Tuesday, 15 May 2012

Coreg CR Extended-Release Capsules


Pronunciation: kar-VE-dil-ol
Generic Name: Carvedilol
Brand Name: Coreg CR


Coreg CR Extended-Release Capsules are used for:

Treating high blood pressure or certain types of heart failure. It may also be used after a heart attack to improve survival in certain patients. It may be used along with other medicines. It may also be used for other conditions as determined by your doctor.


Coreg CR Extended-Release Capsules are a beta-blocker. It works by relaxing the blood vessels, slowing down the heart, and decreasing the amount of blood it pumps out. This decreases blood pressure, helps the heart pump more efficiently, and reduces the workload on the heart.


Do NOT use Coreg CR Extended-Release Capsules if:


  • you are allergic to any ingredient in Coreg CR Extended-Release Capsules

  • you have certain types of irregular heartbeat (eg, moderate to severe heart block, sick sinus syndrome), very severe heart failure (eg, requires treatment in a hospital), or shock caused by severe heart problems

  • you have a very slow heartbeat and you do not have a permanent pacemaker

  • you have asthma or other severe breathing problems

  • you have severe liver problems

  • you are taking mibefradil

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



Before using Coreg CR Extended-Release Capsules:


Some medical conditions may interact with Coreg CR Extended-Release Capsules. 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 or are taking medicine for allergies

  • if you have a history of other heart problems (eg, heart failure, slow or irregular heartbeat, angina) or low blood pressure

  • if you have a history of liver or kidney problems, blood vessel disease, blood flow problems (eg, in the legs or feet), lung or breathing problems (eg, chronic bronchitis, emphysema, chronic obstructive pulmonary disease), diabetes, low blood sugar, thyroid problems, or glaucoma

  • if you have an adrenal gland tumor (pheochromocytoma)

  • if you drink alcohol or will be having surgery

Some MEDICINES MAY INTERACT with Coreg CR Extended-Release Capsules. Tell your health care provider if you are taking any other medicines, especially any of the following:


  • Mibefradil because the risk of serious heart side effects may be increased

  • Many prescription and nonprescription medicines (eg, used for infections, inflammation, aches and pains, high blood pressure, heart problems, irregular heartbeat, cancer, diabetes, depression, mental or mood problems, multiple sclerosis [MS], prostate problems, immune system suppression, allergic reactions, asthma, high cholesterol, seizures, thyroid problems), multivitamin products, and herbal or dietary supplements (eg, herbal teas, coenzyme Q10, garlic, ginseng, ginkgo, St. John's wort) may interact with Coreg CR Extended-Release Capsules, increasing the risk of side effects

This may not be a complete list of all interactions that may occur. Ask your health care provider if Coreg CR Extended-Release Capsules 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 Coreg CR Extended-Release Capsules:


Use Coreg CR Extended-Release Capsules as directed by your doctor. Check the label on the medicine for exact dosing instructions.


  • An extra patient leaflet is available with Coreg CR Extended-Release Capsules. Talk to your pharmacist if you have questions about this information.

  • Take Coreg CR Extended-Release Capsules by mouth with food. Take it in the morning unless your doctor tells you otherwise.

  • Swallow Coreg CR Extended-Release Capsules whole. Do not break, crush, or chew before swallowing. If you cannot swallow the capsule whole, you may open it and sprinkle the contents over a spoonful of cool applesauce. Mix the medicine with the applesauce and swallow the mixture right away, followed by a glass of water. Do not crush or chew the medicine before swallowing. Do not store mixture for future use.

  • Do not drink alcohol or take medicines that contain alcohol within 2 hours before or after you take Coreg CR Extended-Release Capsules.

  • Take Coreg CR Extended-Release Capsules on a regular schedule to get the most benefit from it. Taking Coreg CR Extended-Release Capsules at the same time each day will help you remember to take it.

  • Continue to use Coreg CR Extended-Release Capsules even if you feel well. Do not miss any doses.

