Plavix

Generic Name: Clopidogrel Bisulfate
Class: Platelet-Aggregation Inhibitors
ATC Class: B01AC04

• 
  

  Clopidogrel is a prodrug; requires activation by CYP enzyme system (principally by CYP2C19) to produce its pharmacologically active metabolite.^{1 2 6 8 11 121}

  
  


• 
  

  Genetic variations of CYP2C19 can result in impaired metabolism and reduced effectiveness of clopidogrel.^{1 121} (See Reduced Efficacy Associated with Impaired CYP2C19 Function under Cautions.) Higher rates of major adverse cardiovascular events (e.g., death, MI, stroke) have been reported in poor metabolizers of CYP2C19 receiving clopidogrel at recommended dosages following acute coronary syndrome or PCI compared with those who have normal CYP2C19 function.^{1 121}

  
  


• 
  

  Genetic tests are available to determine a patient's CYP2C19 genotype; results of such tests may be used to guide treatment decisions.^{1 20 121 122}

  
  


• 
  

  Consider use of other antiplatelet agents or alternative dosing strategies for clopidogrel in patients with variant CYP2C19 genotypes.^{1 121}

  
  

REMS:

FDA approved a REMS for clopidogrel to ensure that the benefits of a drug outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Platelet-aggregation inhibitor; thienopyridine derivative.¹

Uses for Plavix

Cardiovascular Risk Reduction Following Recent Myocardial Infarction or Stroke or in Established Peripheral Arterial Disease

Reduction of the risk of cardiovascular or cerebrovascular events (new MI, new ischemic stroke, and vascular death) in patients with a history of recent MI, recent ischemic stroke, or established peripheral arterial disease.^{1 2 6 8 15 23 25 27} Recommended as an alternative to aspirin in those with aspirin allergy.^{10 14 17 21 25 26 28 30}

Clopidogrel monotherapy or aspirin in combination with dipyridamole may be preferable to aspirin monotherapy for secondary prevention of stroke based on a somewhat greater absolute risk reduction for stroke; weigh benefit against additional costs of therapy.^{25 63}

In patients with peripheral arterial disease, clopidogrel recommended over ticlopidine or no antiplatelet therapy for prevention of death and disability from stroke or MI.²⁹

In children who have recurrent arterial ischemic strokes or TIAs despite aspirin therapy, ACCP suggests changing from aspirin therapy to clopidogrel or an anticoagulant, such as a low molecular weight heparin or warfarin.⁶³

Use of aspirin rather than clopidogrel for most patients requiring long-term antiplatelet therapy is suggested by many clinicians because of lower cost and modest additional benefit of clopidogrel over aspirin.^{5 8 10 20 23 29 66 71}

Acute Coronary Syndromes: Unstable Angina or Non-ST-Segment Elevation MI

Used in combination with aspirin for reduction of the risk of cardiovascular or cerebrovascular events in patients with non-ST-segment elevation (NSTE) acute coronary syndromes (NSTE ACS), including unstable angina and non-ST-segment-elevation MI (NSTEMI).^{1 5 10 14 17 18 21 26 28 30 34 35 39 64 65 66} Used in patients who are managed medically or with coronary intervention (e.g., PCI with or without coronary artery stenting, CABG).^{1 5 10 18 21 26 28 30 34 35 39 40}

Long-term use recommended by ACCP as an alternative to aspirin in patients with unstable angina or NSTEMI, including those undergoing CABG, who are allergic to aspirin†.^{10 14 17 26 28 30}

Recommended by ACC/AHA and other clinicians as an adjunct to acute therapy with heparin and aspirin in patients with NSTE ACS who are managed medically and in those undergoing PCI who are not at high risk for bleeding.^{18 21 34 39}

Dual-drug antiplatelet therapy (aspirin plus clopidogrel or prasugrel) recommended by ACC/AHA for patients with definite or likely NSTEMI in whom an invasive approach is selected.¹³⁴ Begin treatment as early as possible before or at the time of PCI and continue for ≥1 month, ideally ≤1 year in patients who are not at high risk for bleeding.¹³⁴

Balance potential benefit of pretreatment with clopidogrel in patients undergoing PCI against increased risk of bleeding should emergency CABG be needed.^{28 34 35} Temporarily discontinue therapy 5–10 days prior to CABG and reinitiate therapy in conjunction with aspirin after the procedure.^{26 30 35 40 66 69}

In patients undergoing PCI with an absolute contraindication to aspirin†, ACCP states that pretreatment with clopidogrel and/or a GP IIb/IIIa-receptor inhibitor is reasonable.⁶⁴ (See General under Dosage and Administration.)

Following implantation of a bare-metal coronary artery stent in patients at low risk for bleeding, ACC/AHA currently recommend use in combination with aspirin for ≥1 month, ideally for ≤12 months.¹³⁴

In patients at low atherosclerotic risk, ACCP recommends combination therapy with aspirin for ≥2 weeks after implantation of a bare-metal stent.²⁸

Following bare-metal stent placement in patients at high risk for bleeding, ACC/AHA recommend short-term (a minimum of 2 weeks) therapy with clopidogrel and aspirin.¹³⁴

Prolonged dual-drug therapy (≥12 months) with clopidogrel and aspirin recommended in patients with drug-eluting stents (DES) who are not at high risk of bleeding.^{43 44 45 46 50 51 52 54 134} (See Compliance with Therapy in Patients with Drug-eluting Stents under Cautions.)

Acute Coronary Syndromes: ST-Segment Elevation MI

Used in combination with aspirin for reduction of the rate of ischemic cardiovascular and cerebrovascular events in patients with ST-segment elevation MI (STEMI).^{1 10 27 31 36 67 134} Net benefits of a particular thienopyridine (clopidogrel or prasugrel) in patients with STEMI undergoing PCI not fully elucidated; ACC/AHA state that choice of clopidogrel or prasugrel in individual patients should take into account antithrombotic efficacy, bleeding risk, and clinician experience with a given drug.¹³⁴

Recommended by ACCP, ACC, AHA, and other clinicians for 14–28 days in addition to aspirin, with or without reperfusion therapy (i.e., thrombolytic therapy, primary PCI), in patients with suspected acute STEMI.^{67 68} ACCP suggests continuance of clopidogrel and aspirin beyond 28 days and up to 1 year in patients with STEMI who have not undergone stent implantation.⁶⁷

In patients in whom CABG is planned, withhold clopidogrel for at least 5 days and preferably for 7–10 days prior to surgery unless urgency of revascularization outweighs risks of excess bleeding.^{69 134}

Suggested as adjunct to thrombolytic therapy in patients with acute STEMI who are allergic to aspirin or in whom aspirin is otherwise contraindicated.^{10 23 27}

In patients with STEMI in whom PCI is planned, ACC/AHA and ACCP recommend pretreatment with a loading dose of a thienopyridine derivative (e.g., clopidogrel, prasugrel) before or at the time of PCI in conjunction with aspirin therapy.^{67 134}

Recommended by ACC/AHA in combination with aspirin as short-term prophylaxis (≥ 1 month) in patients with STEMI who have undergone PCI with bare-metal coronary artery stent implantation.^{39 134}

