Elaprase

Pronunciation: EYE-dur-SUL-fase
Generic Name: Idursulfase
Brand Name: Elaprase

Elaprase may sometimes cause severe and possibly fatal allergic reactions. Tell your doctor at once if you develop trouble breathing; tightness in the chest; severe dizziness; swelling of the mouth, face, lips, or tongue; hoarseness; or seizures. You should receive Elaprase only under medical supervision in a facility where treatment for an allergic reaction is available in case it occurs.

Tell your doctor if you have lung or breathing problems. Sudden and serious worsening of your breathing problems could occur if you have an allergic reaction. Discuss any questions or concerns with your doctor.

Elaprase is used for:

Treating Hunter syndrome (mucopolysaccharidosis type II; MPS II).

Elaprase is a lysosomal enzyme. It works in by increasing the amount of iduronate-2-sulfatase in patients with Hunter syndrome who do not make this enzyme on their own.

Do NOT use Elaprase if:

• you have had a severe allergic reaction to Elaprase unless your doctor tells you otherwise. If you must continue Elaprase, your doctor may prescribe other medicines or treatments to reduce your risk of an allergic reaction

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

Before using Elaprase:

Some medical conditions may interact with Elaprase. 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 fever, lung or breathing problems, or a respiratory tract infection

Some MEDICINES MAY INTERACT with Elaprase. However, no specific interactions with Elaprase are known at this time.

Ask your health care provider if Elaprase 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 Elaprase:

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

• Elaprase is usually given as an injection at your doctor's office, hospital, or clinic.


• If you miss a dose of Elaprase, contact your doctor right away.

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

Important safety information:

• Elaprase should be used with extreme caution in CHILDREN younger than 5 years old; safety and effectiveness in these children have not been confirmed.


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

Possible side effects of Elaprase:

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:

Anxiety; general unwell feeling; headache; irritability; pain, swelling, or redness at the injection site; stomach upset.

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

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); blue/purple discoloration of lips, nails, or skin; chest pain; fever; hoarseness; irregular heartbeat; joint pain; seizures; severe headache or dizziness; shortness of breath; vision changes; 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: Elaprase 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 Elaprase:

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

General information:

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


• Elaprase 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 Elaprase. 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 Elaprase resources

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

• Elaprase Prescribing Information (FDA)


• Elaprase Consumer Overview


• Elaprase Monograph (AHFS DI)


• Elaprase Advanced Consumer (Micromedex) - Includes Dosage Information


• Idursulfase Professional Patient Advice (Wolters Kluwer)

Compare Elaprase with other medications

• Mucopolysaccharidosis Type II

Kinlytic

Generic Name: Urokinase
Class: Thrombolytic Agents
CAS Number: 9039-53-6

Introduction

Thrombolytic agent; plasminogen activator isolated from human neonatal kidney cell cultures.^{111 122 125 136 137 153 155}

Uses for Kinlytic

PE

Lysis of acute massive PE (obstruction or substantial filling defects of ≥2 lobar pulmonary arteries or multiple segments of lungs).^{111 117 120 132 133 134 136 140 155}

Lysis of PE accompanied by unstable hemodynamics (i.e., failure to maintain BP without supportive measures).^{111 117 120 132 133 134 136 140 155}

Generally reserve IV thrombolytic therapy for those with acute massive PE accompanied by unstable hemodynamics (e.g., shock) who do not have major contraindications because of bleeding risk^{117 120 121 122 132 133 140 156} or in those with stable hemodynamics with other poor prognostic factors (e.g., marked dyspnea, anxiety, and low oxygen saturation; elevated troponin concentrations indicative of right ventricular microinfarction; echocardiographic evidence of right ventricular dysfunction; right ventricular enlargement on a chest computed-tomography scan).^{133 135 138 156}

The American College of Chest Physicians (ACCP) suggests that thrombolytic agents with a short infusion time (e.g., 2 hours for alteplase) are preferred over those with a longer infusion time (e.g., 12 hours for urokinase)¹⁵⁶ because of increased bleeding risk with prolonged infusion.^{136 143 146} Urokinase also has been effective and safe when given as a 2-hour IV infusion† for PE.^{132 134 135 148} (See PE under Dosage.)

Confirm diagnosis of PE objectively by pulmonary angiography or lung scan (e.g., computed tomography with IV contrast).^{111 119 122 133 152 155}

Perform a rapid risk assessment to determine if thrombolytic therapy is appropriate; irreversible cardiogenic shock may occur if therapy is delayed in patients with evidence of hemodynamic compromise.¹⁵⁶

If thrombolytic therapy fails or is contraindicated in patients with massive PE and hemodynamic instability, pulmonary embolectomy may be required.^{117 120 156}

DVT

Has been used in selected patients for treatment of DVT† (e.g., popliteal or posterior tibial vein).^{117 140}

ACCP suggests thrombolytic therapy be reserved for use in selected patients at low risk of bleeding who have extensive acute proximal DVT† (e.g., iliofemoral DVT) with symptom onset of <14 days, life expectancy of ≥1 year, and good functional status.¹⁵⁶ ACCP also suggests thrombolytic therapy as initial treatment in patients with severe upper extremity DVT† who have recent symptom onset and low risk of bleeding.¹⁵⁶

Coronary Artery Thrombosis and MI

Has been used for lysis of coronary artery thrombi in selected patients with acute evolving transmural MI†, in conjunction with heparin and/or platelet-aggregation inhibitors (e.g., aspirin).^{101 102 104 105 106 107 151} (See Adjunctive Anticoagulant Therapy under Dosage and Administration.)

Clinical evaluation of IV urokinase therapy in patients with MI is limited; offers no clinical advantage over other currently available thrombolytic agents (e.g., alteplase, reteplase, tenecteplase).^{102 127 154}

Arterial Thrombosis and Embolism

Used intra-arterially for lysis of arterial occlusions in peripheral vessels and bypass grafts† in selected patients with acute (<14 days old) thromboembolic arterial ischemia.¹¹⁸ ACCP suggests that such therapy should be used in patients who have a low risk for development of myonecrosis and ischemic nerve damage in the affected extremity.¹¹⁸

Occluded IV Catheters

Restoration of patency to IV catheters†, including central venous catheters, obstructed by clotted blood or fibrin.^{112 116}

Thromboembolism Associated with Prosthetic Heart Valves

Has been used in a limited number of patients for treatment of prosthetic heart-valve thrombosis†.¹⁵⁸

ACCP suggests thrombolytic therapy for patients with right-sided prosthetic valve thrombosis and NYHA functional class III or IV heart failure and in patients with left-sided prosthetic valve thrombosis and NYHA functional class I–IV with small thrombi (<0.8 cm²).¹⁵⁸ In patients with a large (≥0.8 cm²) left-sided prosthetic valve thrombus, ACCP suggests thrombolytic therapy if emergency surgery is not available or considered high risk.¹⁵⁸

Kinlytic Dosage and Administration

General

• 
  

  Use in hospitals where recommended diagnostic and monitoring techniques are available.^{111 155} Observe clinical response and vital signs frequently during and after urokinase infusion.^{111 155}

  
  

PE

• 
  

  Initiate therapy as soon as possible (preferably within several days) after onset of symptoms of PE to achieve greatest clinical benefit;^{111 131 134 140 155} thrombolysis is still beneficial ≤14 days following symptom onset.^{124 131 134 135 136}

  
  


• 
  

  Determine aPTT, hematocrit, and platelet count to assess patient's hemostatic status (e.g., determine if a serious hemostatic defect exists) prior to initiating urokinase.^{111 155} However, results of coagulation tests and measures of thrombolytic activity do not reliably predict either drug efficacy or risk of bleeding.^{111 125 152 155}

  
  

DVT

• 
  

  To avoid dislodgement of possible DVT, do not take BP in lower extremities when monitoring vital signs.^{111 155}

  
  

Adjunctive Anticoagulant Therapy for PE

• 
  

  Heparin should not be infused concurrently with urokinase in patients with PE.^{117 152} In patients who have received heparin, generally allow aPTT to diminish to <2 times the control value before urokinase therapy is initiated.^{111 155}

  
  


• 
  

  To minimize risk of rethrombosis and recurrent PE following thrombolytic therapy,^{120 122} institute anticoagulant therapy (e.g., heparin) when the aPTT has decreased to <2 times the control value.^{111 136 155} Follow heparin therapy with oral anticoagulant therapy.^{111 136 155}

  
  

Adjunctive Anticoagulant Therapy for Coronary Artery Thrombosis and MI

• 
  

  In patients with acute MI† who are at high risk for systemic emboli (e.g., large or anterior acute MI, atrial fibrillation, history of embolism, known left ventricular thrombus),¹⁵¹ IV heparin sodium, usually 5000 units by rapid IV injection followed by a continuous IV infusion, has been administered concomitantly with or immediately following urokinase infusion.^{104 105 106 107}

  
  

Administration

For drug compatibility information, see Compatibility under Stability.

