^b

  
  


• 
  

  Risk of decreased number of platelets and/or WBCs, including lymphocytes.^b Necessity of administration under supervision of a clinician with regular monitoring of platelet and WBC counts.^b

  
  


• 
  

  Potential for reduction of lymphocyte counts, which could increase risk of infection or malignancy.^b Importance of informing clinicians promptly if any signs or symptoms of infection or malignancy occur.^b

  
  


• 
  

  Advise patient of risk of possible fever, chills, itching, and/or rash during ATG (rabbit) infusion and that medication will be given to help control these reactions.^b

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal or nutritional supplements, as well as any concomitant illnesses.^b

  
  


• 
  

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

  
  


• 
  

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

  
  

Preparations

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

Antithymocyte Globulin (Rabbit)

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, for IV infusion	25 mg	Thymoglobulin	Genzyme

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 July 2008. 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. Sangstat Medical Corporation. Thymoglobulin (anti-thymocyte globulin [rabbit]) prescribing information. Menlo Park, CA; 1998 Dec.

2. Gaber AO, First MR, Tesi RJ et al. Results of the double-blind, randomized, multicenter, phase III clinical trial of Thymoglobulin versus Atgam in the treatment of acute graft rejection episodes after renal transplantation. Transplantation. 1998; 66:29-37. [IDIS 410978] [PubMed 9679818]

3. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97?414). Rockville, MD; 2001 May. From FDA web site ()

4. Broyer M, Gagnadoux MF, Guest G et al. Triple therapy including cyclosporine A versus conventional regimen-a randomized prospective study in pediatric kidney transplantation. Transplant Proc. 1987; 19: 3582-5. [PubMed 3313862]

5. Brennan DC, Flavin K, Lowell JA et al. A randomized, double-blinded comparison of Thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal transplant recipients. Transplantation. 1999; 67:1011-8. [IDIS 427773] [PubMed 10221486]

6. Regan JF, Campbell K, Van Smith L et al. Sensitization following Thymoglobulin and Atgam rejection therapy as determined with a rapid enzyme-linked immunosorbent assay: US Thymoglobulin Multi-Center Study Group. Transpl Immunol. 1999; 7:115-21. [PubMed 10544442]

7. Di Bona E, Rodeghiero F, Bruno B et al for the Gruppo Italiano Trapianto di Midollo Osseo (GITMO). Rabbit antithymocyte globulin (r-ATG) plus cyclosporine and granulocyte colony stimulating factor is an effective treatment for aplastic anaemia patients unresponsive to a first course of intensive immunosuppressive therapy. Br J Haematol. 1999; 107:330-4. [PubMed 10583220]

8. Ormrod D, Jarvis B. Antithymocyte globulin (rabbit): a review of the use of Thymoglobulin in the prevention and treatment of acute renal allograft rejection. Biodrugs. 2000; 14:255-73.

9. Sangstat. Fremont, CA: Personal communication.

10. Brophy PD, Thomas SE, McBryde KD et al. Comparison of polyclonal induction agents in pediatric renal transplantation. Pediatr Transplant. 2001; 5:174-8. [PubMed 11422819]

a. www.ahfsdruginformation.com. Antithymocyte globulin (rabbit). Accessed February 2008.

b. Genzyme Corporation. Thymoglobulin (anti-thymocyte globulin [rabbit]) prescribing information. Cambridge, MA; 2007 Sep.

c. Hoffmann-La Roche Inc. Zenapax (daclizumab) sterile concentrate for injection prescribing information. Nutley, NJ; 2005 Sep.

d. Hardinger KL, Schnitzler MA, Miller B et. al. Five-year follow up of Thymoglobulin versus ATGAM induction in adult renal transplantation. Transplantation. 2004; 78:136-41. [PubMed 15257052]

e. Schnitzler MA, Woodward RS, Lowell JA et. al. Economics of the antithymocyte globulins Thymoglobulin and Atgam in the treatment of acute renal transplant rejection. Pharmacoeconomics. 2000; 17:287-93. [PubMed 10947303]

f. Novartis Pharmaceuticals Corporation. Simulect (basiliximab) for injection prescribing information. East Hanover, NJ; 2005 Sep.

g. Hardinger KL. Rabbit antithymocyte globulin induction therapy in adult renal transplantation. Pharmacotherapy. 2006; 26:1771-83. [PubMed 17125438]

h. Marvin MR, Droogan C, Sawinski D et al. Administration of rabbit antithymocyte globulin (thymoglobulin) in ambulatory renal-transplant patients. Transplantation. 2003; 76:488-9.

i. Mathis AS, Rao V. Deep vein thrombosis during rabbit antithymocyte globulin administration. Transplant Proc. 2004; 36:3250-1. [PubMed 15686740]

j. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97?414). Rockville, MD; 2007 Oct. From FDA web site ()

k. Stadler M, Germing U, Kliche KO et al. A prospective, randomised, phase II study of horse antithymocyte globulin vs. rabbit antithymocyte globulin as immune-modulating therapy in patients with low-risk myelodysplastic syndromes. Leukemia. 2004; 18:460-5. [PubMed 14712285]

l. Scheinberg P, Nunez O, Young NS. Retreatment with rabbit antithymocyte globulin and ciclosporin for patients with relapsed or refractory severe aplastic anaemia. Br J Haematol. 2006; 133:622-7. [PubMed 16704436]

m. Khositseth S, Matas A, Cook ME et al. Thymoglobulin versus ATGAM induction therapy in pediatric kidney transplant recipients: a single-center report. Transplantation. 2005; 79:958-63. [PubMed 15849550]

n. Schwartz JJ, Ishitani MB, Weckwerth J et al. Decreased incidence of acute rejection in adolescent kidney transplant recipients using antithymocyte induction and triple immunosuppression. Transplantation. 2007; 84:715-21. [PubMed 17893604]

o. Buchler M, Hurault de Ligny B, Madec C et al. Induction therapy by antithymocyte globulin (rabbit) in renal transplantation: a 1-yr follow-up of safety and efficacy. Clin Transplantation. 2003; 17:539-45.