Ideally, use long term (≥12 months) in conjunction with aspirin therapy in patients with STEMI who have undergone PCI with bare-metal stent implantation and are at low risk of bleeding.¹³⁴

Recommended as short-term (minimum of 2 weeks) therapy with aspirin in patients with STEMI who have undergone PCI with bare-metal stent implantation and are at high risk of bleeding.¹³⁴

Prolonged (≥12 months) prophylaxis in combination with aspirin strongly recommended in patients who have undergone PCI with DES implantation and are not at high risk of bleeding.^{43 44 45 46 50 51 52 54 134} (See Compliance with Therapy in Patients with Drug-eluting Stents under Cautions.) Consider continuation of thienopyridine therapy beyond 15 months in patients with drug-eluting stents; may use abbreviated period of thienopyridine therapy (less than 12 months) in patients with STEMI and a drug-eluting stent in whom the risk of morbidity due to bleeding outweighs the anticipated benefit of such therapy.¹³⁴

Triple antithrombotic therapy with clopidogrel, low-dose aspirin, and warfarin anticoagulation† (target INR 2–2.5) recommended, based on case studies or expert opinion, in patients who have indications for anticoagulation (e.g., atrial fibrillation, left ventricular dysfunction, cerebral emboli, extensive wall-motion abnormality, mechanical heart valves) and who require clopidogrel and aspirin after PCI.^{23 42 65} In patients who have undergone stent placement and have indications for anticoagulation, warfarin (INR 2–3) and aspirin suggested in addition to clopidogrel;^{23 42 66} continue clopidogrel therapy for 4 weeks or 1 year following bare-metal or drug-eluting stent implantation, respectively, in addition to warfarin and aspirin.⁶⁶ Such triple antithrombotic regimens are associated with an increased risk of bleeding; monitor closely.^{65 70}

Suggested by American Diabetes Association (ADA) as alternative to aspirin for primary prevention of MI† in aspirin-allergic patients with type 1 or type 2 diabetes mellitus who are at high risk for cardiovascular events (i.e., family history of CHD, smoking, hypertension, obesity, albuminuria, and elevated blood cholesterol or triglyceride concentrations).⁹⁵ Recommended by ACCP for primary prevention of cardiovascular events as an alternative to aspirin for aspirin-allergic patients who are at moderate to high risk for cardiovascular events.⁶⁶

Chronic Stable Angina

Use in combination with aspirin suggested by ACCP for reduction of the risk of AMI in high-risk patients with symptomatic chronic stable angina†.²⁶

Used as an alternative to aspirin in patients with symptomatic chronic stable angina who cannot tolerate aspirin†.⁹⁶

Other Uses

Aspirin generally recommended for all clinical conditions in which antiplatelet prophylaxis has a favorable benefit-to-risk profile.^{5 8 10 11} However, use recommended by ACCP as alternative and/or adjunctive antithrombotic therapy in selected patients with a number of atherosclerotic and ischemic conditions,^{13 14 15 16 17} including rheumatic mitral valve disease† ^{13 24} and saphenous vein CABG†.^{14 26 30 40}

Use in combination with aspirin in patients undergoing brachytherapy for restenosis following PCI and coronary artery stent implantation† suggested by ACC/AHA.³⁴

Considered a reasonable choice for antiplatelet therapy in high-risk patients with prosthetic heart valves in whom aspirin cannot be used† or in patients with prosthetic heart valves receiving aspirin who have breakthrough embolic events†.⁴¹

Plavix Dosage and Administration

General

Timing of Treatment in Relation to PCI or CABG

• 
  

  In patients with ACS in whom PCI is planned, ACC/AHA recommend administration of a loading dose of clopidogrel as early as possible before or at the time of the procedure.¹³⁴

  
  


• 
  

  Temporarily discontinue therapy 5–10 days prior to CABG and reinitiate clopidogrel in conjunction with aspirin after the procedure.^{26 30 35 40 69 134}

  
  

Administration

Administer orally without regard to meals.^{1 6 8}

Dosage

Available as clopidogrel bisulfate; dosage expressed in terms of clopidogrel.¹

Pharmacogenomic factors can influence response to clopidogrel; although a higher dosage or administration of additional loading doses may increase the antiplatelet response in patients who are poor metabolizers, manufacturer states that an appropriate dosage of the drug in such patients has not been determined.^{1 121 123 130} (See Reduced Efficacy Associated with Impaired CYP2C19 Function under Cautions.)

Adults

Cardiovascular Risk Reduction Following Recent MI or Stroke or in Established Peripheral Arterial Disease

Oral

75 mg once daily.^{1 2 3 5 6 8 23 25 26}

Acute Coronary Syndromes

Unstable Angina or Non-ST-Segment Elevation MI

Oral

300-mg initial loading dose promptly at diagnosis, then 75 mg daily given with aspirin daily for ≥1 month, ideally for ≤1 year in patients at low risk of bleeding.^{1 17 18 20 21 22 26 34 39 64 66}

Most patients generally have received concomitant heparin acutely.^{1 18}

Patients allergic to or intolerant of aspirin†: 300-mg loading dose, then 75 mg daily continued indefinitely.^{10 14 17 21 26 28 30 64}

Planned PCI: 300–600 mg as loading dose as early as possible prior to or at time of the procedure with aspirin, then 75 mg once daily for ≤1 year in patients at low risk of bleeding.^{64 66 134} Larger loading doses (e.g., ≥900 mg) used to achieve higher level of antiplatelet activity more rapidly, but efficacy and safety not established.^{64 134}

Planned PCI in patients unable to tolerate aspirin†: 600-mg loading dose ≥24 hours prior to procedure, followed by 75 mg once daily.⁶⁴

Patients undergoing CABG: 75 mg once daily with aspirin, beginning postoperatively and continuing for 9–12 months.⁶⁶

Patients undergoing CABG who are allergic to aspirin: ACCP recommends initiation of a 300-mg loading dose of clopidogrel 6 hours after the procedure, followed by 75 mg once daily, continued indefinitely.⁶⁶

Following bare-metal stent implantation: 75 mg once daily with aspirin for ≥1 month.¹³⁴ Ideally, continue for ≤12 months in conjunction with daily aspirin therapy in patients at low risk for bleeding.¹³⁴ In patients in whom a high risk of bleeding is deemed to outweigh anticipated benefit, administer clopidogrel with aspirin for a minimum of 2 weeks.¹³⁴

Following drug-eluting stent (DES) implantation: 75 mg once daily with aspirin for ≥12 months in patients not at high risk for bleeding.^{43 44 45 46 50 51 52 54 66 134} (See Compliance with Therapy in Patients with Drug-eluting Stents under Cautions.)