Administer by IV infusion via a controlled-infusion device only.^{111 155}

Also has been administered by intracoronary infusion†, intra-arterial infusion†, or intracatheter instillation†.^{101 102 112 116 118 154}

IV Administration

For treatment of PE, administer by IV infusion via a constant infusion pump capable of delivering a total volume of 195 mL.^{111 155}

Reconstitution

Reconstitute vial containing 250,000 units of urokinase by adding 5 mL of sterile water for injection without preservatives to provide a concentration of 50,000 units/mL.^{111 155} Gently roll and tilt vial until lyophilized powder dissolves to produce a clear or slightly straw-colored solution.¹⁵⁵ Avoid shaking to minimize formation of filaments.^{111 155} Presence of such filaments does not indicate any decrease in potency;^{111 155} such solutions may be filtered through ≤0.45-mcm cellulose membrane filter.^{111 155}

Dilution

Following reconstitution, dilute further with 0.9% sodium chloride or 5% dextrose injection to yield a final infusion volume of 195 mL.^{111 155}

Rate of Administration

PE: Infuse at 90 mL/hour over 10 minutes (loading dose), then 15 mL/hour for 12 hours (maintenance dosage).^{111 117 155} To ensure delivery of entire dose, flush IV tubing with a volume of compatible diluent equal to that of tubing volume at a rate of 15 mL/hour.^{111 155}

PE: Has also been administered as a 2-hour IV infusion†.^{132 134 135 148} (See PE under Dosage.)

Coronary artery thrombosis and MI†: Administer 50% or 100% of the dose over 5 minutes as a rapid IV injection and the remainder, if any, as a continuous infusion over 45–90 minutes.^{104 105 106 107}

Dosage

Dosage of urokinase is expressed in international units (units);^{111 155} biologic activity determined using an in vitro lysis assay.^a

Adults

PE

IV

Loading dose: Initially, 4400 units/kg over 10 minutes recommended by manufacturer.^{111 117 155}

Maintenance dosage: 4400 units/kg per hour for 12 hours recommended by manufacturer.^{111 155} To ensure delivery of entire dose, flush IV tubing with a volume of 0.9% sodium chloride or 5% dextrose injection equal to that of tubing volume.^{111 155}

Repeat administration as necessary.¹⁵⁵

Has also been administered in a dosage of 3 million units over 2 hours†, with initial 1 million units infused over 10 minutes.^{132 134 135 148}

Coronary Artery Thrombosis and MI†

IV

2–3 million units has been administered over 45–90 minutes, with 50% or 100% of the dose given as an initial rapid IV injection (e.g., over 5 minutes) and the remainder, if any, as a continuous infusion.^{104 105 106 107}

Cautions for Kinlytic

Contraindications

• 
  

  Active internal bleeding.^{111 152 155}

  
  


• 
  

  Recent (≤2 months) cerebrovascular accident.^{111 152 155}

  
  


• 
  

  Recent trauma, including CPR.^{111 155}

  
  


• 
  

  Known bleeding diathesis.^{111 155}

  
  


• 
  

  Severe uncontrolled arterial hypertension.^{111 155}

  
  


• 
  

  Intracranial neoplasms.^{111 152 155}

  
  


• 
  

  Intracranial vascular disease (i.e., aneurysm, arteriovenous malformation).^{111 152 155}

  
  


• 
  

  Recent (≤2 months) intracranial or intraspinal surgery.^{111 155}

  
  


• 
  

  Known hypersensitivity to urokinase or any ingredient in the formulation.^{111 155}

  
  

Warnings/Precautions

Warnings

Effects on Hemostasis

Possible bleeding and hemorrhagic complications, including intracranial hemorrhage and other major bleeding complications.^{111 120 126 133 134 137 155} May be more common in geriatric patients, patients with renal or hepatic dysfunction, and those receiving intense or prolonged antithrombotic therapy.^{133 136}

Weigh increased risks of therapy against anticipated benefits in patients with recent (≤10 days) major surgery, obstetric delivery, organ biopsy, previous puncture of noncompressible vessels, cerebrovascular disease (other than contraindicated conditions), hemostatic defects (e.g., secondary to severe hepatic or renal disease), recent (≤10 days) serious GI bleeding, high likelihood of left heart thrombus (e.g., mitral stenosis with atrial fibrillation), pregnancy, diabetic hemorrhagic retinopathy, or subacute bacterial endocarditis.^{111 155} Weigh risks against benefits in patients with any condition in which bleeding constitutes a substantial hazard or would be especially difficult to manage because of its location.^{111 155}

Minimize risk of bleeding by carefully selecting patients and monitoring all potential bleeding sites (e.g., sites of all cutdowns; arterial, venous, and other needle punctures; catheter insertion sites).^{111 134 155} Avoid IM injections and nonessential handling of patient.^{111 134 155} Perform invasive venous procedures as carefully and as infrequently as possible.^{111 134 136 155} Avoid arterial invasive procedures;^a use upper extremity artery (radial or brachial) if arterial puncture is essential.^{111 155} Apply pressure to puncture site for ≥30 minutes, apply pressure dressing, and check site frequently for evidence of bleeding.^{111 155}

Severe and fatal spontaneous (e.g., cerebral, retroperitoneal) bleeding has occurred.^{111 120 126 133 134 137 155}

Internal bleeding with urokinase may be more difficult to control than that which occurs with conventional anticoagulant therapy.^{111 155} Possible lysis of fibrin deposits that provide hemostasis (e.g., at sites of needle punctures, cuts); bleeding from such sites may result.^{125 126 134}

If serious spontaneous bleeding occurs, immediately discontinue urokinase therapy.^{111 133 134 152 155} Initiate appropriate hemostatic therapy as needed (e.g., plasma volume expanders other than dextrans, packed RBCs, cryoprecipitate, fresh frozen plasma) to replace blood volume deficits and/or reverse bleeding tendency.^{111 134 152 155 a}

Concomitant Antithrombotic Therapy

Concomitant use with other thrombolytic agents, anticoagulants, or agents inhibiting platelet function may increase risk of serious bleeding.^{111 155} (See Specific Drugs under Interactions.)

Do not use aspirin and other NSAIAs that inhibit platelet function for treatment of fever (e.g., fever associated with infusion reactions).¹¹¹ (See Sensitivity Reactions under Cautions.)

Cholesterol Embolization

Cholesterol embolization and associated serious complications reported rarely in patients receiving thrombolytic therapy, including urokinase.^{111 155} Possibly fatal cholesterol embolization associated with invasive vascular procedures (e.g., cardiac catheterization, angiography, vascular surgery) and/or anticoagulant agents.^{111 155} Clinical features of cholesterol embolism include livedo reticularis, “purple toe” syndrome, acute renal failure, gangrenous digits, hypertension, pancreatitis, MI, cerebral infarction, spinal cord infarction, retinal artery occlusion, bowel infarction, and rhabdomyolysis.^{111 155}

Risk of Transmissible Agents in Serum-derived Preparations

Potential vehicle for transmission of human viruses (e.g., HIV, hepatitis B virus [HBV], hepatitis C virus [HCV], human T-lymphotropic virus [HTLV], cytomegalovirus [CMV], human papilloma virus [HPV], Epstein-Barr virus [EBV]) or other infectious agents.^{111 155}

Despite application of a number of viral elimination/reduction steps (e.g., heat treatment in solution, purification, screening for certain viruses) to prevent transmission of infectious agents, risk of transmission still remains.^{111 155}

Report all infections thought possibly to have been transmitted by urokinase to the manufacturer at 866-634-6279.^{111 155}

Risk of Creutzfeldt-Jakob Disease

Formulation contains 5% albumin.^{111 155} May carry a remote risk of transmitting causative agent of Creutzfeldt-Jakob disease (CJD).^{111 155} Currently, no evidence of transmission of CJD via albumin component.^{111 155}

Sensitivity Reactions

Possible anaphylaxis; rare fatalities.^{111 134 155} Other allergic-type reactions (e.g., orolingual edema, bronchospasm, urticaria) reported.^{111 134 155}

Acute infusion reactions, including fever, chills or shaking chills (rigors), hypotension, nausea, vomiting, hypoxia, cyanosis, dyspnea, tachycardia, hypertension, acidosis, and/or back pain, may occur; such reactions generally begin ≤1 hour after treatment initiation.^{111 134 155}

If infusion reactions occur, immediately discontinue therapy, monitor patient closely, and institute appropriate therapy (e.g., IV antihistamines, adrenergic agents, corticosteroids).^{111 155} (See Concomitant Antithrombotic Therapy under Cautions.)