p. Kamel MH, Mohan P, Little DM et al. Rabbit antithymocyte globulin as induction immunotherapy for pediatric deceased donor kidney transplantation. J Urol. 2005; 174:703-7. [PubMed 16006954]

q. Ault BH, Honaker MR, Gaber AO et al. Short term outcomes of thymoglobulin induction in pedatric renal transplant recipients. Pediatr Nephrol. 2002; 17:815-8. [PubMed 12376809]

r. Hardinger KL, Schnitzler MA, Miller B et. al. Five-year follow up of Thymoglobulin versus ATGAM induction in adult renal transplantation. Transplantation. 2004; 78:136-41. [PubMed 15257052]

s. Agha IA, Rueda J, Alvarez A et. al. Short course induction immunosuppression with Thymoglobulin for renal transplant recipients. Transplant. 2002; 73:473-5.

t. Shah A, Agarwal A, Mangus R et al. Induction immunosuppression with rabbit antithymocyte globulin in pediatric liver transplantation. Liver Transpl. 2006; 12:1210-4. [PubMed 16868953]

u. Brennan DC, Daller JA, Lake KD et al. Rabbit antithymocyte globulin versus basiliximab in renal transplantation. N Engl J Med. 2006; 355:1967-7. [PubMed 17093248]

v. Bajjoka I, Hsaiky L, Brown K et al. Preserving renal function in liver transplant recipients with rabbit anti-thymocyte globulin and delayed initiation of calcineurin inhibitors. Liver Transpl. 2008; 14:66-72. [PubMed 18161842]

w. Peddi VR, Bryant M, Roy-Chaudhury P et al. Safety, efficacy, and cost analysis of thymoglobulin induction therapy with internittent dosing based on CD3+ lymphocyte counts in kidney and kidney-pancreas transplant recipients. Transplantation. 2002; 73:1514-8. [PubMed 12023634]

x. Guttmann RD, Flemming C. Sequential biological immunosuppression: induction therapy with rabbit antithymocyte globulin. Clin Transplant. 1997; 11:185-92. [PubMed 9193840]

y. Bieber CP, Griepp RB, Oyer PE et al. Use of rabbit antithymocyte globulin in cardiac transplantation: relationship of clearance rates to clinical outcome. Transplantation. 1976; 22:478-88. [PubMed 793103]

z. Genzyme Corporation. Cambridge, MA: Personal communication.

HID. Trissel LA. Handbook on injectable drugs. 14th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:167-8.

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• Thymoglobulin Prescribing Information (FDA)


• Thymoglobulin rabbit Concise Consumer Information (Cerner Multum)


• Thymoglobulin Advanced Consumer (Micromedex) - Includes Dosage Information


• Thymoglobulin MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Thymoglobulin with other medications

• Renal Transplant

Adenosine

Pronunciation: a-DEN-oh-seen
Generic Name: Adenosine
Brand Name: Adenocard

Adenosine is used for:

Treating supraventricular tachycardia, a certain type of irregular heartbeat. It may also be used for other conditions as determined by your doctor.

Adenosine is an antiarrhythmic. It works by slowing the electrical conduction in the heart, slowing heart rate, or normalizing heart rhythm.

Do NOT use Adenosine if:

• you are allergic to any ingredient in Adenosine


• you have second- or third-degree heart block and do not have an artificial pacemaker


• you have sinus node disease (eg, sick sinus syndrome) and do not have an artificial pacemaker


• you have certain breathing problems (eg, asthma)

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

Before using Adenosine:

Some medical conditions may interact with Adenosine. 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 lung or breathing problems (eg, emphysema, bronchitis)

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

• Digoxin or verapamil because the risk of severe and sometimes fatal irregular heartbeat may be increased


• Carbamazepine or dipyridamole because they may increase the risk of Adenosine's side effects


• Methylxanthines (eg, caffeine, theophylline) because they may decrease Adenosine's effectiveness

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

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

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


• Do not use Adenosine if it contains particles, is cloudy or discolored, or if the vial is cracked or damaged.


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


• If you miss a dose of Adenosine, contact your doctor immediately.

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

Important safety information:

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


• Avoid large amounts of food or drink that have caffeine (eg, coffee, tea, cocoa, cola, chocolate).


• Contact your doctor immediately if you experience a return of an unusually fast heartbeat or chest pain.


• Lab tests, including electrocardiogram (ECG), may be performed while you use Adenosine. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


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


• PREGNANCY and BREAST-FEEDING: If you plan on becoming pregnant, contact your doctor. You will need to discuss the benefits and risks of using Adenosine while you are pregnant. If you are or will be breast-feeding while you use Adenosine, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Adenosine:

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:

Chest pressure; dizziness; flushing of the face; headache; lightheadedness; nausea; tingling in the arms.

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); chest pain; fast, slow, or irregular heartbeat; seizure; shortness of breath or wheezing.

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: Adenosine side effects (in more detail)

If OVERDOSE is suspected:

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

Proper storage of Adenosine:

Adenosine is usually handled and stored by a health care provider. If you are using Adenosine at home, store Adenosine as directed by your pharmacist or health care provider. Keep Adenosine out of the reach of children and away from pets.

General information:

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


• Adenosine 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 Adenosine. 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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• Adenosine Side Effects (in more detail)
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• Adenosine Prescribing Information (FDA)


• Adenosine Professional Patient Advice (Wolters Kluwer)


• Adenosine Monograph (AHFS DI)


• Adenocard Prescribing Information (FDA)


• Adenoscan


• Adenoscan Prescribing Information (FDA)

Compare Adenosine with other medications

• Supraventricular Tachycardia
• Wolff-Parkinson-White Syndrome

Chlorex-A 12

Generic Name: chlorpheniramine, pyrilamine, and phenylephrine (KLOR fe NEER a meen, pir IL a meen, FEN il EFF rin)

Brand Names: AllerTan, Chlorex-A 12, Conal, MyHist-PD, Nalex A 12, Phena-Plus, Phena-S, Poly Hist PD, R-Tannate, Ru-Hist Forte, Tri-Hist Pediatric, Triotann-S Pediatric, Triple Tannate Pediatric, Triplex AD

What is chlorpheniramine, phenylephrine, and pyrilamine?