ST-Segment Elevation MI

Oral

Usual recommended dosage: 75 mg once daily with or without a loading dose in combination with aspirin.^{1 39 67 134} ACCP recommends a clopidogrel loading dose of 300 mg in patients ≤75 years of age;⁶⁷ loading dose for patients >75 years of age not established.¹³⁴

ACC/AHA state that clopidogrel should be continued as the thienopyridine of choice in patients with STEMI who will undergo PCI and have already received clopidogrel and thrombolytic therapy.¹³⁴

Patients with STEMI who have received any thrombolytic agent (fibrin-specific or not) and in whom PCI is planned within 24 hours: ACC/AHA recommend a clopidogrel loading dose of 300 mg.¹³⁴

Patients with STEMI receiving a non-fibrin-specific thrombolytic agent who will undergo PCI within 24–48 hours: ACC/AHA recommend a clopidogrel 300-mg loading dose.¹³⁴

Patients with STEMI who have received a fibrin-specific thrombolytic agent and will undergo PCI >24 hours later: ACC/AHA recommend a clopidogrel loading dose of 300–600 mg.¹³⁴

Patients with STEMI who have received a non-fibrin-specific thrombolytic agent and will be undergoing PCI >48 hours later: ACC/AHA recommend a clopidogrel loading dose of 300–600 mg.¹³⁴

Patients with STEMI who have not received thrombolytic or thienopyridine therapy and who will undergo nonprimary PCI: ACC/AHA recommend a clopidogrel loading dose of 300–600 mg.¹³⁴

Patients allergic to or intolerant of aspirin†: 75 mg of clopidogrel once daily indefinitely as an adjunct to thrombolytic therapy.⁶⁶

Planned PCI: ACC/AHA recommend a loading dose of 300–600 mg as early as possible before or at the time of PCI in conjunction with aspirin therapy.¹³⁴ Larger loading doses (e.g., ≥900 mg) have been used to achieve higher level of antiplatelet activity more rapidly, but efficacy and safety not established.^{67 134}

Following bare-metal stent implantation: 75 mg once daily with aspirin for ≥1 month.^{66 134} Ideally, continue for ≤12 months in conjunction with daily aspirin therapy in patients at low risk for bleeding.^{66 134} In patients at high risk for bleeding, administer clopidogrel and aspirin for a minimum of 2 weeks.¹³⁴

Following DES implantation: 75 mg once daily with aspirin for ≤1 month.^{66 134} Continue for ≥12 months with aspirin in patients not at high risk for bleeding.^{28 43 44 45 46 50 51 52 54 66 134}

Special Populations

Geriatric Patients

No dosage adjustment necessary.¹

Hepatic Impairment

No dosage adjustment necessary.¹

Cautions for Plavix

Contraindications

• 
  

  Active pathological bleeding (e.g., peptic ulcer, intracranial hemorrhage).^{1 6}

  
  


• 
  

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

  
  

Warnings/Precautions

Warnings

Compliance with Therapy in Patients with Drug-eluting Stents

Stent thrombosis with potentially fatal sequelae, particularly with DES, associated with premature discontinuance of therapy with a thienopyridine derivative and aspirin.^{43 44 45 46 47 48 49 54} (See Acute Coronary Syndromes: Unstable Angina or Non-ST-Segment Elevation MI under Uses.)

Before implantation of a DES, carefully assess patients for likelihood of compliance with prolonged dual-drug antiplatelet therapy.^{45 59} Consider avoiding use of a DES in patients who are not expected to comply.^{45 59} (See Advice to Patients.) In patients who are likely to require invasive or surgical procedures ≤12 months after DES implantation, consider implantation of a bare-metal stent or use of balloon angioplasty with provisional stent implantation instead.⁴⁵

Clinicians performing invasive procedures must understand the consequences of premature discontinuance of thienopyridine derivative therapy in patients with DES.⁴⁵ If issues about a patient’s antiplatelet therapy are unclear (e.g., concern about periprocedural bleeding), such professionals should contact the patient’s cardiologist.⁴⁵ Defer elective procedures with substantial bleeding risk until completion of dual-drug antiplatelet therapy.⁴⁵ For non-elective procedures that mandate discontinuance of thienopyridine-derivative therapy, continue aspirin therapy if at all possible.⁴⁵ Restart thienopyridine therapy as soon as possible after the procedure.⁴⁵

Reduced Efficacy Associated with Impaired CYP2C19 Function

Possible reduced efficacy of clopidogrel (i.e., increased risk of cardiovascular events) due to genetic polymorphism of CYP2C19 or concurrent use of drugs (e.g., omeprazole) that inhibit CYP2C19.^{1 72 76 78 79 80 81 82 83 84 85 86 100 101 121} Consider use of other antiplatelet agents or alternative dosing strategies for clopidogrel in patients with variant CYP2C19 genotypes.^{1 121 123} (See Boxed Warning.)

Specific variant alleles of CYP2C19 (e.g., CYP2C19*2, CYP2C19*3) associated with reduced metabolism of and diminished antiplatelet response to clopidogrel; data on clinical outcomes are conflicting, but higher rates of major adverse cardiovascular events (e.g., death, MI, stroke, stent thrombosis) reported in patients receiving recommended dosages of clopidogrel who possess such alleles.^{1 76 78 79 80 82 83 88 89 90 92 104 117 118 121} (See Actions.) Genetic tests (e.g., Plavitest) are available to identify patients with variant CYP2C19 genotypes.^{1 20 121 122} While such tests are appropriate for any patient currently receiving or considering treatment with clopidogrel, the need for pharmacogenetic testing should be determined individually.^{121 122 123} Genetic variants of other CYP isoenzymes (e.g., CYP2C19*17, CYP2B6) also may affect response to clopidogrel.^{1 78 123 131} Role of either pharmacogenomic testing or platelet function testing in managing therapy with thienopyridines and proton-pump inhibitors not established.¹³⁶

Concurrent use of clopidogrel and omeprazole, a potent inhibitor of CYP2C19, also shown to reduce antiplatelet effects of clopidogrel.^{1 72 79 84 88 89 98 100 101 102 103 109} (See Proton-Pump Inhibitors under Interactions.) Clinical importance not fully elucidated, but reduced effectiveness in preventing cardiovascular events possible.^{1 73 74 81 89 91 92 98 100 101 102 103 115} Concomitant use of other drugs that inhibit CYP2C19 also may decrease response to clopidogrel.^{1 100 101} (See Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes under Interactions.) Avoid concomitant therapy with known inhibitors of CYP2C19 activity.^{1 20 101}

Thrombotic Thrombocytopenic Purpura (TTP)

Rarely reported, sometimes after short exposure (<2 weeks) to the drug.^{1 11 12} Potentially fatal; requires urgent treatment, including plasmapheresis.¹

General Precautions

Bleeding

Increased risk of bleeding.^{1 136 138}

Discontinue clopidogrel 5–10 days prior to elective surgery if antiplatelet effect is undesirable.^{1 23 43 68 69}

May restore hemostasis with exogenous administration of platelets; however, platelet transfusions within 4 hours of a loading dose or within 2 hours of a maintenance dose may have reduced effectiveness.¹

Bleeding is unlikely to be resolved or prevented by withholding a dose of clopidogrel because of the drug's prolonged inhibitory effects on platelet function.¹

American College of Cardiology Foundation/American College of Gastroenterology/American Heart Association (ACCF/ACG/AHA) recommends prophylactic proton-pump inhibitor therapy to reduce risk of ulcer complications and GI bleeding in patients with additional GI risk factors receiving clopidogrel and aspirin.^{81 87 89 136} However, consider possibility of reduced antiplatelet effects when clopidogrel is used concomitantly with a proton-pump inhibitor (e.g., omeprazole).^{1 76 100 101} (See Interactions: Proton-Pump Inhibitors.)