Specific Populations

Pregnancy

Category B.^{111 155}

Lactation

Not known whether urokinase is distributed into milk.^{111 155} Use caution.^{111 155}

Pediatric Use

Safety and efficacy of urokinase not established.^{111 155}

Thrombolytic therapy generally not recommended for treatment of venous thromboembolism in neonates and children unless vessel occlusion is severe and causes organ dysfunction or limb ischemia.¹⁵⁷ If thrombolysis is required, ACCP states that alteplase is the drug of choice in pediatric patients because of greater fibrin specificity, lower immunogenicity, and more effective clot lysis in vitro compared with urokinase.¹⁵⁷

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether such patients respond differently than younger adults.^{111 155} Use with caution.^{111 155}

Common Adverse Effects

Bleeding.^{111 155}

Interactions for Kinlytic

Specific Drugs

Drug	Interaction	Comments
Dipyridamole	Increased risk of hemorrhage111 155	Monitor carefully for evidence of bleeding111 155
GP IIb/IIIa inhibitors	Increased risk of hemorrhage111 155	Monitor carefully for evidence of bleeding111 155
Heparin	Increased risk of hemorrhage111 155	Concurrent use not recommended in patients with PE111 117 152 (see Adjunctive Anticoagulant Therapy under Dosage and Administration) If used, monitor carefully for evidence of bleeding111 155
NSAIAs (e.g., aspirin)	Increased risk of hemorrhage111 155	Do not use for treatment of fever (e.g., infusion reactions)111 155 If used, monitor carefully for evidence of bleeding111 155
Thrombolytic agents	Increased risk of hemorrhage111 155	Monitor carefully for evidence of bleeding111 155

Kinlytic Pharmacokinetics

Absorption

Onset

PE: Clinical improvement and measurable hemodynamic changes may occur within a few hours but may not be observed until 6–8 hours after treatment initiation.^a

Duration

PE: Fibrinolytic effects usually disappear within a few hours.^{111 155} Decreased plasma concentrations of fibrinogen and plasminogen and increased circulating concentrations of degradation products of fibrinogen and fibrin may persist for 12–24 hours after discontinuance of IV infusion.^{111 155}

Elimination

Elimination Route

Rapidly cleared by liver.^{111 155} Small amount of urokinase eliminated in urine and feces via biliary excretion.^{111 122 155}

Half-life

12.6 minutes.^{111 155}

Special Populations

Pharmacokinetics not characterized in patients with hepatic impairment.^{111 155} Endogenous urokinase-type plasminogen activator plasma concentrations are elevated twofold to fourfold in patients with moderate to severe cirrhosis; hepatic impairment might be expected to reduce clearance of urokinase.^{111 155}

Stability

Storage

Parenteral

Powder for Injection

Refrigerate at 2–8°C.^{111 155}

Compatibility

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

Parenteral

Drug Compatibility

Do not mix with other drugs for IV infusion.^{111 155}

ActionsActions

• 
  

  Directly activates conversion of fibrin-bound and circulating plasminogen to proteolytic enzyme plasmin.^{111 136 144 145 153 155} Plasmin degrades fibrin, fibrinogen and other clotting factors, and other plasma procoagulant proteins.^{111 144 145 153 155}

  
  


• 
  

  Decreases plasma concentrations of fibrinogen and plasminogen and increases circulating concentrations of degradation products of fibrinogen and fibrin.^{111 155}

  
  


• 
  

  Exhibits less fibrin selectivity than alteplase, reteplase, and tenecteplase.^{117 152 153 151} May lyse fibrin deposits that provide hemostasis (e.g., at sites of needle punctures, cuts); bleeding from such sites may result.^{117 125 126 134}

  
  


• 
  

  Degradation of fibrinogen and fibrin and other clotting factors induces anticoagulant effect.^{a 151 152 153}

  
  

Advice to Patients

• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹¹¹

  
  


• 
  

  Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs.¹¹¹

  
  


• 
  

  Importance of advising patients of other important precautionary information.¹¹¹ (See Cautions.)

  
  

Preparations

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

Urokinase powder for injection, formerly marketed as Abbokinase (Abbott Laboratories), has been rebranded as Kinlytic after completion of stability studies on existing inventory to extend the expiration dating.¹⁵⁴ Urokinase injection may continue to be available from some suppliers as Abbokinase until that inventory is exhausted.¹⁵⁴ Hospitals should deplete their current stocks of Abbokinase before using Kinlytic.¹⁵⁴

Urokinase

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, IV infusion	250,000 units	Abbokinase (heat-treated, wet method)	ImaRX
			Kinlytic (heat-treated, wet method)	ImaRX

Disclaimer

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

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

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions December 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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

References

Only references cited for selected revisions after 1984 are available electronically.

100. Abbott Laboratories. Abbokinase prescribing information. Chicago, IL; 1988 Mar.

101. Tennant SN, Dixon J, Venable TC et al. Intracoronary thrombolysis in patients with acute myocardial infarction: comparison of the efficacy of urokinase with streptokinase. Circulation. 1984; 69:756-60. [IDIS 183631] [PubMed 6607784]

102. Ohman EM, Harrington RA, Cannon CP et al. Intravenous thrombolysis in acute myocardial infarction. Chest. 2001; 119:253S-277S. [IDIS 459453] [PubMed 11157653]

103. Van Scoik S. Dear pharmacist letter regarding new formulation of Abbokinase (urokinase for injection). Abbott Laboratories. North Chicago, IL. 1988 Nov.

104. Mathey DG, Schofer J, Sheehan FH. Coronary thrombolysis with intravenous urokinase in patients with acute myocardial infarction. Am J Med. 1987; 83(Suppl 2A):26-30. [IDIS 235311] [PubMed 3631114]

105. Neuhaus KL, Tebbe U, Gottwik M et al. Intravenous recombinant tissue plasminogen activator (rt-PA) and urokinase in acute myocardial infarction: results of the German Activator Urokinase Study (GAUS). J Am Coll Cardiol. 1988; 12:581-7. [PubMed 3042835]

106. Mathey DG, Schofer J, Sheehan FH et al. Intravenous urokinase in acute myocardial infarction. Am J Cardiol. 1985; 55:878-82. [IDIS 199031] [PubMed 3984876]

107. Wall TC, Phillips HR III, Stack RS et al. Results of high dose intravenous urokinase for acute myocardial infarction. Am J Cardiol. 1990; 65:124-31. [IDIS 262976] [PubMed 2296881]

108. American College of Cardiology and American Heart Association. ACC/AHA guidelines for the management of patients with acute myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). J Am Coll Cardiol. 1996; 28:1328-428. [IDIS 376249] [PubMed 8890834]

109. Food and Drug Administration Center for Biologics Evaluation and Research. Difficulties in obtaining sufficient of urokinase (Abbokinase). Rockville, MD; December 11, 1998. From FDA websit.

110. Pizzutti D. Dear Abbott customer letter regarding shortage of parenteral urokinase (Abbokinase). Abbott Park, IL: Abbott Laboratories; 1998 Dec 9.

111. ImaRX Therapeutics Inc. Abbokinase (urokinase) prescribing information. Tuscon, AR; 2006 Dec.

112. Abbott Laboratories. Abbokinase Open-Cath(urokinase for catheter clearance) prescribing information (dated 1999 Jan). In: Physicians’ desk reference. 54th ed. Montvale, NJ: Medical Economics Company Inc; 2000:404.

113. Zoon KC. Dear healthcare provider letter: Important drug warning: safety information regarding the use of Abbokinase (urokinase). Rockville, MD: US Food and Drug Administration; 1999 Jan 25. From FDA web site.

114. Food and Drug Administration Center for Biologics Evaluation and Research. Update on Abbokinase (urokinase). Rockville, MD; March 22, 1999. From FDA web site.

115. Abbott Laboratories, Chicago, IL: Personal communication.

116. National Kidney Foundation. Kidney Disease Outcomes Quality Initiative (NKF-DOQI) clinical practice guideline 7. Prevention and treatment of catheter and port complications. 2006 update. From NKF website. Accessed 2007 Feb 12.

117. Buller HR, Agnelli G, Hull RD et al. Antithrombotic therapy for venous thromboembolic disease. Chest. 2004; 126(Suppl):401S-28S. [IDIS 523841] [PubMed 15383479]

118. Sobel M, Verhaeghe R.. Antithrombotic therapy for peripheral artery occlusive disease: American College of Chest Physicians evidence-based clinical practice guidelines (8th ed). Chest. 2008; 133(Suppl):815S-43S. [PubMed 18574279]

119. Piazza G, Goldhaber SZ. Acute pulmonary embolism. Part I: epidemiology and diagnosis. Circulation. 2006; 114:28-32.

120. Piazza G, Goldhaber SZ. Acute pulmonary embolism. Part II: Treatment and prophylaxis. Circulation. 2006; 114:42-7.

121. Wan S, Quinlan DJ, Agnelli G et al. Thrombolysis compared with heparin for the initial treatment of pulmonary embolism. A meta-analysis of the randomized controlled trials. Circulation. 2004; 110:744-9. [PubMed 15262836]

122. Sasahara AA, Hyers TM, Cole CM et al. The urokinase pulmonary embolism trial: a national cooperative study. Summary, conclusions, and recommendations. Circulation. 1973; 47 (Suppl 2):7-12.