Chlorpheniramine and pyrilamine are antihistamines that reduce the effects of natural chemical histamine in the body. Histamine can produce symptoms of sneezing, itching, watery eyes, and runny nose.

Phenylephrine is a decongestant that shrinks blood vessels in the nasal passages. Dilated blood vessels can cause nasal congestion (stuffy nose).

The combination of chlorpheniramine, phenylephrine, and pyrilamine is used to treat runny or stuffy nose, sneezing, itching, watery eyes, and sinus congestion caused by allergies, the common cold, or the flu.

Chlorpheniramine, phenylephrine, and pyrilamine may also be used for purposes not listed in this medication guide.

What is the most important information I should know about chlorpheniramine, phenylephrine, and pyrilamine?

Do not use this medicine if you have used an MAO inhibitor such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam, Zelapar), or tranylcypromine (Parnate) in the last 14 days. A dangerous drug interaction could occur, leading to serious side effects. Do not give this medication to a child younger than 4 years old. Always ask a doctor before giving a cough or cold medicine to a child. Death can occur from the misuse of cough and cold medicines in very young children. Ask a doctor or pharmacist before using any other cold, cough, allergy, or pain medicine. Antihistamines and decongestants are contained in many combination medicines. Taking certain products together can cause you to get too much of a certain drug. Check the label to see if a medicine contains an antihistamine or decongestant. This medication may cause blurred vision and may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert and able to see clearly. Drinking alcohol can increase drowsiness caused by chlorpheniramine, phenylephrine, and pyrilamine. Before using chlorpheniramine, phenylephrine, and pyrilamine, tell your doctor if you regularly use other medicines that make you sleepy (such as sedatives, narcotic pain medicine, sleeping pills, muscle relaxers, and medicine for seizures, depression, or anxiety). They can add to sleepiness caused by chlorpheniramine and pyrilamine.

What should I discuss with my healthcare provider before taking chlorpheniramine, phenylephrine, and pyrilamine?

Do not use this medicine if you have used an MAO inhibitor such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam, Zelapar), or tranylcypromine (Parnate) in the last 14 days. A dangerous drug interaction could occur, leading to serious side effects. You should not use this medication if you are allergic to chlorpheniramine, phenylephrine, pyrilamine, or to other decongestants, or if you have:

• 
  

  severe or uncontrolled high blood pressure;

  
  


• 
  

  severe coronary artery disease;

  
  


• 
  

  diabetes;

  
  


• 
  

  overactive thyroid; or

  
  


• 
  

  asthma, pneumonia, or other breathing problems.

  
  

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

• liver disease;


• kidney disease;


• 
  

  heart disease or high blood pressure;

  
  


• 
  

  glaucoma;

  
  


• 
  

  enlarged prostate;

  
  


• 
  

  bladder obstruction or other urination problems; or

  
  


• 
  

  a blockage in your digestive tract (stomach or intestines).

  
  

FDA pregnancy category C. It is not known whether chlorpheniramine, phenylephrine, and pyrilamine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. Chlorpheniramine, phenylephrine, and pyrilamine can pass into breast milk and may harm a nursing baby. You should not breast-feed while you are using chlorpheniramine, phenylephrine, and pyrilamine.

How should I take chlorpheniramine, phenylephrine, and pyrilamine?

Use exactly as directed on the label, or as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. Cough or cold medicine is usually taken only for a short time until your symptoms clear up.

Do not give this medication to a child younger than 4 years old. Always ask a doctor before giving a cough or cold medicine to a child. Death can occur from the misuse of cough and cold medicines in very young children. Do not crush, chew, or break an extended-release tablet. Swallow the pill whole. Breaking or crushing the pill may cause too much of the drug to be released at one time.

Measure liquid medicine with a special dose-measuring spoon or cup, not a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.

Shake the oral suspension (liquid) well just before you measure a dose. Store at room temperature away from moisture, heat, and light.

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

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

Overdose symptoms may include dry mouth, dilated pupils, nausea, vomiting, and warmth, redness, or tingly feeling under your skin.

What should I avoid while taking chlorpheniramine, phenylephrine, and pyrilamine?

Ask a doctor or pharmacist before using any other cold, cough, allergy, or pain medicine. Antihistamines and decongestants are contained in many combination medicines. Taking certain products together can cause you to get too much of a certain drug. Check the label to see if a medicine contains an antihistamine or decongestant. This medication may cause blurred vision and may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert and able to see clearly. Drinking alcohol can increase certain side effects of this medication.

Avoid taking this medication if you also take diet pills, caffeine pills, or other stimulants (such as ADHD medications). Taking a stimulant together with a decongestant can increase your risk of unpleasant side effects.

Chlorpheniramine, phenylephrine, and pyrilamine side effects

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

• 
  

  severe dizziness, anxiety, restless feeling, or nervousness;

  
  


• 
  

  fast, pounding, or uneven heartbeats;

  
  


• 
  

  confusion, hallucinations, unusual thoughts or behavior;

  
  


• 
  

  feeling like you might pass out;

  
  


• 
  

  urinating less than usual or not at all;

  
  


• 
  

  easy bruising or bleeding, unusual weakness, fever, chills, body aches, flu symptoms;

  
  


• 
  

  increased blood pressure (severe headache, blurred vision, trouble concentrating, chest pain, numbness, seizure); or

  
  


• 
  

  nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

  
  

Less serious side effects may include:

• 
  

  upset stomach, constipation;

  
  


• 
  

  dry mouth;

  
  


• 
  

  blurred vision;

  
  


• 
  

  dizziness, drowsiness;

  
  


• 
  

  problems with memory;

  
  


• 
  

  sleep problems (insomnia); or

  
  


• 
  

  feeling restless or excited (especially in children).

  
  

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

What other drugs will affect chlorpheniramine, phenylephrine, and pyrilamine?