Risks of Interruption or Discontinuance of Therapy

In general, treatment with a thienopyridine derivative should not be discontinued prematurely because of the increased risk of cardiovascular events.¹ (See Compliance with Therapy in Patients with Drug-eluting Stents under Cautions.)

Advise patient to never stop clopidogrel therapy without first consulting prescribing clinician.^{1 45}

If temporary discontinuance is necessary (e.g., prior to surgery), reinitate therapy as soon as possible.¹ (See Advice to Patients.)

Specific Populations

Pregnancy

Category B.¹

Lactation

Distributed into milk in rats; not known whether distributed into human milk.¹ Discontinue nursing or the drug.¹

Pediatric Use

Manufacturer states that safety and efficacy not established in patients <21 years of age.^{1 20}

In neonates and infants† up to 24 months of age with systemic to pulmonary artery shunts or other cardiac conditions predisposing to thrombosis, clopidogrel 0.2 mg/kg daily for 1–4 weeks achieved similar inhibition of platelet aggregation as a 75-mg daily dosage in adults; no serious hemorrhagic events reported.⁹⁷

Geriatric Use

In patients ≥75 years of age, no difference in platelet aggregation observed compared with younger healthy individuals.¹ In a clinical trial, geriatric patients were at greater risk for thrombotic events and major bleeding than younger patients.¹

Hepatic Impairment

Inhibition of ADP-induced platelet aggregation in patients with severe hepatic impairment appears to be similar to that observed in healthy individuals.¹

Renal Impairment

Experience limited in patients with moderate or severe renal impairment.¹

Inhibition of ADP-induced platelet aggregation is decreased in patients with moderate (Cl_cr 30–60 mL/minute) or severe (Cl_cr 5–15 mL/minute) renal impairment.¹

Common Adverse Effects

Chest pain,^{1 6} accidental injury,^{1 6} influenza-like symptoms,^{1 6} pain,^{1 6} headache,^{1 6} dizziness,^{1 6} abdominal pain,^{1 6 8} dyspepsia,^{1 2 3 6 8} diarrhea,^{1 2 3 6 8 10 11} nausea,^{1 2 3 6} arthralgia,^{1 6} back pain,^{1 6} purpura,^{1 6} upper respiratory tract infection,^{1 6} rash,^{1 2 3 6 8 10 11} pruritus.^{1 6}

Interactions for Plavix

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Appears to inhibit CYP2C9 isoenzyme in vitro at high concentrations.^{1 8 20}

Converted to active metabolite by CYP2C19.^{1 72 78 80 81 82 83} (See Metabolism under Pharmacokinetics.) Potential pharmacokinetic (decreased concentrations of active metabolite) and pharmacodynamic (reduced antiplatelet effects) interaction with inhibitors of CYP2C19.^{1 72 76 81 88 89} Avoid concomitant use of drugs (e.g., omeprazole) known to be potent inhibitors of CYP2C19.^{1 20 101}

Proton-Pump Inhibitors

Potential for reduced systemic exposure to clopidogrel's active metabolite and reduced antiplatelet effects with certain proton-pump inhibitors (via inhibition of CYP2C19 by proton-pump inhibitor).^{1 20 72 73 74 84 86 88 89 91 100 101 102 103 106 107 109} (See Reduced Efficacy Associated with Impaired CYP2C19 Function under Cautions and see Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes under Interactions.) Interaction demonstrated with omeprazole, but not consistently observed with other proton-pump inhibitors.^{1 20 72 79 84 88 102 103 106 109} Conflicting data on clinical outcomes reported, but increased risk of adverse cardiovascular events possible.^{1 72 73 74 81 91 98 102 103 104 105 107 108 110 111 112 113 115 119}

Based on currently available information, FDA and manufacturer of clopidogrel state that concomitant use (including separation of administration times) of clopidogrel and omeprazole should be avoided.^{1 100 101 113} FDA also states that esomeprazole should be avoided in patients receiving clopidogrel because of its potent CYP2C19-inhibitory activity.¹⁰¹ Extent to which other proton-pump inhibitors, which differ in CYP2C19-inhibitory potency, also may interfere with clopidogrel’s effects is unknown.^{100 106 114} If concomitant proton-pump inhibitor therapy is considered necessary, pantoprazole (which appears to be the weakest inhibitor of CYP2C19 among proton-pump inhibitors) has been suggested by some clinicians.^{81 89 92 102 103 109 111 112 114} However, weigh risks and benefits of concomitant use of any proton-pump inhibitor in individual patients.^{102 103 112 119} American College of Cardiology Foundation/American College of Gastroenterology/American Heart Association (ACCF/ACG/AHA) states that use of a proton-pump inhibitor concomitantly with dual antiplatelet therapy may provide the optimal balance of risk and benefit in patients with acute coronary syndrome (ACS) who have a history of upper GI bleeding.¹³⁶ Risk/benefit tradeoff may favor concomitant use of dual antiplatelet therapy and a proton-pump inhibitor in stable patients with a history of GI bleeding who undergo coronary revascularization and receive a coronary stent.¹³⁶ ACCF/ACG/AHA states that the risk reduction with proton-pump inhibitors is substantial in patients with risk factors for GI bleeding (e.g., advanced age; concomitant use of warfarin, corticosteroids, or nonsteroidal anti-inflammatory drugs (NSAIDs); H. pylori infection) and may outweigh potential reduction in cardiovascular efficacy of antiplatelet treatment associated with a drug–drug interaction.¹³⁶ In patients without such risk factors for GI bleeding, risk/benefit balance may favor use of antiplatelet therapy without a concomitant proton-pump inhibitor.¹³⁶ Alternatively, consider concomitant therapy with antacids or H₂-receptor antagonists (i.e., ranitidine, famotidine, nizatidine), except for cimetidine (also a potent CYP2C19 inhibitor).^{1 81 89 92 100 103 112}

Specific Drugs

Drug	Interaction	Comments
Antacids	Currently no evidence that antacids interfere with antiplatelet effects of clopidogrel101
Cilostazol	Potential additive antiplatelet effects93 94 Pharmacokinetic interaction unlikely19 93	Caution advised; monitor bleeding times during concurrent administration93
Dexlansoprazole	Reduced efficacy observed with concomitant clopidogrel and omeprazole; extent to which other proton-pump inhibitors also may interfere with clopidogrel’s effects is unknown1 100 101 106 114	FDA states that insufficient information available to make specific recommendations about concomitant use with clopidogrel100
Esomeprazole	Possible decreased plasma concentrations of clopidogrel's active metabolite and diminished antiplatelet effect101	FDA recommends that concomitant use be avoided101
Histamine H2-receptor antagonists (ranitidine, famotidine, nizatidine)	Currently no evidence that H2-receptor antagonists (except cimetidine) interfere with antipl

Mirtazapine 45mg Tablets (Actavis UK Ltd)

1. Name Of The Medicinal Product

Mirtazapine 45mg Tablets

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 45mg of mirtazapine

Excipient: Lactose monohydrate.