123. Dong B, Jirong Y, Liu G et al. Thrombolytic therapy for pulmonary embolism. Cochrane Database of Systematic Reviews 2006, Issue 2. Article No.: CD004437. DOI: 10.1002/14651858.CD004437.pub2.

124. Sasahara AA, Cannilla JE, Belko JS et al. Urokinase therapy in clinical pulmonary embolism: a new thrombolytic agent. N Engl J Med. 1967; 277:1168-73. [PubMed 6058604]

125. Tow DE, Wagner HN Jr, Holmes RA. Urokinase in pulmonary embolism. N Engl J Med. 1967; 277:1161-7. [PubMed 6058603]

126. Anderson DR, Levine MN. Thrombolytic therapy for the treatment of acute pulmonary embolism. Can Med Assoc J. 1992; 146:1317-24. [PubMed 1555162]

127. Rossi P, Bolognese L. Comparison of intravenous urokinase plus heparin versus heparin alone in acute myocardial infarction. Am J Cardiol. 1991; 68:585–92.

128. Urokinase pulmonary embolism trial. Phase 1 results: a cooperative study. JAMA. 1970; 214:2163-72. [PubMed 5536580]

129. Hyers TM, Stengle JM, Sherry S. Treatment of pulmonary embolism with urokinase: results of clinical trial (Phase 1). Circulation. 1970; 42:979-80. Editorial. [PubMed 5492546]

130. Urokinase-streptokinase embolism trial. Phase 2 results. A cooperative study JAMA. 1974; 229:1606-13.

131. Daniels LB, Parker JA, Patel SR et al. Relation of duration of symptoms with response to thrombolytic therapy in pulmonary embolism. Am J Cardiol. 1997; 80:184-8. [PubMed 9230156]

132. Dalen JE, Alpert JS, Hirsh J. Thrombolytic therapy for pulmonary embolism. Is it effective? When is it indicated? Arch Intern Med. 1997; 157:2550-6. Editorial.

133. Hyers TM. Venous thromboembolism. Am J Respir Crit Care Med. 1999; 159:1-14. [PubMed 9872811]

134. Arcasoy SM, Kreit JW. Thrombolytic therapy of pulmonary embolism. A comprehensive review of current evidence. Chest. 1999; 115:1695-1707. [PubMed 10378570]

135. Goldhaber SZ. Thrombolysis in pulmonary embolism: a debatable indication. Thromb Haemost. 2001; 86:444-51. [PubMed 11487035]

136. Riedel M. Venous thromboembolic disease. Acute pulmonary embolism 2: treatment. Heart. 2001; 85:351-60. [PubMed 11179282]

137. Dalen JE. Pulmonary embolism: what have we learned since Virchow? Chest. 2002; 122:1801-7.

138. Goldhaber SZ. Thrombolytic therapy for patients with pulmonary embolism who are hemodynamically stable but have right ventricular dysfunction: Pro. Arch Intern Med. 2005; 165:2197-9. Commentary. [PubMed 16246980]

139. Thabut G, Logeart D. Thrombolysis for pulmonary embolism in patients with right ventricular dysfunction: Con. Arch Intern Med. 2005; 165:2200-3. Commentary. [PubMed 16246981]

140. Emmerich J, Meyer G, Decousus H et al. Role of fibrinolysis and interventional therapy for acute venous thromboembolism.Thromb Haemost. 2006; 96:251-7. [PubMed 16953264]

141. Meyerovitz MF, Goldhaber SZ, Reagan K et al. Recombinant tissue-type plasminogen activator versus urokinase in peripheral arterial and graft occlusions: a randomized trial. Radiology. 1990; 175:75–8.

142. The STILE Investigators. Results of a prospective randomized trial evaluating surgery versus thrombolysis for ischemia of the lower extremity: the STILE trial. Ann Surg. 1994; 220:251–68.

143. Goldhaber SZ, Kessler CM, Heit J et al. Randomised controlled trial of recombinant tissue plasminogen activator versus urokinase in the treatment of acute pulmonary embolism. Lancet. 1988; 2(8606):293-8. [IDIS 244867] [PubMed 2899718]

144. Lijnen HR, Collen D. Fibrinolytic agents: mechanisms of activity and pharmacology. Thromb Haemost. 1995; 74:387-90. [PubMed 8578491]

145. Bell WR. Present-day thrombolytic therapy: therapeutic agents--pharmacokinetics and pharmacodynamics. Rev Cardiovasc Med. 2002;3 Suppl 2:S34-44.

146. Gold HK, Johns JA, Leinbach RC et al. A randomized, blinded, placebo-controlled trial of recombinant human tissue-type plamsminogen activator in patients with unstable angina pectoris. Circulation. 1987; 75:1192-9. [IDIS 230356] [PubMed 3105913]

147. Ryan TJ, Antman EM, Brooks NH et al. ACC/AHA guidelines for the management of patients with acute myocardial infarction: 1999 update: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). From ACC website.

148. Goldhaber SZ, Kessler CM, Heit JA et al. Recombinant tissue-type plasminogen activator versus a novel dosing regimen of urokinase in acute pulmonary embolism: a randomized controlled multicenter trial. J Am Coll Cardiol. 1992; 20:24-30. [PubMed 1607532]

149. Meyer G, Sors H, Charbonnier B et al. Effects of intravenous urokinase versus alteplase on total pulmonary resistance in acute massive pulmonary embolism: a European multicenter double-blind trial. The European Cooperative Study Group for Pulmonary Embolism. J Am Coll Cardiol. 1992; 19:239-45. [PubMed 1732347]

151. Antman EM, Anbe DT, Armstrong PW et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 guidelines for the Management of Patients with Acute Myocardial Infarction). 2004. Available from ACC website. Accessed 2008 Mar 6.

152. Marder VJ. The use of thrombolytic agents: choice of patient, drug administration, laboratory monitoring. Ann Intern Med. 1979; 90:802-8. [PubMed 434689]

153. Weitz JI, Stewart RJ, Fredenburgh JC. Mechanism of action of plasminogen activators. Throm Haemost. 1999; 82:974-82.

154. ImaRX Therapeutics, Tucson, AZ: Personal communication.

155. ImaRX Therapeutics Inc. Kinlytic (urokinase) for injection prescribing information. Tucson, AZ; 2007 June.

156. Kearon C, Kahn SR, Agnelli G et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians evidence-based clinical practice guidelines (8th ed). Chest. 2008; 133 (Suppl): 454S-545S. [PubMed 18574272]

157. Monagle P, Chalmers E, Chan A et al. Antithrombotic therapy in neonates and children: American College of Chest Physicians evidence-based clinical practice guidelines (8th ed). Chest. 2008; 133:887S-968S. [PubMed 18574281]

158. Salem DN, O'Gara PT, Madias C et al. Valvular and structural heart disease: American College of Chest

Allantoin/Coal Tar Shampoo

Pronunciation: a-LAN-toyn/kohl tar
Generic Name: Allantoin/Coal Tar
Brand Name: Original Tegrin Medicated

Allantoin/Coal Tar Shampoo is used for:

Relieving itching, scaling, dryness, and flaking of the skin due to dandruff, eczema, psoriasis, and seborrhea. It may also be used for other conditions as determined by your doctor.

Allantoin/Coal Tar Shampoo is a keratolytic. It works by slowing bacterial growth and loosing and softening scales and crust.

Do NOT use Allantoin/Coal Tar Shampoo if:

• you are allergic to any ingredient in Allantoin/Coal Tar Shampoo


• you have a condition that makes you sensitive to sunlight (eg, lupus, allergy to sunlight)

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

Before using Allantoin/Coal Tar Shampoo:

Some medical conditions may interact with Allantoin/Coal Tar Shampoo. 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 are using any other treatment for psoriasis, including ultraviolet radiation or a prescription medicine

Some MEDICINES MAY INTERACT with Allantoin/Coal Tar Shampoo. However, no specific interactions with Allantoin/Coal Tar Shampoo are known at this time.

This may not be a complete list of all interactions that may occur. Ask your health care provider if Allantoin/Coal Tar Shampoo 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 Allantoin/Coal Tar Shampoo:

Use Allantoin/Coal Tar Shampoo as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Wet the scalp and hair. Apply the medicine to the scalp, massage into a lather, and allow it to remain on the scalp for 5 minutes. Rinse thoroughly and repeat.


• Wash your hands after using Allantoin/Coal Tar Shampoo.


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

Ask your health care provider any questions you may have about how to use Allantoin/Coal Tar Shampoo.

Important safety information:

• Avoid getting Allantoin/Coal Tar Shampoo in your eyes, nose, and mouth. If you get Allantoin/Coal Tar Shampoo in your eyes, immediately wash them out with cool tap water.