Cold or allergy medicine, narcotic pain medicine, sleeping pills, muscle relaxers, and medicine for seizures, depression or anxiety can add to sleepiness caused by chlorpheniramine or pyrilamine. Tell your doctor if you regularly use any of these medicines, or any other cough and cold medications.

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

• 
  

  digoxin (Lanoxin);

  
  


• 
  

  blood pressure medication;

  
  


• 
  

  an antidepressant;

  
  


• 
  

  a barbiturate such as phenobarbital (Solfoton) and others;

  
  


• 
  

  a diuretic (water pill);

  
  


• 
  

  medication to treat irritable bowel syndrome;

  
  


• 
  

  bladder or urinary medications such as oxybutynin (Ditropan, Oxytrol) or tolterodine (Detrol);

  
  


• 
  

  aspirin or salicylates (such as Disalcid, Doan's Pills, Dolobid, Salflex, Tricosal, and others); or

  
  


• 
  

  a beta-blocker such as atenolol (Tenormin), carteolol (Cartrol), metoprolol (Lopressor, Toprol), nadolol (Corgard), propranolol (Inderal), sotalol (Betapace), timolol (Blocadren), and others.

  
  

This list is not complete and there may be other drugs that can interact with chlorpheniramine, phenylephrine, and pyrilamine. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.

More Chlorex-A 12 resources

• Chlorex-A 12 Side Effects (in more detail)
• Chlorex-A 12 Use in Pregnancy & Breastfeeding
• Chlorex-A 12 Drug Interactions
• Chlorex-A 12 Support Group
• 0 Reviews for Chlorex-A2 - Add your own review/rating

• Chlorex-A 12 Suspension MedFacts Consumer Leaflet (Wolters Kluwer)


• Chlorpheniramine/Phenylephrine/Pyrilamine MedFacts Consumer Leaflet (Wolters Kluwer)


• Phena-S Liquid MedFacts Consumer Leaflet (Wolters Kluwer)


• Poly Hist PD Prescribing Information (FDA)


• Ru-Hist Forte Controlled-Release Tablets MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Chlorex-A 12 with other medications

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Where can I get more information?

• Your pharmacist can provide more information about chlorpheniramine, phenylephrine, and pyrilamine.

See also: Chlorex-A2 side effects (in more detail)

Naphcon

naphazoline hydrochloride

Dosage Form: Ophthalmic Solution

DESCRIPTION

Naphcon® FORTE (Naphazoline Hydrochloride Ophthalmic Solution USP), 0.1% is a sterile preparation. Naphazoline HCl, an ocular vasoconstrictor, is an imidazoline derivative sympathomimetic amine. It occurs as a white, odorless crystalline powder having a bitter taste and is freely soluble in water and in alcohol. The active ingredient is represented by the structural formula:

C14H14N2HCl

MW=246.74

Chemical name:

2-(1-naphthylmethyl)-2-imidazoline monohydrochloride

Each mL contains: Active: Naphazoline Hydrochloride 0.1%. Preservative: Benzalkonium Chloride 0.01%. Inactives: Boric Acid, Sodium Chloride, Potassium Chloride, Edetate Disodium, Sodium Carbonate and/or Hydrochloric Acid (to adjust pH), Purified Water. DM-00

The solution has a pH of 5.5 to 7.0.

CLINICAL PHARMACOLOGY

Naphazoline constricts the vascular system of the conjunctiva. It is presumed that this effect is due to direct stimulation action of the drug upon the alpha adrenergic receptors in the arterioles of the conjunctiva resulting in decreased conjunctival congestion. Naphazoline belongs to the imidazoline class of sympathomimetics.

INDICATIONS AND USAGE

Naphcon® FORTE (Naphazoline Hydrochloride Ophthalmic Solution USP), 0.1% is indicated for use as a topical ocular vasoconstrictor.

CONTRAINDICATIONS

Contraindicated in the presence of an anatomically narrow angle or in narrow angle glaucoma or in persons who have shown hypersensitivity to any component of this preparation.

WARNINGS

NOT FOR INJECTION – FOR OPHTHALMIC USE ONLY. Patients under therapy with MAO inhibitors may experience a severe hypertensive crisis if given a sympathomimetic drug. Use in children, especially infants, may result in CNS depression leading to coma and marked reduction in body temperature.

Remove contact lenses before using.

PRECAUTIONS

General

For topical ophthalmic use only. Use with caution in the presence of hypertension, cardiovascular abnormalities, hyperglycemia (diabetes), hyperthyroidism, infection or injury.

Information for Patients

Patients should be advised to discontinue the drug and consult a physician if relief is not obtained within 48 hours of therapy, if irritation, blurring or redness persists or increases, or if symptoms of systemic absorption occur, i.e., dizziness, headache, nausea, decrease in body temperature, or drowsiness.

To prevent contaminating the dropper tip and solution, do not touch the eyelids or the surrounding area with the dropper tip of the bottle. If solution changes color or becomes cloudy, do not use.

Drug Interactions

Concurrent use of maprotiline or tricyclic antidepressants and naphazoline may potentiate the pressor effect of naphazoline. Patients under therapy with MAO inhibitors may experience a severe hypertensive crisis if given a sympathomimetic drug. (See WARNINGS.)

Pregnancy Category C

Animal reproduction studies have not been conducted with naphazoline. It is also not known whether naphazoline can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Naphazoline should be given to a pregnant woman only if clearly needed.

Nursing Mothers

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

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. See “WARNINGS” and “CONTRAINDICATIONS.”

ADVERSE REACTIONS

Ocular: Mydriasis, increased redness, irritation, discomfort, blurring, punctuate keratitis, lacrimation, increased intraocular pressure.

Systemic: Dizziness, headache, nausea, sweating, nervousness, drowsiness, weakness, hypertension, cardiac irregularities, and hyperglycemia.

DOSAGE AND ADMINISTRATION

Instill one or two drops in the conjunctival sac(s) every three to four hours as needed.