Each tablet contains 305.4mg

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet.

White, 14.5 x 7.5 mm oval, biconvex, film-coated tablets. Marked with I on one side.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of episodes of major depression.

4.2 Posology And Method Of Administration

Adults

The effective daily dose is usually between 15 and 45mg; the starting dose is 15 or 30mg.

Mirtazapine begins to exert its effect in general after 1-2 weeks of treatment. Treatment with an adequate dose should result in a positive response within 2-4 weeks. With an insufficient response, the dose can be increased up to the maximum dose. If there is no response within a further 2-4 weeks, then treatment should be stopped.

Elderly

The recommended dose is the same as that for adults. In elderly patients an increase in dosing should be done under close supervision to elicit a satisfactory and safe response.

Children and adolescents under the age of 18 years

Mirtazapine should not be used in children and adolescents under the age of 18 years (see section 4.4).

Renal impairment

The clearance of mirtazapine may be decreased in patients with moderate to severe renal impairment (creatinine clearance <40ml/min). This should be taken into account when prescribing Mirtazapine to this category of patients (see section 4.4).

Hepatic impairment

The clearance of mirtazapine may be decreased in patients with hepatic impairment. This should be taken into account when prescribing Mirtazapine to this category of patients, particularly with severe hepatic impairment, as patients with severe hepatic impairment have not been investigated (see section 4.4).

Mirtazapine has an elimination half-life of 20-40 hours and therefore Mirtazapine is suitable for once daily administration. It should be taken preferably as a single night-time dose before going to bed. Mirtazapine may also be given in two divided doses (once in the morning and once at night-time, the higher dose should be taken at night).

The tablets should be taken orally, with fluid, and swallowed without chewing.

Patients with depression should be treated for a sufficient period of at least 6 months to ensure that they are free from symptoms.

It is recommended to discontinue treatment with mirtazapine gradually to avoid withdrawal symptoms (see section 4.4).

4.3 Contraindications

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

Concomitant use of mirtazapine with monoamine oxidase (MAO) inhibitors (see section 4.5).

4.4 Special Warnings And Precautions For Use

Use in children and adolescents under 18 years of age

Mirtazapine should not be used in the treatment of children and adolescents under the age of 18 years. Suicide-related behaviours (suicide attempt and suicidal thoughts), and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo. If, based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for the appearance of suicidal symptoms. In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking.

Suicide/suicidal thoughts or clinical worsening

Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.

Patients with a history of suicide-related events or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo controlled clinical trials of antidepressants in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than years old.

Close supervision of patients and in particular those at high risk should accompany therapy with antidepressants especially in early treatment and following dose changes. Patients (and care givers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

With regard to the chance of suicide, in particular at the beginning of treatment, only a limited number of Mirtazapine film-coated tablets should be given to the patient.

Bone marrow depression

Bone marrow depression, usually presenting as granulocytopenia or agranulocytosis, has been reported during treatment with mirtazapine. Reversible agranulocytosis has been reported as a rare occurrence in clinical studies with mirtazapine. In the postmarketing period with mirtazapine very rare cases of agranulocytosis have been reported, mostly reversible, but in some cases fatal. Fatal cases mostly concerned patients with an age above 65. The physician should be alert for symptoms like fever, sore throat, stomatitis or other signs of infection; when such symptoms occur, treatment should be stopped and blood counts taken.

Jaundice

Treatment should be discontinued if jaundice occurs.

Conditions which need supervision

Careful dosing as well as regular and close monitoring is necessary in patients with:

– epilepsy and organic brain syndrome: Although clinical experience indicates that epileptic seizures are rare during mirtazapine treatment, as with other antidepressants, Mirtazapine should be introduced cautiously in patients who have a history of seizures. Treatment should be discontinued in any patient who develops seizures, or where there is an increase in seizure frequency.

– hepatic impairment: Following a single 15mg oral dose of mirtazapine, the clearance of mirtazapine was approximately 35% decreased in mild to moderate hepatically impaired patients, compared to subjects with normal hepatic function. The average plasma concentration of mirtazapine was about 55% increased.

– renal impairment: Following a single 15mg oral dose of mirtazapine, in patients with moderate (creatinine clearance <40ml/min) and severe (creatinine clearance <10ml/min) renal impairment the clearance of mirtazapine was about 30% and 50% decreased respectively, compared to normal subjects. The average plasma concentration of mirtazapine was about 55% and 115% increased respectively. No significant differences were found in patients with mild renal impairment (creatinine clearance <80ml/min) as compared to the control group.

– cardiac diseases like conduction disturbances, angina pectoris and recent myocardial infarction, where normal precautions should be taken and concomitant medicines carefully administered– low blood pressure – diabetes mellitus: In patients with diabetes, antidepressants may alter glycaemic control. Insulin and/or oral hypoglycaemic dosage may need to be adjusted and close monitoring is recommended.

Like with other antidepressants, the following should be taken into account:

– Worsening of psychotic symptoms can occur when antidepressants are administered to patients with schizophrenia or other psychotic disturbances; paranoid thoughts can be intensified

– When the depressive phase of bipolar disorder is being treated, it can transform into the manic phase. Patients with a history of mania/hypomania should be closely monitored. Mirtazapine should be discontinued in any patient entering a manic phase.

– Although mirtazapine is not addictive, post-marketing experience shows that abrupt termination of treatment after long term administration may sometimes result in withdrawal symptoms. The majority of withdrawal reactions are mild and self-limiting. Among the various reported withdrawal symptoms, dizziness, agitation, anxiety, headache and nausea are the most frequently reported. Even though they have been reported as withdrawal symptoms, it should be realized that these symptoms may be related to the underlying disease. As advised in section 4.2, it is recommended to discontinue treatment with mirtazapine gradually.

– Care should be taken in patients with micturition disturbances like prostate hypertrophy and in patients with acute narrow-angle glaucoma and increased intra-ocular pressure (although there is little chance of problems with Mirtazapine because of its very weak anticholinergic activity).

– Akathisia/psychomotor restlessness: The use of antidepressants have been associated with the development of akathisia, characterised by a subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.

Hyponatraemia

Hyponatraemia, probably due to inappropriate antidiuretic hormone secretion (SIADH), has been reported very rarely with the use of mirtazapine. Caution should be exercised in patients at risk, such as elderly patients or patients concomitantly treated with medications known to cause hyponatraemia.

Serotonin syndrome

Interaction with serotonergic active substances: serotonin syndrome may occur when selective serotonin reuptake inhibitors (SSRIs) are used concomitantly with other serotonergic active substances (see section 4.5). Symptoms of serotonin syndrome may be hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes that include confusion, irritability and extreme agitation progressing to delirium and coma. From post marketing experience it appears that serotonin syndrome occurs very rarely in patients treated with mirtazapine alone (see section 4.8).