• Allantoin/Coal Tar Shampoo may be harmful if swallowed. If you may have taken Allantoin/Coal Tar Shampoo by mouth, contact your local poison control center or emergency room immediately.


• Do not use Allantoin/Coal Tar Shampoo on open, raw, inflamed, or infected skin.


• Do not use Allantoin/Coal Tar Shampoo in or around the genital area, groin, or rectum unless you doctor tells you otherwise.


• Do not use any other medicines or special cleansers on the affected area without first checking with your doctor.


• Do not use Allantoin/Coal Tar Shampoo over a large area of your body without first talking to your doctor.


• Do not use Allantoin/Coal Tar Shampoo for a prolonged period of time without consulting your doctor.


• Allantoin/Coal Tar Shampoo may cause increased sensitivity to the sun. Avoid exposure to the sun, sunlamps, or tanning booths until you know how you react to Allantoin/Coal Tar Shampoo. Use a sunscreen or protective clothing if you must be outside for a prolonged period.


• Allantoin/Coal Tar Shampoo may stain hair, skin, and clothing.


• Do not use soap, detergent, or other shampoo on your hair before or after using Allantoin/Coal Tar Shampoo.


• Use Allantoin/Coal Tar Shampoo with extreme caution in CHILDREN younger than 2 years of age. Safety and effectiveness in this age group have not been confirmed.


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

Possible side effects of Allantoin/Coal Tar Shampoo:

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:

Itching, burning, tenderness, or redness; sensitivity to sunlight.

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

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); excessive dryness; irritation.

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: Allantoin/Coal Tar 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 Allantoin/Coal Tar Shampoo:

Store Allantoin/Coal Tar Shampoo at room temperature between 68 and 77 degrees F (20 and 25 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Keep Allantoin/Coal Tar Shampoo out of the reach of children and away from pets.

General information:

• If you have any questions about Allantoin/Coal Tar Shampoo, please talk with your doctor, pharmacist, or other health care provider.


• Allantoin/Coal Tar Shampoo 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 Allantoin/Coal Tar Shampoo. 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 Allantoin/Coal Tar resources

• Allantoin/Coal Tar Side Effects (in more detail)
• Allantoin/Coal Tar Use in Pregnancy & Breastfeeding
• Allantoin/Coal Tar Support Group
• 4 Reviews for Allantoin/Coal Tar - Add your own review/rating

Compare Allantoin/Coal Tar with other medications

• Dermatitis
• Psoriasis
• Seborrheic Dermatitis

ConZip

Generic Name: tramadol (TRAM a dol)

Brand Names: ConZip, Rybix ODT, Ryzolt, Ultram, Ultram ER

What is ConZip (tramadol)?

Tramadol is a narcotic-like pain reliever.

Tramadol is used to treat moderate to severe pain. Tramadol extended-release is used to treat moderate to severe chronic pain when treatment is needed around the clock.

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

What is the most important information I should know about ConZip (tramadol)?

You should not take tramadol if you are allergic to it, if you have ever been addicted to drugs or alcohol, or if you have ever attempted suicide. Do not take tramadol while you are intoxicated (drunk) or taking any of the following: alcohol or street drugs, narcotic pain medicine, sedatives or tranquilizers, or medicine for depression, anxiety, or mental illness.

Seizures (convulsions) have occurred in some people taking tramadol. Tramadol may be more likely to cause a seizure if you have a history of seizures or head injury, a metabolic disorder, or if you are taking certain medicines such as antidepressants, muscle relaxers, narcotic, or medicine for nausea and vomiting.

Seek emergency medical attention if you think you have used too much of this medicine. A tramadol overdose can be fatal. Tramadol may be habit-forming and should be used only by the person it was prescribed for. Keep the medication in a secure place where others cannot get to it. Do not crush the tramadol tablet. This medicine is for oral (by mouth) use only. Powder from a crushed tablet should not be inhaled or diluted with liquid and injected into the body. Using this medicine by inhalation or injection can cause life-threatening side effects, overdose, or death.

What should I discuss with my healthcare provider before taking ConZip (tramadol)?

You should not take tramadol if you are allergic to it, if you have ever been addicted to drugs or alcohol, or if you have ever attempted suicide.

Do not take tramadol while you are intoxicated (drunk) or taking any of the following:

• 
  

  alcohol or street drugs;

  
  


• 
  

  narcotic pain medicine;

  
  


• 
  

  sedatives or tranquilizers (such as Valium);

  
  


• 
  

  medicine for depression or anxiety; or

  
  


• 
  

  medicine for mental illness (such as bipolar disorder, schizophrenia).

  
  

Seizures have occurred in some people taking tramadol. Talk with your doctor about your seizure risk, which may be higher if you have:

• 
  

  a history of drug or alcohol addiction;

  
  


• 
  

  a history of epilepsy or other seizure disorder;

  
  


• 
  

  a history of head injury;

  
  


• 
  

  a metabolic disorder; or

  
  


• 
  

  if you are also taking an antidepressant, muscle relaxer, narcotic, antipsychotic, or medicine for nausea and vomiting.

  
  

To make sure you can safely take tramadol, tell your doctor if you have any of these other conditions:

• 
  

  kidney disease (or if you are on dialysis);

  
  


• 
  

  cirrhosis or other liver disease;

  
  


• 
  

  a stomach disorder; or

  
  


• 
  

  a history of depression, mental illness, or thoughts of suicide.

  
  

Tramadol may be habit forming and should be used only by the person it was prescribed for. Never share tramadol with another person, especially someone with a history of drug abuse or addiction. Keep the medication in a place where others cannot get to it. FDA pregnancy category C. It is not known whether tramadol will harm an unborn baby. Tramadol may cause serious or fatal side effects in a newborn if the mother uses the medication during pregnancy or labor. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. Tramadol can pass into breast milk and may harm a nursing baby. You should not breast-feed while you are taking tramadol. Do not give this medication to anyone younger than 16 years old without the advice of a doctor.

Rybix ODT may contain phenylalanine. Talk to your doctor before using this form of tramadol if you have phenylketonuria (PKU).

How should I take ConZip (tramadol)?

Take exactly as prescribed. Never take tramadol in larger amounts, or for longer than recommended by your doctor. Follow the directions on your prescription label. Tell your doctor if the medicine seems to stop working as well in relieving your pain.

Tramadol can be taken with or without food, but take it the same way each time.

Do not crush, chew, or break a tramadol tablet. Swallow it whole. Breaking the pill may cause too much of the drug to be released at one time. This medicine is for oral (by mouth) use only. Powder from a crushed tablet should not be inhaled or diluted with liquid and injected into the body. Using this medicine by inhalation or injection can cause life-threatening side effects, overdose, or death.

To take tramadol orally disintegrating tablets (Rybix ODT):

• 
  

  Keep the tablet in its blister pack until you are ready to take it.

  
  


• 
  

  Using dry hands, remove the tablet and place it in your mouth. It will begin to dissolve right away.

  
  


• 
  

  Do not swallow the tablet whole. Allow it to dissolve in your mouth without chewing.

  
  


• 
  

  Swallow several times as the tablet dissolves. If desired, you may drink liquid to help swallow the dissolved tablet.

  
  

If you use the tramadol extended-release tablet, the tablet shell may pass into your stools (bowel movements). This is normal and does not mean that you are not receiving enough of the medicine.

Do not stop using tramadol suddenly, or you could have unpleasant withdrawal symptoms. Talk to your doctor about how to avoid withdrawal symptoms when stopping the medication. Store at room temperature away from moisture and heat.

Keep track of the amount of medicine used from each new bottle. Tramadol is a drug of abuse and you should be aware if anyone is using your medicine improperly or without a prescription.

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. A tramadol overdose can be fatal.

Overdose symptoms may include extreme drowsiness, shallow breathing, muscle weakness, slow heartbeat, cold or clammy skin, fainting, or seizure.

What should I avoid while taking ConZip (tramadol)?

Do not drink alcohol. It may cause a dangerous decrease in your breathing when used together with tramadol. Tramadol may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

ConZip (tramadol) 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 tramadol and call your doctor at once if you have any of these serious side effects:

• 
  

  agitation, hallucinations, fever, fast heart rate, overactive reflexes, nausea, vomiting, diarrhea, loss of coordination, fainting;

  
  


• 
  

  seizure (convulsions);

  
  


• 
  

  a red, blistering, peeling skin rash; or

  
  


• 
  

  shallow breathing, weak pulse.

  
  

Less serious side effects may include:

• 
  

  dizziness, spinning sensation;

  
  


• 
  

  constipation, upset stomach;

  
  


• 
  

  headache;

  
  


• 
  

  drowsiness; or

  
  


• 
  

  feeling nervous or anxious.

  
  

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 ConZip (tramadol)?