HOW SUPPLIED

Naphcon® FORTE (Naphazoline Hydrochloride Ophthalmic Solution USP), 0.1% is available in 15 mL in DROP-TAINER® dispenser.

NDC 0998-0079-15.

Storage: Store at 8° - 27°C (46° - 80°F).

Caution: Federal ( USA) law prohibits dispensing without prescription.

ALCON ( Puerto Rico) INC.

Humacao, Puerto Rico 00791 USA

Printed in USA

September 1996

236185

Naphcon  naphazoline hydrochloride  solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0998-0079 Route of Administration OPHTHALMIC DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength naphazoline hydrochloride (naphazoline) Active 1 MILLIGRAM  In 1 MILLILITER benzalkonium chloride Inactive   boric acid Inactive   sodium chloride Inactive   potassium chloride Inactive   edetate disodium Inactive   sodium carbonate and/or hydrochloric acid Inactive   water Inactive

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0998-0079-15 15 mL (MILLILITER) In 1 BOTTLE, PLASTIC None

Revised: 09/2006Alcon

More Naphcon resources

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

• Naphcon Concise Consumer Information (Cerner Multum)


• Naphcon Advanced Consumer (Micromedex) - Includes Dosage Information


• Naphcon Drops MedFacts Consumer Leaflet (Wolters Kluwer)


• Clear Eyes Drops MedFacts Consumer Leaflet (Wolters Kluwer)

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Emselex 7.5 mg and 15 mg prolonged-release tablets

1. Name Of The Medicinal Product

Emselex® 7.5 mg prolonged-release tablets

Emselex® 15 mg prolonged-release tablets

2. Qualitative And Quantitative Composition

Emselex 7.5 mg prolonged-release tablets: Each tablet contains 7.5 mg of darifenacin (as hydrobromide)

Emselex 15 mg prolonged-release tablets: Each tablet contains 15 mg of darifenacin (as hydrobromide)

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Prolonged-release tablets

Emselex 7.5 mg prolonged-release tablets: White round, convex tablet, debossed with “DF” on one side and “7.5” on the reverse.

Emselex 15 mg prolonged-release tablets: Light peach round, convex tablet debossed with “DF” on one side and “15” on the reverse.

4. Clinical Particulars

4.1 Therapeutic Indications

Symptomatic treatment of urge incontinence and/or increased urinary frequency and urgency as may occur in adult patients with overactive bladder syndrome.

4.2 Posology And Method Of Administration

Adults

The recommended starting dose is 7.5 mg daily. After 2 weeks of starting therapy, patients should be reassessed. For those patients requiring greater symptom relief, the dose may be increased to 15 mg daily, based on individual response.

Emselex is for oral use. The tablets should be taken once daily with liquid. They can be taken with or without food, and must be swallowed whole and not chewed, divided or crushed.

Elderly patients (

The recommended starting dose for the elderly is 7.5 mg daily. After 2 weeks of starting therapy, patients should be reassessed for efficacy and safety. For those patients who have an acceptable tolerability profile but require greater symptom relief, the dose may be increased to 15 mg daily, based on individual response (see section 5.2).

Children

Emselex is not recommended for use in children below 18 years of age due to a lack of data on safety and efficacy.

Use in renal impairment

No dose adjustment is required in patients with impaired renal function. However, caution should be exercised when treating this population (see section 5.2).

Use in hepatic impairment

No dose adjustment is required in patients with mild hepatic impairment (Child Pugh A). However, there is a risk of increased exposure in this population (see section 5.2).

Patients with moderate hepatic impairment (Child Pugh B) should only be treated if the benefit outweighs the risk, and the dose should be restricted to 7.5 mg daily (see section 5.2). Emselex is contraindicated in patients with severe hepatic impairment (Child Pugh C) (see section 4.3).

Patients receiving concomitant treatment with substances that are potent inhibitors of CYP2D6 or moderate inhibitors of CYP3A4

In patients receiving substances that are potent CYP2D6 inhibitors, such as paroxetine, terbinafine, quinidine and cimetidine, treatment should start with the 7.5 mg dose. The dose may be titrated to 15 mg daily to obtain an improved clinical response provided the dose is well tolerated. However, caution should be exercised.

In patients receiving substances that are moderate CYP3A4 inhibitors, such as fluconazole, grapefruit juice and erythromycin, the recommended starting dose is 7.5 mg daily. The dose may be titrated to 15 mg daily to obtain an improved clinical response provided the dose is well tolerated. However, caution should be exercised.

4.3 Contraindications

Emselex is contraindicated in patients with:

- Hypersensitivity to the active substance or to any of the excipients.

- Urinary retention.

- Gastric retention.

- Uncontrolled narrow-angle glaucoma.

- Myasthenia gravis.

- Severe hepatic impairment (Child Pugh C).

- Severe ulcerative colitis.

- Toxic megacolon.

- Concomitant treatment with potent CYP3A4 inhibitors (see section 4.5).

4.4 Special Warnings And Precautions For Use

Emselex should be administered with caution to patients with autonomic neuropathy, hiatus hernia, clinically significant bladder outflow obstruction, risk for urinary retention, severe constipation or gastrointestinal obstructive disorders, such as pyloric stenosis.

Emselex should be used with caution in patients being treated for narrow-angle glaucoma (see section 4.3).

Other causes of frequent urination (heart failure or renal disease) should be assessed before treatment with Emselex. If urinary tract infection is present, an appropriate antibacterial therapy should be started.

Emselex should be used with caution in patients with risk of decreased gastrointestinal motility, gastro-oesophagal reflux and/or who are concurrently taking medicinal products (such as oral bisphosphonates) that can cause or exacerbate oesophagitis.

Safety and efficacy have not yet been established in patients with a neurogenic cause for detrusor overactivity.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Effects of other medicinal products on darifenacin

Darifenacin metabolism is primarily mediated by the cytochrome P450 enzymes CYP2D6 and CYP3A4. Therefore, inhibitors of these enzymes may increase darifenacin exposure.