Elderly patients

Elderly patients are often more sensitive, especially with regard to the undesirable effects of antidepressants. During clinical research with mirtazapine, undesirable effects have not been reported more often in elderly patients than in other age groups.

Lactose

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Pharmacodynamic interactions

- Mirtazapine should not be administered concomitantly with MAO inhibitors or within two weeks after discontinuation of MAO inhibitor therapy. In the opposite way about two weeks should pass before patients treated with mirtazapine should be treated with MAO inhibitors (see section 4.3).

In addition, as with SSRIs, co-administration with other serotonergic active substances (L-tryptophan, triptans, tramadol, linezolid, SSRIs, venlafaxine, lithium and St. John's Wort – Hypericum perforatum – preparations) may lead to an incidence of serotonin associated effects (serotonin syndrome: see section 4.4). Caution should be advised and a closer clinical monitoring is required when these active substances are combined with mirtazapine.

- Mirtazapine may increase the sedating properties of benzodiazepines and other sedatives (notably most antipsychotics, antihistamine H1 antagonists, opioids). Caution should be exercised when these medicinal products are prescribed together with mirtazapine.

- Mirtazapine may increase the CNS depressant effect of alcohol. Patients should therefore be advised to avoid alcoholic beverages while taking mirtazapine.

- Mirtazapine dosed at 30mg once daily caused a small but statistically significant increase in the international normalized ratio (INR) in subjects treated with warfarin. As at a higher dose of mirtazapine a more pronounced effect can not be excluded, it is advisable to monitor the INR in case of concomitant treatment of warfarin with mirtazapine.

Pharmacokinetic interactions

- Carbamazepine and phenytoin, CYP3A4 inducers, increased mirtazapine clearance about twofold, resulting in a decrease in average plasma mirtazapine concentration of 60% and 45%, respectively. When carbamazepine or any other inducer of hepatic metabolism (such as rifampicin) is added to mirtazapine therapy, the mirtazapine dose may have to be increased. If treatment with such medicinal product is discontinued, it may be necessary to reduce the mirtazapine dose.

- Co-administration of the potent CYP3A4 inhibitor ketoconazole increased the peak plasma levels and the AUC of mirtazapine by approximately 40% and 50% respectively.

- When cimetidine (weak inhibitor of CYP1A2, CYP2D6 and CYP3A4) is administered with mirtazapine, the mean plasma concentration of mirtazapine may increase more than 50%. Caution should be exercised and the dose may have to be decreased when co-administering mirtazapine with potent CYP3A4 inhibitors, HIV protease inhibitors, azole antifungals, erythromycin, cimetidine or nefazodone.

- Interaction studies did not indicate any relevant pharmacokinetic effects on concurrent treatment of mirtazapine with paroxetine, amitriptyline, risperidone or lithium.

4.6 Pregnancy And Lactation

Limited data of the use of mirtazapine in pregnant women do not indicate an increased risk for congenital malformations. Studies in animals have not shown any teratogenic effects of clinical relevance, however developmental toxicity has been observed (see section 5.3). Caution should be exercised when prescribing to pregnant women. If Mirtazapine is used until, or shortly before birth, postnatal monitoring of the newborn is recommended to account for possible discontinuation effects.

Epidemiological data have suggested that the use of SSRIs in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). Although no studies have investigated the association of PPHN to mirtazapine treatment, this potential risk cannot be ruled out taking into account the related mechanism of action (increase in serotonin concentrations).

Animal studies and limited human data have shown excretion of mirtazapine in breast milk only in very small amounts. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Mirtazapine should be made taking into account the benefit of breastfeeding to the child and the benefit of Mirtazapine therapy to the woman.

4.7 Effects On Ability To Drive And Use Machines

Mirtazapine has minor or moderate influence on the ability to drive and use machines. Mirtazapine may impair concentration and alertness (particularly in the initial phase of treatment). Patients should avoid the performance of potentially dangerous tasks, which require alertness and good concentration, such as driving a motor vehicle or operating machinery, at any time when affected.

4.8 Undesirable Effects

Depressed patients display a number of symptoms that are associated with the illness itself. It is therefore sometimes difficult to ascertain which symptoms are a result of the illness itself and which are a result of treatment with mirtazapine.

The most commonly reported adverse reactions, occurring in more than 5% of patients treated with mirtazapine in randomized placebo-controlled trials (see below) are somnolence, sedation, dry mouth, weight increased, increase in appetite, dizziness and fatigue.

All randomized placebo-controlled trials in patients (including indications other than major depressive disorder), have been evaluated for adverse reactions of mirtazapine. The meta-analysis considered 20 trials, with a planned duration of treatment up to 12 weeks, with 1501 patients (134 person years) receiving doses of mirtazapine up to 60 mg and 850 patients (79 person years) receiving placebo. Extension phases of these trials have been excluded to maintain comparability to placebo treatment.

Table 1 shows the categorized incidence of the adverse reactions, which occurred in the clinical trials statistically significantly more frequently during treatment with mirtazapine than with placebo, added with adverse reactions from spontaneous reporting. The frequencies of the adverse reactions from spontaneous reporting are based on the reporting rate of these events in the clinical trials. The frequency of adverse reactions from spontaneous reporting for which no cases in the randomized placebo-controlled patient trials were observed with mirtazapine has been classified as 'not known'.

Table 1. Adverse reactions of mirtazapine

System organ class	Very common (	Common (	Uncommon (	Rare (	Frequency not known
Investigations	Weight increased1
Blood and the lymphatic system disorders					Bone marrow depression (granulocytopenia, agranulocytosis, aplastic anemia thrombocytopenia) Eosinophilia
Nervous system disorders	Somnolence1, 4 Sedation1, 4 Headache2	Lethargy1 Dizziness Tremor	Paraesthesia2 Restless legs Syncope	Myoclonus	Convulsions (insults) Serotonin syndrome Oral paraesthesia
Gastrointestinal disorders	Dry mouth	Nausea3 Diarrhea2 Vomiting2	Oral hypoaesthesia		Mouth oedema
Skin and subcutaneous tissue disorders		Exanthema2
Musculoskeletal and connective tissue disorders		Arthralgia Myalgia Back pain1
Metabolism and nutrition disorders	Increase in appetite1				Hyponatraemia
Vascular disorders		Orthostatic hypotension	Hypotension2
General disorders and administration site conditions		Oedema peripheral1 Fatigue
Hepatobiliary disorders				Elevations in serum transaminase activities
Psychiatric disorders		Abnormal dreams Confusion Anxiety2, 5 Insomnia3, 5	Nightmares2 Mania Agitation2 Hallucinations Psychomotor restlessness (incl. akathisia, hyperkinesia)		Suicidal ideation6 Suicidal behaviour6
Endocrine disorders					Inappropriate antidiuretic hormone secretion

¹ In clinical trials these events occurred statistically significantly more frequently during treatment with mirtazapine than with placebo.

² In clinical trials these events occurred more frequently during treatment with placebo than with mirtazapine, however not statistically significantly more frequently.