You may be more likely to have a seizure (convulsions) if you take tramadol while you are using certain other medicines. Do not take tramadol without telling your doctor if you also use any of the following medications:

• 
  

  an MAO inhibitor such as isocarboxazid (Marplan), tranylcypromine (Parnate), phenelzine (Nardil), or selegiline (Eldepryl, Emsam); or

  
  


• 
  

  an antidepressant such as amitriptyline (Elavil, Vanatrip), citalopram (Celexa), clomipramine (Anafranil), desipramine (Norpramin), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem), fluvoxamine (Luvox), imipramine (Tofranil), nortriptyline (Pamelor), paroxetine (Paxil), or sertraline (Zoloft).

  
  

Cold or allergy medicine, sleeping pills, muscle relaxers, and medicine for seizures or anxiety can add to sleepiness caused by tramadol. Tell your doctor if you regularly use any of these medicines, or any other pain medication.

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

• 
  

  carbamazepine (Carbatrol, Equetro, Tegretol);

  
  


• 
  

  lithium (Eskalith, LithoBid);

  
  


• 
  

  ADHD medications (Adderall, Ritalin, Strattera);

  
  


• 
  

  an antibiotic such as clarithromycin (Biaxin), erythromycin (E.E.S., EryPed, Ery-Tab, Erythrocin, Pediazole), linezolid (Zyvox), rifampin (Rifadin, Rimactane, Rifater); or telithromycin (Ketek);

  
  


• 
  

  antifungal medication such as clotrimazole (Mycelex Troche), itraconazole (Sporanox), ketoconazole (Nizoral), miconazole (Oravig), or voriconazole (Vfend);

  
  


• 
  

  cancer medications such as gefitinib (Iressa), imatinib (Gleevec), or nilotinib (Tasigna);

  
  


• 
  

  a heart rhythm medication such as amiodarone (Cordarone, Pacerone), flecainide (Tambocor), propafenone (Rythmol), or quinidine (Quin-G);

  
  


• 
  

  heart or blood pressure medication such as diltiazem (Cartia, Cardizem), felodipine (Plendil), nifedipine (Nifedical, Procardia), verapamil (Calan, Covera, Isoptin, Verelan), and others;

  
  


• 
  

  HIV/AIDS medicine such as atazanavir (Reyataz), delavirdine (Rescriptor), fosamprenavir (Lexiva), indinavir (Crixivan), nelfinavir (Viracept), saquinavir (Invirase), or ritonavir (Norvir, Kaletra); or

  
  


• 
  

  migraine headache medicine such as sumatriptan (Imitrex, Treximet).

  
  

This list is not complete and there are many other drugs that can interact with tramadol. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor. Keep a list of all your medicines and show it to any healthcare provider who treats you.

More ConZip resources

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

• ConZip Prescribing Information (FDA)


• ConZip Extended-Release Capsules MedFacts Consumer Leaflet (Wolters Kluwer)


• ConZip Advanced Consumer (Micromedex) - Includes Dosage Information


• Rybix ODT Orally Disintegrating Tablets MedFacts Consumer Leaflet (Wolters Kluwer)


• Rybix ODT Prescribing Information (FDA)


• Ryzolt Extended-Release Tablets MedFacts Consumer Leaflet (Wolters Kluwer)


• Ryzolt Consumer Overview


• Ryzolt Prescribing Information (FDA)


• Tramadol MedFacts Consumer Leaflet (Wolters Kluwer)


• Tramadol Hydrochloride Monograph (AHFS DI)


• Ultram Consumer Overview


• Ultram Prescribing Information (FDA)


• Ultram ER Prescribing Information (FDA)

Compare ConZip with other medications

• Back Pain
• Pain

Where can I get more information?

• Your pharmacist can provide more information about tramadol.

See also: ConZip side effects (in more detail)

Inderal

In some countries, this medicine may only be approved for veterinary use.

In the US, Inderal (propranolol systemic) is a member of the following drug classes: group II antiarrhythmics, non-cardioselective beta blockers and is used to treat Angina, Aortic Stenosis, Arrhythmia, Benign Essential Tremor, Heart Attack, Hemangioma, High Blood Pressure, Migraine Prevention, Mitral Valve Prolapse, Performance Anxiety, Pheochromocytoma and Thyrotoxicosis.

US matches:

• Inderal


• Inderal LA Sustained-Release Capsules


• Inderal LA


• Inderal Intravenous

UK matches:

• Inderal Injection
• Inderal LA 160mg and Half-Inderal LA 80mg
• Inderal Injection (SPC)
• Inderal LA 160mg (SPC)
• Inderal Tablets 10mg (SPC)
• Inderal Tablets 40mg (SPC)
• Inderal Tablets 80mg (SPC)

Ingredient matches for Inderal

Propranolol

Propranolol is reported as an ingredient of Inderal in the following countries:

• Taiwan

Propranolol hydrochloride (a derivative of Propranolol) is reported as an ingredient of Inderal in the following countries:

• Argentina


• Australia


• Austria


• Bahrain


• Belgium


• Brazil


• Bulgaria


• Canada


• Colombia


• Costa Rica


• Cyprus


• Ecuador


• El Salvador


• Ethiopia


• Georgia


• Ghana


• Greece


• Guatemala


• Guyana


• Honduras


• Hong Kong


• India


• Indonesia


• Iraq


• Ireland


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• Italy


• Japan


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• Luxembourg


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International Drug Name Search

Glossary

SPC	Summary of Product Characteristics (UK)

Click for further information on drug naming conventions and International Nonproprietary Names.

Synflorix suspension for injection in pre-filled syringe

1. Name Of The Medicinal Product

Synflorix

Pneumococcal polysaccharide conjugate vaccine (adsorbed)

2. Qualitative And Quantitative Composition

1 dose (0.5 ml) contains:

Pneumococcal polysaccharide serotype 11,2	1 microgram
Pneumococcal polysaccharide serotype 41,2	3 micrograms
Pneumococcal polysaccharide serotype 51,2	1 microgram
Pneumococcal polysaccharide serotype 6B1,2	1 microgram
Pneumococcal polysaccharide serotype 7F1,2	1 microgram
Pneumococcal polysaccharide serotype 9V1,2	1 microgram
Pneumococcal polysaccharide serotype 141,2	1 microgram
Pneumococcal polysaccharide serotype 18C1,3	3 micrograms
Pneumococcal polysaccharide serotype 19F1,4	3 micrograms
Pneumococcal polysaccharide serotype 23F1,2	1 microgram
1 adsorbed on aluminium phosphate	0.5 milligram Al3+
2 conjugated to protein D (derived from non-typeable Haemophilus influenzae) carrier protein	9-16 micrograms
3 conjugated to tetanus toxoid carrier protein	5-10 micrograms
4 conjugated to diphtheria toxoid carrier protein	3-6 micrograms

For the full list of excipients, see section 6.1.

3. Pharmaceutical Form

Suspension for injection (injection).

The vaccine is a turbid white suspension.

4. Clinical Particulars

4.1 Therapeutic Indications

Active immunisation against invasive disease and acute otitis media caused by Streptococcus pneumoniae in infants and children from 6 weeks up to 5 years of age. See sections 4.4 and 5.1 for information on protection against specific pneumococcal serotypes.

The use of Synflorix should be determined on the basis of official recommendations taking into consideration the impact of invasive disease in different age groups as well as the variability of serotype epidemiology in different geographical areas.

4.2 Posology And Method Of Administration

Posology

The immunisation schedules for Synflorix should be based on official recommendations.

Infants from 6 weeks to 6 months of age

Three-dose primary series

The recommended immunisation series to ensure optimal protection consists of four doses, each of 0.5 ml. The primary infant series consists of three doses with the first dose usually given at 2 months of age and with an interval of at least 1 month between doses. The first dose may be given as early as six weeks of age. A booster dose is recommended at least 6 months after the last priming dose and preferably between 12 and 15 months of age. (see sections 4.4 and 5.1)

Two-dose primary series

Alternatively, when Synflorix is given as part of a routine infant immunisation programme, a series consisting of three doses, each of 0.5 ml may be given. The first dose may be administered from the age of 2 months, with a second dose 2 months later. A booster dose is recommended at least 6 months after the last primary dose (see section 5.1).

Infants born between 27-36 weeks gestation

In preterm infants born after at least 27 weeks of gestational age, the recommended immunisation series consists of four doses, each of 0.5ml. The primary infant series consists of three doses with the first dose given at 2 months of age and with an interval of at least 1 month between doses. A booster dose is recommended at least 6 months after the last primary dose (see sections 4.4 and 5.1).

Previously unvaccinated older infants and children

- infants aged 7-11 months: The vaccination schedule consists of two doses of 0.5 ml with an interval of at least 1 month between doses. A third dose is recommended in the second year of life with an interval of at least 2 months between doses.

- children aged 12-23 months: The vaccination schedule consists of two doses of 0.5 ml with an interval of at least 2 months between doses. The need for a booster dose after this immunisation schedule has not been established. (see section 4.4)

- children aged 2– 5 years: The vaccination schedule consists of two doses of 0.5 ml with an interval of at least 2 months between doses.