CYP2D6 inhibitors

In patients receiving substances that are potent CYP2D6 inhibitors (e.g. paroxetine, terbinafine, cimetidine and quinidine) the recommended starting dose should be 7.5 mg daily. The dose may be titrated to 15 mg daily to obtain an improved clinical response provided the dose is well tolerated. Concomitant treatment with potent CYP2D6 inhibitors results in an increase in exposure (e.g. of 33% with 20 mg paroxetine at the 30 mg dose of darifenacin).

CYP3A4 inhibitors

Darifenacin should not be used together with potent CYP3A4 inhibitors (see section 4.3) such as protease inhibitors (e.g. ritonavir), ketoconazole and itraconazole. Potent P-glycoprotein inhibitors such as ciclosporin and verapamil should also be avoided. Co-administration of darifenacin 7.5 mg with the potent CYP3A4 inhibitor ketoconazole 400 mg resulted in a 5-fold increase in steady-state darifenacin AUC. In subjects who are poor metabolisers, darifenacin exposure increased approximately 10-fold. Due to a greater contribution of CYP3A4 after higher darifenacin doses, the magnitude of the effect is expected to be even more pronounced when combining ketoconazole with darifenacin 15 mg.

When co-administered with moderate CYP3A4 inhibitors such as erythromycin, clarithromycin, telithromycin, fluconazole and grapefruit juice, the recommended starting dose of darifenacin should be 7.5 mg daily. The dose may be titrated to 15 mg daily to obtain an improved clinical response provided the dose is well tolerated. Darifenacin AUC₂₄ and C_max from 30 mg once daily dosing in subjects who are extensive metabolisers were 95% and 128% higher, when erythromycin (moderate CYP3A4 inhibitor) was co-administered with darifenacin than when darifenacin was taken alone.

Enzyme inducers

Substances that are inducers of CYP3A4, such as rifampicin, carbamazepine, barbiturates and St John´s wort (Hypericum perforatum) are likely to decrease the plasma concentrations of darifenacin.

Effects of darifenacin on other medicinal products

CYP2D6 substrates

Darifenacin is a moderate inhibitor of the enzyme CYP2D6. Caution should be exercised when darifenacin is used concomitantly with medicinal products that are predominantly metabolised by CYP2D6 and which have a narrow therapeutic window, such as flecainide, thioridazine, or tricyclic antidepressants such as imipramine. The effects of darifenacin on the metabolism of CYP2D6 substrates are mainly clinically relevant for CYP2D6 substrates which are individually dose titrated.

CYP3A4 substrates

Darifenacin treatment resulted in a modest increase in the exposure of the CYP3A4 substrate midazolam. However the data available do not indicate that darifenacin changes either midazolam clearance or bioavailability. It can therefore be concluded that darifenacin administration does not alter the pharmacokinetics of CYP3A4 substrates in vivo. The interaction with midazolam lacks clinical relevance, and therefore no dose adjustment is needed for CYP3A4 substrates.

Warfarin

Standard therapeutic prothrombin time monitoring for warfarin should be continued. The effect of warfarin on prothrombin time was not altered when co-administered with darifenacin.

Digoxin

Therapeutic drug monitoring for digoxin should be performed when initiating and ending darifenacin treatment as well as changing the darifenacin dose. Darifenacin 30 mg once daily (two times greater than the recommended daily dose) co-administered with digoxin at steady state resulted in a small increase in digoxin exposure (AUC: 16% and C_max: 20%). The increase in digoxin exposure could be caused by competition between darifenacin and digoxin for P-glycoprotein. Other transporter-related interactions cannot be excluded.

Antimuscarinic agents

As with any other antimuscarinic agents, concomitant use of medicinal products that possess antimuscarinic properties, such as oxybutynin, tolterodine and flavoxate, may result in more pronounced therapeutic and side effects. The potentiation of anticholinergic effects with anti-parkinson agents and tricyclic antidepressants may also occur if antimuscarinic agents are used concurrently with such medicinal products. However, no studies involving the interaction with anti-parkinson agents and tricyclic antidepressants have been performed.

4.6 Pregnancy And Lactation

Fertility

There are no human fertility data for darifenacin. Darifenacin had no effect on male or female fertility in rats or any effect in the reproductive organs of either sex in rats and dogs (for details, see section 5.3). Women of child bearing potential should be made aware of the lack of fertility data, and Emselex should only be given after consideration of individual risks and benefits.

Pregnancy

There are limited amount of data from the use of darifenacin in pregnant women. Studies in animals have shown toxicity to parturition (for details, see section 5.3). Emselex is not recommended during pregnancy.

Lactation

Darifenacin is excreted in the milk of rats. It is not known whether darifenacin is excreted in human milk. A risk to the nursing child cannot be excluded. A decision whether to avoid breast-feeding or to abstain from Emselex therapy during lactation should be based on a benefit and risk comparison.

4.7 Effects On Ability To Drive And Use Machines

No studies of the effects of Emselex on the ability to drive and use machines have been performed. As with other antimuscarinic agents, Emselex may produce effects such as dizziness, blurred vision, insomnia and somnolence. Patients experiencing these side effects should not drive or use machines. For Emselex, these side effects have been reported to be uncommon.

4.8 Undesirable Effects

Consistent with the pharmacological profile, the most commonly reported adverse reactions were dry mouth (20.2% and 35% for the 7.5 mg and 15 mg dose, respectively, 18.7% after flexible dose titration, and 8% - 9% for placebo) and constipation (14.8% and 21% for the 7.5 mg and 15 mg dose, respectively, 20.9% after flexible dose titration, and 5.4% - 7.9% for placebo). Anticholinergic effects, in general, are dose-dependent.

However, the patient discontinuation rates due to these adverse reactions were low (dry mouth: 0% - 0.9% and constipation: 0.6% - 2.2% for darifenacin, depending on the dose; and 0% and 0.3% for placebo, for dry mouth and constipation, respectively).