³ In clinical trials these events occurred statistically significantly more frequently during treatment with placebo than with mirtazapine.

⁴N.B. dose reduction generally does not lead to less somnolence/sedation but can jeopardize antidepressant efficacy.

⁵ Upon treatment with antidepressants in general, anxiety and insomnia (which may be symptoms of depression) can develop or become aggravated. Under mirtazapine treatment, development or aggravation of anxiety and insomnia has been reported.

⁶ Cases of suicidal ideation and suicidal behaviours have been reported during mirtazapine therapy or early after treatment discontinuation (see section 4.4).

In laboratory evaluations in clinical trials transient increases in transaminases and gammaglutamyltransferase have been observed (however associated adverse events have not been reported statistically significantly more frequently with mirtazapine than with placebo).

4.9 Overdose

Present experience concerning overdose with mirtazapine alone indicates that symptoms are usually mild. Depression of the central nervous system with disorientation and prolonged sedation have been reported, together with tachycardia and mild hyper- or hypotension. However, there is a possibility of more serious outcomes (including fatalities) at dosages much higher than the therapeutic dose, especially with mixed overdoses.

Cases of overdose should receive appropriate symptomatic and supportive therapy for vital functions.

Activated charcoal or gastric lavage should also be considered.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: other antidepressants, ATC code: N06AX11

Mirtazapine is a centrally active presynaptic α2-antagonist, which increases central noradrenergic and serotonergic neurotransmission. The enhancement of serotonergic neurotransmission is specifically mediated via 5-HT1 receptors, because 5-HT2 and 5-HT3 receptors are blocked by mirtazapine. Both enantiomers of mirtazapine are presumed to contribute to the antidepressant activity, the S(+) enantiomer by blocking α2 and 5-HT2 receptors and the R(-) enantiomer by blocking 5-HT3 receptors.

The histamine H1-antagonistic activity of mirtazapine is associated with its sedative properties. It has practically no anticholinergic activity and, at therapeutic doses, has practically no effect on the cardiovascular system.

5.2 Pharmacokinetic Properties

After oral administration of mirtazapine, the active substance mirtazapine is rapidly and well absorbed (bioavailability ≈ 50%), reaching peak plasma levels after approx. two hours. Binding of mirtazapine to plasma proteins is approx. 85%. The mean half-life of elimination is 20-40 hours; longer half-lives, up to 65 hours, have occasionally been recorded and shorter half-lives have been seen in young men. The half-life of elimination is sufficient to justify once-a-day dosing. Steady state is reached after 3-4 days, after which there is no further accumulation. Mirtazapine displays linear pharmacokinetics within the recommended dose range. Food intake has no influence on the pharmacokinetics of mirtazapine.

Mirtazapine is extensively metabolized and eliminated via the urine and faeces within a few days. Major pathways of biotransformation are demethylation and oxidation, followed by conjugation. In vitro data from human liver microsomes indicate that cytochrome P450 enzymes CYP2D6 and CYP1A2 are involved in the formation of the 8-hydroxy metabolite of mirtazapine, whereas CYP3A4 is considered to be responsible for the formation of the N-demethyl and N-oxide metabolites. The demethyl metabolite is pharmacologically active and appears to have the same pharmacokinetic profile as the parent compound.

The clearance of mirtazapine may be decreased as a result of renal or hepatic impairment.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, carcinogenicity or genotoxicity.

In reproductive toxicity studies in rats and rabbits no teratogenic effects were observed. At two-fold systemic exposure compared to maximum human therapeutic exposure, there was an increase in postimplantation loss, decrease in the pup birth weights, and reduction in pup survival during the first three days of lactation in rats.

Mirtazapine was not genotoxic in a series of tests for gene mutation and chromosomal and DNA damage. Thyroid gland tumours found in a rat carcinogenicity study and hepatocellular neoplasms found in a mouse carcinogenicity study are considered to be species-specific, non-genotoxic responses associated with long-term treatment with high doses of hepatic enzyme inducers.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Core:

Lactose monohydrate

Pregelatinised maize starch

Anhydrous colloidal silica

Croscarmellose sodium

Magnesium stearate.

Coating:

Hypromellose

Macrogol 8000

Titanium dioxide (E171).

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions

6.5 Nature And Contents Of Container

Pack sizes

10, 14, 20, 28, 30, 50, 56 and 100 tablets in clear PVC/Al blister.

30, 100 and 500 tablets in white polypropylene tablet containers with LDPE/HDPE caps.

The pack size of 500 tablets is intended for hospital use. Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Actavis Group PTC ehf.

Reykjavíkurvegi 76-78

IS-220 Hafnarfjordur

Iceland

8. Marketing Authorisation Number(S)

PL 30306/0171

9. Date Of First Authorisation/Renewal Of The Authorisation

20/03/2008

10. Date Of Revision Of The Text

20.07.10

Tylenol Allergy Sinus Gelcap

Generic Name: acetaminophen, chlorpheniramine, and pseudoephedrine (a seet a MIN oh fen, klor fen IR a meen, soo doe e FED rin)

Brand Names: Alka-Seltzer Plus Cold Liquigel, Allerest Headache Strength, Allerest Sinus, Cold Medicine Plus, Comtrex Allergy Sinus, Comtrex Allergy Sinus Maximum Strength, Comtrex Allergy Sinus Night and Day, Kolephrin, Sinarest, Sinutab Ex-Strength, Theraflu Cold & Sore Throat (pseudoephedrine), Theraflu Flu & Sore Throat (pseudoephedrine), Theraflu Maximum Strength

What is Tylenol Allergy Sinus Gelcap (acetaminophen, chlorpheniramine, and pseudoephedrine)?

Acetaminophen is a pain reliever and fever reducer.

Chlorpheniramine is an antihistamine that reduces the natural chemical histamine in the body. Histamine can produce symptoms of sneezing, itching, watery eyes, and runny nose.

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

The combination of acetaminophen, chlorpheniramine, and pseudoephedrine is used to treat headache, fever, body aches, runny or stuffy nose, sneezing, itching, watery eyes, and sinus congestion caused by allergies, the common cold, or the flu.

Acetaminophen, chlorpheniramine, and pseudoephedrine may also be used for purposes not listed in this medication guide.

What is the most important information I should know about Tylenol Allergy Sinus Gelcap (acetaminophen, chlorpheniramine, and pseudoephedrine)?

Do not take more of this medication than is recommended. An overdose of acetaminophen can damage your liver or cause death. Do not take this medication without a doctor's advice if you have ever had alcoholic liver disease (cirrhosis) or if you drink more than 3 alcoholic beverages per day. You should not use this medicine if you have severe constipation, a blockage in your stomach or intestines, or if you are unable to urinate. Do not use this medicine if you have untreated or uncontrolled diseases such as glaucoma, asthma or COPD, high blood pressure, heart disease, coronary artery disease, or overactive thyroid. Avoid drinking alcohol. It may increase your risk of liver damage while taking acetaminophen and can increase certain side effects of chlorpheniramine. 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. Ask a doctor or pharmacist before using any other cold, allergy, pain, or sleep medication. Acetaminophen (sometimes abbreviated as APAP) is contained in many combination medicines. Taking certain products together can cause you to get too much acetaminophen which can lead to a fatal overdose.