It is recommended that subjects who receive a first dose of Synflorix complete the full vaccination course with Synflorix.

Paediatric population

The safety and efficacy of Synflorix in children over 5 years of age have not been established.

Method of administration

The vaccine should be given by intramuscular injection. The preferred sites are anterolateral aspect of the thigh in infants or the deltoid muscle of the upper arm in young children.

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1, or to any of the carrier proteins.

As with other vaccines, the administration of Synflorix should be postponed in subjects suffering from acute severe febrile illness. However, the presence of a minor infection, such as a cold, should not result in the deferral of vaccination.

4.4 Special Warnings And Precautions For Use

As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in case of a rare anaphylactic reaction following the administration of the vaccine.

The potential risk of apnoea and the need for respiratory monitoring for 48-72h should be considered when administering the primary immunisation series to very premature infants (born

Synflorix should under no circumstances be administered intravascularly or intradermally. No data are available on subcutaneous administration of Synflorix.

As for other vaccines administered intramuscularly, Synflorix should be given with caution to individuals with thrombocytopenia or any coagulation disorder since bleeding may occur following an intramuscular administration to these subjects.

Official recommendations for the immunisation against diphtheria, tetanus and Haemophilus influenzae type b should also be followed.

There is insufficient evidence that Synflorix provides protection against pneumococcal serotypes not contained in the vaccine or against non-typeable Haemophilus influenzae. Synflorix does not provide protection against other micro-organisms.

As with any vaccine, Synflorix may not protect all vaccinated individuals against invasive pneumococcal disease or otitis media caused by the serotypes in the vaccine. Protection against otitis media caused by pneumococcal serotypes in the vaccine is expected to be substantially lower than protection against invasive disease. In addition, as otitis media is caused by many micro-organisms other than the Streptococcus pneumoniae serotypes represented in the vaccine, the overall protection against otitis media is expected to be limited (see section 5.1)

In clinical trials Synflorix elicited an immune response to all ten serotypes included in the vaccine, but the magnitude of the responses varied between serotypes. The functional immune response to serotypes 1 and 5 was lower in magnitude than the response against all other vaccine serotypes. It is not known whether this lower functional immune response against serotypes 1 and 5 will result in lower protective efficacy against invasive disease or otitis media caused by these serotypes (see section 5.1).

Synflorix is indicated for use in children aged from 6 weeks up to 5 years. Children should receive the dose regimen of Synflorix that is appropriate to their age at the time of commencing the vaccination series (see section 4.2). Safety and immunogenicity data are not yet available in children above 5 years of age.

Children with impaired immune responsiveness, whether due to the use of immunosuppressive therapy, a genetic defect, HIV infection, or other causes, may have reduced antibody response to vaccination.

Safety and immunogenicity data in children with increased risk for pneumococcal infections (e.g. sickle cell disease, congenital and acquired splenic dysfunction, HIV-infected, malignancy, nephrotic syndrome) are not yet available for Synflorix. Vaccination in high-risk groups should be considered on an individual basis (see section 4.2).

The immune response elicited after two doses of Synflorix in children 12-23 months of age is comparable to the response elicited after three doses in infants (see section 5.1). The immune response to a booster dose after two doses in children aged 12-23 months has not been evaluated, but a booster dose may be needed to ensure optimal individual protection.

However, a 2-dose schedule in children aged 12-23 months with high risk of pneumococcal disease (such as children with sickle-cell disease, asplenia, HIV infection, chronic illness or who are immunocompromised) may not be sufficient to provide optimal protection. In these children, a 23-valent pneumococcal polysaccharide vaccine should be given

Prophylactic administration of antipyretics before or immediately after vaccine administration can reduce the incidence and intensity of post-vaccination febrile reactions. However, data suggest that the prophylactic use of paracetamol might reduce the immune response to Synflorix. The clinical relevance of this observation, as well as the impact of antipyretics other than paracetamol on the immune response to Synflorix remains unknown.

The use of prophylactic antipyretic medicinal products is recommended:

- for all children receiving Synflorix simultaneously with vaccines containing whole cell pertussis because of higher rate of febrile reactions (see section 4.8).

- for children with seizure disorders or with a prior history of febrile seizures.

Antipyretic treatment should be initiated according to local treatment guidelines.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Use with other vaccines

Synflorix can be given concomitantly with any of the following monovalent or combination vaccines [including DTPa-HBV-IPV/Hib and DTPw-HBV/Hib]: diphtheria-tetanus-acellular pertussis vaccine (DTPa), hepatitis B vaccine (HBV), inactivated polio vaccine (IPV), Haemophilus influenzae type b vaccine (Hib), diphtheria-tetanus-whole cell pertussis vaccine (DTPw), measles-mumps-rubella vaccine (MMR), varicella vaccine (V), meningococcal serogroup C conjugate vaccine (CRM₁₉₇ and TT conjugates), oral polio vaccine (OPV) and oral rotavirus vaccine. Different injectable vaccines should always be given at different injection sites.

Clinical studies demonstrated that the immune responses and the safety profiles of the co-administered vaccines were unaffected, with the exception of the inactivated poliovirus type 2 response, for which inconsistent results were observed across studies (seroprotection ranging from 78% to 100%). The clinical relevance of this observation is not known. No negative interference was observed with meningococcal conjugate vaccines irrespective of the carrier protein (CRM₁₉₇ and TT conjugates). Enhancement of antibody response to Hib-TT conjugate, diphtheria and tetanus antigens was observed.

Use with systemic immunosuppressive medicinal products

As with other vaccines, it may be expected that in patients receiving immunosuppressive treatment an adequate response may not be elicited.

Use with prophylactic administration of antipyretics

See section 4.4.

4.6 Pregnancy And Lactation

Synflorix is not intended for use in adults. Human data on the use during pregnancy or lactation and animal reproduction studies are not available.

4.7 Effects On Ability To Drive And Use Machines

Not relevant.

4.8 Undesirable Effects

Summary of safety profile

Clinical trials involved the administration of 12,879 doses of Synflorix to 4,595 healthy children and 137 preterm infants as primary vaccination. Furthermore, 3,870 children and 116 preterm infants received a booster dose of Synflorix in the second year of life.

Safety was also assessed in 212 previously unvaccinated children from 2 to 5 years old of which 62 subjects received 2 doses of Synflorix.

In all trials, Synflorix was administered concurrently with the recommended childhood vaccines.

In infants, the most common adverse reactions observed after primary vaccination were redness at the injection site and irritability which occurred after 38.3% and 52.3% of all doses respectively. Following booster vaccination, these adverse reactions occurred at 52.6% and 55.4% respectively. The majority of these reactions were of mild to moderate severity and were not long lasting.

No increase in the incidence or severity of the adverse reactions was seen with subsequent doses of the primary vaccination series.

Reactogenicity was similar in infants < 12 months of age and in children > 12 months of age except for injection site pain for which the incidence increased with increasing age: pain was reported by more than 31% of the infants < 12 months of age and by more than 60% of the children > 12 months of age.

Reactogenicity was higher in children receiving whole cell pertussis vaccines concomitantly. In a clinical study children received either Synflorix (N=603) or 7-valent Prevenar (N=203) concomitantly with a DTPw containing vaccine. After the primary vaccination course, fever

In comparative clinical studies, the incidence of local and general adverse events reported within 4 days after each vaccination dose was within the same range as after vaccination with 7-valent Prevenar.

List of adverse reactions

Adverse reactions (for all age groups) considered as being at least possibly related to vaccination have been categorised by frequency.

Frequencies are reported as:

Very common:	(
Common:	(
Uncommon:	(
Rare:	(

Clinical trial data

Immune system disorders

Rare: allergic reactions (such as allergic dermatitis, atopic dermatitis, eczema)

Metabolism and nutrition disorders

Very common: appetite lost

Psychiatric disorders

Very common: irritability

Uncommon: crying abnormal

Nervous system disorders

Very common: drowsiness

Rare: febrile and non-febrile convulsions

Respiratory, thoracic and mediastinal disorders

Uncommon: apnoea in very premature infants (

Gastrointestinal disorders

Uncommon: diarrhoea, vomiting

Skin and subcutaneous tissue disorders

Rare: rash, urticaria

General disorders and administration site conditions

Very common: pain, redness, swelling at the injection site, fever

Common: injection site induration, fever >39°C rectally (age<2 years), fever

Uncommon: injection site haematoma, haemorrhage and nodule, fever >40°C rectally* (age<2 years), fever >39°C (age 2 to 5 years)

*reported following booster vaccination of primary series

Post-marketing data

Nervous system disorders:

Rare: hypotonic-hyporesponsive episode

4.9 Overdose

No case of overdose has been reported.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: pneumococcal vaccines, ATC code: J07AL52

Epidemiological data

The 10 pneumococcal serotypes included in this vaccine represent the major disease-causing serotypes in Europe covering approximately 56% to 90% of invasive pneumococcal disease (IPD) in children <5 years of age. In this age group, serotypes 1, 5 and 7F account for 3.3% to 24.1% of IPD depending on the country and time period studied.