Table 1: Adverse reactions with Emselex 7.5 mg and 15 mg prolonged-release tablets

Frequency estimate: very common (

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Infections and infestations
Uncommon	Urinary tract infection
Psychiatric disorders
Uncommon	Insomnia, thinking abnormal
Nervous system disorders
Common	Headache
Uncommon	Dizziness, dysgeusia, somnolence
Eye disorders
Common	Dry eye
Uncommon	Visual disturbance, including vision blurred
Vascular disorders
Uncommon	Hypertension
Respiratory, thoracic and mediastinal disorders
Uncommon	Dyspnoea, cough, rhinitis
Gastrointestinal disorders
Very common	Constipation, dry mouth
Common	Abdominal pain, nausea, dyspepsia
Uncommon	Flatulence, diarrhoea, mouth ulceration
Skin and subcutaneous tissue disorders
Uncommon	Rash, dry skin, pruritus, hyperhidrosis
Not known	Angioedema
Renal and urinary disorders
Uncommon	Urinary retention, urinary tract disorder, bladder pain
Reproductive system and breast disorders
Uncommon	Erectile dysfunction, vaginitis
General disorders and administration site conditions
Uncommon	Oedema peripheral, asthenia, face oedema, oedema
Investigations
Uncommon	Aspartate aminotransferase increased, alanine aminotransferase increased
Injury, poisoning, and procedural complications
Uncommon	Injury

In the pivotal clinical trials with doses of Emselex 7.5 mg and 15 mg, adverse reactions were reported as presented in the table above. Most of the adverse reactions were of mild or moderate intensity and did not result in discontinuation in the majority of the patients.

Treatment with Emselex may possibly mask symptoms associated with gallbladder disease. However, there was no association between the occurrence of adverse events related to the biliary system in darifenacin-treated patients and increasing age.

The incidence of adverse reactions with the doses of Emselex 7.5 mg and 15 mg decreased during the treatment period up to 6 months. A similar trend is also seen for the discontinuation rates.

Post-marketing experience

The following events have been reported in association with darifenacin use in worldwide post-marketing experience: generalised hypersensitivity reactions including angioedema mood/mood alterations, hallucination.. Because these spontaneously reported events are from the worldwide post-marketing experience, the frequency of events cannot be estimated from the available data.

4.9 Overdose

Emselex has been administered in clinical trials at doses up to 75 mg (five times maximum therapeutic dose). The most common adverse reactions seen were dry mouth, constipation, headache, dyspepsia and nasal dryness. However, overdose with darifenacin can potentially lead to severe anticholinergic effects and should be treated accordingly. Therapy should be aimed at reversing the anticholinergic symptoms under careful medical supervision. The use of agents such as physostigmine can assist in reversing such symptoms.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Urinary antispasmodic, ATC code: G04BD10.

Darifenacin is a selective muscarinic M₃ receptor antagonist (M₃ SRA) in vitro. The M₃ receptor is the major subtype that controls urinary bladder muscle contraction. It is not known whether this selectivity for the M₃ receptor translates into any clinical advantage when treating symptoms of overactive bladder syndrome.

Cystometric studies performed with darifenacin in patients with involuntary bladder contractions showed increased bladder capacity, increased volume threshold for unstable contractions and diminished frequency of unstable detrusor contractions.

Treatment with Emselex administered at dosages of 7.5 mg and 15 mg daily has been investigated in four double-blind, Phase III, randomised, controlled clinical studies in male and female patients with symptoms of overactive bladder. As seen in Table 2 below, a pooled analysis of 3 of the studies for the treatment with both Emselex 7.5 mg and 15 mg provided a statistically significant improvement in the primary endpoint, reduction in incontinence episodes, versus placebo.

Table 2: Pooled analysis of data from three Phase III clinical studies assessing fixed doses of 7.5 mg and 15 mg Emselex

Dose	N	Incontinence episodes per week	95% C- I	P value2
Baseline (median)	Week 12 (median)	Change from baseline (median)	Differences from placebo1 (median)
Emselex 7.5 mg once daily	335	16.0	4.9	-8.8 (-68%)	-2.0	(-3.6, -0.7)	0.004
Placebo	271	16.6	7.9	-7.0 (-54%)	--	--	--
Emselex 15 mg once daily	330	16.9	4.1	-10.6 (-77%)	-3.2	(-4.5, -2.0)	<0.001
Placebo	384	16.6	6.4	-7.5 (-58%)	--	--	--

¹ Hodges Lehmann estimate: median difference from placebo in change from baseline

² Stratified Wilcoxon test for difference from placebo.

Emselex 7.5 mg and 15 mg doses significantly reduced both the severity and number of urinary urgency episodes and the number of micturitions, while significantly increasing the mean volume voided from baseline.

Emselex 7.5 mg and 15 mg were associated with statistically significant improvements over placebo in some aspects of quality of life as measured by the Kings Health Questionnaire including incontinence impact, role limitations, social limitations and severity measures.

For both doses of 7.5 mg and 15 mg, the percentage median reduction from baseline in the number of incontinence episodes per week was similar between males and females. The observed differences from placebo for males in terms of percentage and absolute reductions in incontinence episodes was lower than for females.

The effect of treatment with 15 mg and 75 mg of darifenacin on QT/QTc interval was evaluated in a study in 179 healthy adults (44% male: 56% females) aged 18 to 65 for 6 days (to steady state). Therapeutic and supra-therapeutic doses of darifenacin resulted in no increase in QT/QTc interval prolongation from baseline compared to placebo at maximum darifenacin exposure.

5.2 Pharmacokinetic Properties

Darifenacin is metabolised by CYP3A4 and CYP2D6. Due to genetic differences, about 7% of Caucasians lack the CYP2D6 enzyme and are said to be poor metabolisers. A few percent of the population have increased CYP2D6 enzyme levels (ultrafast metabolisers). The information below applies to subjects who have normal CYP2D6 activity (extensive metabolisers) unless otherwise stated.

Absorption

Due to extensive first-pass metabolism darifenacin has a bioavailability of approximately 15% and 19% after 7.5 mg and 15 mg daily doses at steady state. Maximum plasma levels are reached approximately 7 hours after administration of the prolonged-release tablets and steady-state plasma levels are achieved by the sixth day of administration. At steady state, peak-to-trough fluctuations in darifenacin concentrations are small (PTF: 0.87 for 7.5 mg and 0.76 for 15 mg), thereby maintaining therapeutic plasma levels over the dosing interval. Food had no effect on darifenacin pharmacokinetics during multiple-dose administration of prolonged-release tablets.