What should I discuss with my healthcare provider before taking Tylenol Allergy Sinus Gelcap (acetaminophen, chlorpheniramine, and pseudoephedrine)?

You should not use this medicine if you have severe constipation, a blockage in your stomach or intestines, or if you are unable to urinate. Do not take this medication without a doctor's advice if you have ever had alcoholic liver disease (cirrhosis) or if you drink more than 3 alcoholic beverages per day. You may not be able to take medicine that contains acetaminophen. Do not use this medicine if you have untreated or uncontrolled diseases such as glaucoma, asthma or COPD, high blood pressure, heart disease, coronary artery disease, or overactive thyroid. 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.

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

• 
  

  liver disease, cirrhosis, or a history of alcoholism;

  
  


• 
  

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

  
  


• 
  

  diabetes;

  
  


• 
  

  kidney disease;

  
  


• 
  

  epilepsy or other seizure disorder;

  
  


• 
  

  cough with mucus, or cough caused by smoking, emphysema, or chronic bronchitis;

  
  


• 
  

  enlarged prostate or urination problems;

  
  


• 
  

  low blood pressure;

  
  


• 
  

  pheochromocytoma (an adrenal gland tumor); or

  
  


• 
  

  if you take potassium (Cytra, Epiklor, K-Lyte, K-Phos, Kaon, Klor-Con, Polycitra, Urocit-K).

  
  

It is not known whether acetaminophen, chlorpheniramine, and pseudoephedrine will harm an unborn baby. Do not use this medicine without your doctor's advice if you are pregnant. This medication may pass into breast milk and may harm a nursing baby. Antihistamines and decongestants may also slow breast milk production. Do not use this medicine without your doctor's advice if you are breast-feeding a baby.

How should I take Tylenol Allergy Sinus Gelcap (acetaminophen, chlorpheniramine, and pseudoephedrine)?

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. This medicine is usually taken only for a short time until your symptoms clear up.

Do not take more of this medication than is recommended. An overdose of acetaminophen can damage your liver or cause death.

Dissolve one packet of the powder in at least 4 ounces of water. Stir this mixture and drink all of it right away.

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 take for longer than 7 days in a row. Stop taking the medicine and call your doctor if you still have a fever after 3 days of use, you still have pain after 7 days (or 5 days if treating a child), if your symptoms get worse, or if you have a skin rash, ongoing headache, or any redness or swelling.

If you need surgery or medical tests, tell the surgeon or doctor ahead of time if you have taken this medicine within the past few days. Store at room temperature away from moisture and heat. Do not allow liquid medicine to freeze.

What happens if I miss a dose?

Since this medicine is taken when needed, you may not be on a dosing schedule. If you are taking the medication regularly, 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. An overdose of acetaminophen can be fatal.

The first signs of an acetaminophen overdose include loss of appetite, nausea, vomiting, stomach pain, sweating, and confusion or weakness. Later symptoms may include pain in your upper stomach, dark urine, and yellowing of your skin or the whites of your eyes.

Overdose symptoms may also include severe forms of some of the side effects listed in this medication guide.

What should I avoid while taking Tylenol Allergy Sinus Gelcap (acetaminophen, chlorpheniramine, and pseudoephedrine)?

Ask a doctor or pharmacist before using any other cold, allergy, pain, or sleep medication. Acetaminophen (sometimes abbreviated as APAP) is contained in many combination medicines. Taking certain products together can cause you to get too much acetaminophen which can lead to a fatal overdose. Check the label to see if a medicine contains acetaminophen or APAP. Avoid drinking alcohol. It may increase your risk of liver damage while taking acetaminophen, and can increase certain side effects of chlorpheniramine. This medicine may cause blurred vision or impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert and able to see clearly.

Tylenol Allergy Sinus Gelcap (acetaminophen, chlorpheniramine, and pseudoephedrine) 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:

• 
  

  chest pain, rapid pulse, fast or uneven heart rate;

  
  


• 
  

  confusion, hallucinations, severe nervousness;

  
  


• 
  

  tremor, seizure (convulsions);

  
  


• 
  

  easy bruising or bleeding, unusual weakness;

  
  


• 
  

  urinating less than usual or not at all;

  
  


• 
  

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

  
  


• 
  

  dangerously high blood pressure (severe headache, blurred vision, buzzing in your ears, anxiety, chest pain, shortness of breath, uneven heartbeats, seizure).

  
  

Less serious side effects may include:

• 
  

  dizziness, drowsiness;

  
  


• 
  

  mild headache;

  
  


• 
  

  dry mouth, nose, or throat;

  
  


• 
  

  constipation;

  
  


• 
  

  blurred vision;

  
  


• 
  

  feeling nervous; or

  
  


• 
  

  sleep problems (insomnia);

  
  

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 Tylenol Allergy Sinus Gelcap (acetaminophen, chlorpheniramine, and pseudoephedrine)?

Ask a doctor or pharmacist before using this medicine if you regularly use other medicines that make you sleepy (such as narcotic pain medication, sedatives, sleeping pills, muscle relaxers, and medicine for seizures, depression or anxiety). They can add to sleepiness caused by chlorpheniramine.

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

• 
  

  leflunomide (Arava);

  
  


• 
  

  topiramate (Topamax);

  
  


• 
  

  zonisamide (Zonegran);

  
  


• 
  

  an antibiotic, antifungal medicine, sulfa drug, or tuberculosis medicine;

  
  


• 
  

  an antidepressant;

  
  


• 
  

  birth control pills or hormone replacement therapy;

  
  


• 
  

  bladder or urinary medications;

  
  


• 
  

  blood pressure medication;

  
  


• 
  

  a bronchodilator;

  
  


• 
  

  cancer medicine;

  
  


• 
  

  cholesterol-lowering medications such as Lipitor, Niaspan, Zocor, Vytorin, and others;

  
  


• 
  

  gout or arthritis medications (including gold injections);

  
  


• 
  

  HIV/AIDS medication;

  
  


• 
  

  medication for nausea and vomiting, stomach ulcers, or irritable bowel syndrome;

  
  


• 
  

  medicines to treat psychiatric disorders;

  
  


• 
  

  an NSAID such as Advil, Aleve, Arthrotec, Cataflam, Celebrex, Indocin, Motrin, Naprosyn, Treximet, Voltaren, others; or

  
  


• 
  

  seizure medication.

  
  

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

More Tylenol Allergy Sinus Gelcap resources

• Tylenol Allergy Sinus Gelcap Use in Pregnancy & Breastfeeding
• Drug Images
• Tylenol Allergy Sinus Gelcap Drug Interactions
• 0 Reviews for Tylenol Allergy Sinuscap - Add your own review/rating

• Children's Tylenol Cold Chewable Tablets MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Tylenol Allergy Sinus Gelcap with other medications

• Cold Symptoms
• Hay Fever

Where can I get more information?

• Your pharmacist can provide more information about acetaminophen, chlorpheniramine, and pseudoephedrine.