Acute otitis media (AOM) is a common childhood disease with different aetiologies. Bacteria can be responsible for 60-70% of clinical episodes of AOM. Streptococcus pneumoniae and Non-Typeable Haemophilus influenzae (NTHi) are the most common causes of bacterial AOM worldwide.

1. Invasive pneumococcal disease (which includes sepsis, meningitis, bacteraemic pneumonia and bacteraemia)

The protective efficacy of Synflorix against IPD has not been studied. As recommended by WHO, the assessment of potential efficacy against IPD has been based on a comparison of immune responses to the seven serotypes shared between Synflorix and another pneumococcal conjugate vaccine for which protective efficacy was evaluated previously (i.e. 7-valent Prevenar). Immune responses to the extra three serotypes in Synflorix have also been measured.

In a head-to-head comparative trial with 7-valent Prevenar, non inferiority of the immune response to Synflorix measured by ELISA was demonstrated for all serotypes, except for 6B and 23F (upper limit of the 96.5% CI around the difference between groups >10%) (Table 1). For serotypes 6B and 23F, respectively, 65.9% and 81.4% of infants vaccinated at 2, 3 and 4 months reached the antibody threshold (i.e. 0.20 µg/ml) one month after the third dose of Synflorix versus 79.0% and 94.1% respectively, after three doses of 7-valent Prevenar. The clinical relevance of these differences is not known.

The percentage of vaccinees reaching the threshold for the three additional serotypes in Synflorix (1, 5 and 7F) was respectively 97.3%, 99.0% and 99.5% and was at least as good as the aggregate 7-valent Prevenar response against the 7 common serotypes (95.8%).

Table 1: Comparative analysis between 7-valent Prevenar and Synflorix in percentage of subjects with antibody concentrations > 0.20 µg/ml one month post-dose 3

Antibody	SYNFLORIX	7-valent Prevenar	Difference in %
N	%	N	%	%	96.5%CI
Anti-4	1106	97.1	373	100	2.89	1.71	4.16
Anti-6B	1100	65.9	372	79.0	13.12	7.53	18.28
Anti-9V	1103	98.1	374	99.5	1.37	-0.28	2.56
Anti-14	1100	99.5	374	99.5	-0.08	-1.66	0.71
Anti-18C	1102	96.0	374	98.9	2.92	0.88	4.57
Anti-19F	1104	95.4	375	99.2	3.83	1.87	5.50
Anti-23F	1102	81.4	374	94.1	12.72	8.89	16.13

Post-primary antibody geometric mean concentrations (GMCs) elicited by Synflorix against the seven serotypes in common were lower than those elicited by 7-valent Prevenar. Pre-booster GMCs (8 to 12 months after the last primary dose) were generally similar for the two vaccines. After the booster dose the GMCs elicited by Synflorix were lower for most serotypes in common with 7-valent Prevenar.

In the same study, Synflorix was shown to elicit functional antibodies to all vaccine serotypes. For each of the seven serotypes in common, 87.7% to 100% of Synflorix vaccinees and 92.1% to 100% of 7-valent Prevenar vaccinees reached an OPA titre

For serotypes 1, 5 and 7F, the percentages of Synflorix vaccinees reaching an OPA titre

The administration of a fourth dose (booster dose) in the second year of life elicited an anamnestic antibody response as measured by ELISA and OPA for the 10 serotypes included in the vaccine demonstrating the induction of immune memory after the three-dose primary course.

2. Acute Otitis Media (AOM)

In a large randomised double-blind Pneumococcal Otitis Media Efficacy Trial (POET) conducted in the Czech Republic and in Slovakia, 4,968 infants received an 11-valent investigational vaccine (11Pn-PD) containing the 10 serotypes of Synflorix (along with serotype 3 for which efficacy was not demonstrated) or a control vaccine (hepatitis A vaccine) according to a 3, 4, 5 and 12-15 months vaccination schedule.

Efficacy of the 11 Pn-PD vaccine against the first occurrence of vaccine-serotype AOM episode was 52.6% (95% CI: 35.0;65.5). Serotype specific efficacy against the first AOM episode was demonstrated for serotypes 6B (86.5%, 95%CI: 54.9;96.0), 14 (94.8%, 95% CI: 61.0;99.3), 19F (43.3%, 95% CI:6.3;65.4) and 23F (70.8%, 95% CI: 20.8;89.2). For other vaccine serotypes, the number of AOM cases was too limited to allow any efficacy conclusion to be drawn. Efficacy against any AOM episode due to any pneumococcal serotype was 51.5% (95% CI: 36.8;62.9). No increase in the incidence of AOM due to other bacterial pathogens or non-vaccine serotypes was observed in this study. The estimated vaccine efficacy against any clinical episodes of otitis media regardless of aetiology was 33.6% (95% CI: 20.8; 44.3).

Based on immunological bridging of the functional vaccine response (OPA) of Synflorix with the 11-valent formulation used within POET, it is expected that Synflorix provides similar protective efficacy against pneumococcal AOM.

3. Additional immunogenicity data

Infants from 6 weeks to 6 months of age

3-dose primary schedule

In total eight studies, conducted in various countries across Europe, in Chile and in the Philippines, have evaluated the immunogenicity of Synflorix after a three-dose primary series (N=3,089) according to different vaccination schedules (6-10-14 weeks, 2-3-4, 3-4-5 or 2-4-6 months of age). A fourth (booster) dose was given in six clinical studies to 1,976 subjects. In general, comparable vaccine responses were observed for the different schedules, although somewhat higher immune responses were noted for the 2-4-6 month schedule.

2-dose primary schedule

The immunogenicity of Synflorix following a 2-dose primary vaccination schedule in subjects less than 6 months of age was evaluated in two clinical studies.

In the first study, in a post-hoc analysis, the immunogenicity two months after the second dose of Synflorix was compared with 7-valent Prevenar and the percentages of subjects with ELISA antibody concentration

In the second study, the immunogenicity after two or three doses of Synflorix was compared. Although there was no significant difference between the two groups in the percentages of subjects with antibody concentration

Table 2: Percentage of 2-dose primed subjects with antibody concentrations

Antibody
Post-primary	Post-booster
%	95% CI	%	95%CI
Anti-1	97.4	93.4	99.3	99.4	96.5	100
Anti-4	98.0	94.4	99.6	100	97.6	100
Anti-5	96.1	91.6	98.5	100	97.6	100
Anti-6B	55.7	47.3	63.8	88.5	82.4	93.0
Anti-7F	96.7	92.5	98.9	100	97.7	100
Anti-9V	93.4	88.2	96.8	99.4	96.5	100
Anti-14	96.1	91.6	98.5	99.4	96.5	100
Anti-18C	96.1	91.6	98.5	100	97.7	100
Anti-19F	92.8	87.4	96.3	96.2	91.8	98.6
Anti-23F	69.3	61.3	76.5	96.1	91.7	98.6

Table 3: Percentage of 3-dose primed subjects with antibody concentrations

Antibody
Post-primary	Post-booster
%	95% CI	%	95%CI
Anti-1	98.7	95.3	99.8	100	97.5	100
Anti-4	99.3	96.4	100	100	97.5	100
Anti-5	100	97.6	100	100	97.5	100
Anti-6B	63.1	54.8	70.8	96.6	92.2	98.9
Anti-7F	99.3	96.4	100	100	97.5	100
Anti-9V	99.3	96.4	100	100	97.5	100
Anti-14	100	97.6	100	98.6	95.2	99.8
Anti-18C	99.3	96.4	100	99.3	96.3	100
Anti-19F	96.1	91.6	98.5	98.0	94.2	99.6
Anti-23F	77.6	70.2	84.0	95.9	91.3	98.5

In the follow-up of the second study, the persistence of antibodies at 36-46 months of age was demonstrated in subjects that had received a 2-dose primary series followed by a booster dose with at least 83.7% of subjects remaining seropositive for vaccine serotypes. In subjects that had received a 3-dose primary series followed by a booster dose, at least 96.5% of the subjects remained seropositive for vaccine serotypes. A single dose of Synflorix, administered during the 4th year of life, as a challenge dose, elicited similar ELISA antibody GMCs when measured 7-10 days after challenge in 2-dose primed subjects and 3-dose primed subjects. These levels were higher than those seen after challenge of unprimed subjects. The fold increase in ELISA antibody GMCs and OPA GMTs, pre to post vaccination, was also similar in 2-dose primed subjects to that in 3-dose primed subjects. These results are indicative of immunological memory in primed subjects for all vaccine serotypes.

The clinical consequences of the lower post-primary and post-booster immune responses observed after the two-dose primary schedule are not known.

Previously unvaccinated older infants and children

The immune responses in previously unvaccinated older children were evaluated in two clinical studies.