Distribution

Darifenacin is a lipophilic base and is 98% bound to plasma proteins (primarily to alpha-1-acid-glycoprotein). The steady-state volume of distribution (V_ss) is estimated to be 163 litres.

Metabolism

Darifenacin is extensively metabolised by the liver following oral administration.

Darifenacin undergoes significant metabolism by cytochrome CYP3A4 and CYP2D6 in the liver and by CYP3A4 in the gut wall. The three main metabolic routes are as follows:

monohydroxylation in the dihydrobenzofuran ring;

dihydrobenzofuran ring opening and

N-dealkylation of the pyrrolidine nitrogen.

The initial products of the hydroxylation and N-dealkylation pathways are major circulating metabolites but none contribute significantly to the overall clinical effect of darifenacin.

The pharmacokinetics of darifenacin at steady state are dose-dependent, due to saturation of the CYP2D6 enzyme.

Doubling the darifenacin dose from 7.5 mg to 15 mg results in a 150% increase in steady-state exposure. This dose-dependency is probably caused by saturation of the CYP2D6 catalysed metabolism possibly together with some saturation of CYP3A4-mediated gut wall metabolism.

Excretion

Following administration of an oral dose of ¹⁴C-darifenacin solution to healthy volunteers, approximately 60% of the radioactivity was recovered in the urine and 40% in the faeces. Only a small percentage of the excreted dose was unchanged darifenacin (3%). Estimated darifenacin clearance is 40 litres/hour. The elimination half-life of darifenacin following chronic dosing is approximately 13

Special patient populations

Gender

A population pharmacokinetic analysis of patient data indicated that darifenacin exposure was 23% lower in males than females (see section 5.1).

Elderly patients

A population pharmacokinetic analysis of patient data indicated a trend for clearance to decrease with age (19% per decade based on Phase III population pharmacokinetic analysis of patients aged 60–89 years), see section 4.2.

Paediatric patients

The pharmacokinetics of darifenacin have not been established in the paediatric population.

CYP2D6 poor metabolisers

The metabolism of darifenacin in CYP2D6 poor metabolisers is principally mediated by CYP3A4. In one pharmacokinetic study the steady-state exposure in poor metabolisers was 164% and 99% higher during treatment with 7.5 mg and 15 mg once daily, respectively. However, a population pharmacokinetic analyses of Phase III data indicated that on average steady-state exposure is 66% higher in poor metabolisers than in extensive metabolisers. There was considerable overlap between the ranges of exposures seen in these two populations (see section 4.2).

Renal insufficiency

A small study of subjects (n=24) with varying degrees of renal impairment (creatinine clearance between 10 ml/min and 136 ml/min) given darifenacin 15 mg once daily to steady state demonstrated no relationship between renal function and darifenacin clearance (see section 4.2).

Hepatic insufficiency

Darifenacin pharmacokinetics were investigated in subjects with mild (Child Pugh A) or moderate (Child Pugh B) impairment of hepatic function given darifenacin 15 mg once daily to steady state. Mild hepatic impairment had no effect on the pharmacokinetics of darifenacin. However, protein binding of darifenacin was affected by moderate hepatic impairment. Unbound darifenacin exposure was estimated to be 4.7-fold higher in subjects with moderate hepatic impairment than subjects with normal hepatic function (see section 4.2).

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. There were no effects on fertility in male and female rats treated at oral doses up to 50 mg/kg/day (78 times the AUC_0-24h of free plasma concentration at maximum recommended human dose [MRHD]). There were no effects on reproductive organs in either sex in dogs treated for 1 year at oral doses up to 6 mg/kg/day (82 times the AUC_0-24h of free plasma concentration at MRHD). Darifenacin was not teratogenic in rats and rabbits at doses up to 50 and 30 mg/kg/day, respectively. At the dose of 50 mg/kg/day in rats (59 times the AUC_0-24h of free plasma concentration at MRHD), delay in the ossification of the sacral and caudal vertebrae was observed. At the dose of 30 mg/kg/day in rabbits (28 times the AUC_0-24h of free plasma concentration at MRHD), maternal toxicity and foetotoxicity (increased post implantation loss and decreased number of viable foetuses per litter) were observed. In peri and post-natal studies in rats, dystocia, increased foetal deaths in utero and toxicity to post-natal development (pup body weight and development land marks) were observed at systemic exposure levels up to 11 times the AUC_0-24h of free plasma concentration at MRHD.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablet core:

Calcium hydrogen phosphate, anhydrous

Hypromellose

Magnesium stearate

Film coat:

Polyethylene glycol

Hypromellose

Titanium dioxide (E171)

Talc

Yellow iron oxide (E172) for Emselex 15 mg pro-longed release tablets only

Red iron oxide (E172) for Emselex 15 mg pro-longed release tablets only

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Keep the blister packs in the outer carton in order to protect from light.

6.5 Nature And Contents Of Container

Clear PVC/CTFE/aluminium or PVC/PVDC/aluminium blisters in cartons containing 7, 14, 28, 49, 56 or 98 tablets as unit pack or in multipacks containing 140 (10x14) 14 tablets.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Novartis Europharm Limited

Wimblehurst Road

Horsham

West Sussex, RH12 5AB

United Kingdom

8. Marketing Authorisation Number(S)

Emselex 7.5 mg prolonged-release tablets:

EU/1/04/294/001-006

EU/1/04/294/013

EU/1/04/294/015-020

EU/1/04/294/027

Emselex 15 mg prolonged-release tablets:

EU/1/04/294/007-012

EU/1/04/294/014

EU/1/04/294/021-026

EU/1/04/294/028

9. Date Of First Authorisation/Renewal Of The Authorisation

22.10.2004

10. Date Of Revision Of The Text

20.12.2010

LEGAL CATEGORY

POM