  • Do not suddenly stop taking Coreg CR Extended-Release Capsules. You may have an increased risk of side effects. If you need to stop Coreg CR Extended-Release Capsules or add a new medicine, your doctor will gradually lower your dose.

  • If you miss a dose of Coreg CR Extended-Release Capsules, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Coreg CR Extended-Release Capsules.



Important safety information:


  • Coreg CR Extended-Release Capsules may cause drowsiness, dizziness, fainting, or blurred vision. These effects may be worse if you take it with alcohol or certain medicines. Use Coreg CR Extended-Release Capsules with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.

  • Coreg CR Extended-Release Capsules may cause dizziness, light-headedness, or fainting; alcohol, hot weather, exercise, and fever can increase these effects. To prevent them, sit up or stand slowly, especially in the morning. Also, sit or lie down at the first sign of any of these effects. Tell your doctor if these effects occur.

  • Do NOT take more than the recommended dose without checking with your doctor.

  • Do not suddenly stop taking Coreg CR Extended-Release Capsules. Sharp chest pain, irregular heartbeat, and sometimes heart attack may occur if you suddenly stop Coreg CR Extended-Release Capsules. The risk may be greater if you have certain types of heart disease. Your doctor should slowly lower your dose over several weeks if you need to stop taking it. This should be done even if you only take Coreg CR Extended-Release Capsules for high blood pressure. Heart disease is common and you may not know you have it. Limit physical activity while you are lowering your dose. If new or worsened chest pain or other heart problems occur, contact your doctor right away. You may need to start taking Coreg CR Extended-Release Capsules again.

  • Patients who take medicine for high blood pressure often feel tired or run down for a few weeks after starting treatment. Be sure to take your medicine even if you may not feel "normal." Tell your doctor if you develop any new symptoms.

  • Tell your doctor or dentist that you take Coreg CR Extended-Release Capsules before you receive any medical or dental care, emergency care, or surgery.

  • If you have a history of any severe allergic reaction, talk with your doctor. You may be at risk for an even more severe allergic reaction if you come into contact with the substance that caused your allergy. Some medicines used to treat severe allergies may also not work as well while you are using Coreg CR Extended-Release Capsules.

  • Diabetes patients - Coreg CR Extended-Release Capsules may affect your blood sugar. Check blood sugar levels closely. Ask your doctor before you change the dose of your diabetes medicine.

  • Diabetes patients - Coreg CR Extended-Release Capsules may hide signs of low blood sugar, such as a rapid heartbeat. Be sure to watch for other signs of low blood sugar. Low blood sugar may make you anxious, sweaty, weak, dizzy, drowsy, or faint. It may also make your vision change; give you a headache, chills, or tremors; or make you more hungry. Check blood sugar levels closely. Ask your doctor before you change the dose of your diabetes medicine.

  • Lab tests, including blood pressure and heart function, may be performed while you use Coreg CR Extended-Release Capsules. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.

  • Use Coreg CR Extended-Release Capsules with caution in the ELDERLY; they may be more sensitive to its effects, especially dizziness.

  • ELDERLY patients who switch to Coreg CR Extended-Release Capsules from the immediate-release tablets may have an increased risk of dizziness or fainting when they start Coreg CR Extended-Release Capsules. Use caution until you know how you react to Coreg CR Extended-Release Capsules. Tell your doctor if you experience these effects.

  • Coreg CR Extended-Release Capsules should be used with extreme caution in CHILDREN younger than 18 years old; safety and effectiveness in these children have not been confirmed.

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


Possible side effects of Coreg CR Extended-Release Capsules:


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



Diarrhea; dizziness; dry eyes; fatigue; headache; light-headedness; nausea; vomiting; weakness.



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

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); change in the amount of urine produced; chest pain; cold or numb legs or feet; fainting; irregular or unusually slow heartbeat; persistent or severe vision changes; red, swollen, blistered, or peeling skin; severe dizziness; shortness of breath; sudden unusual weight gain; swelling of the hands, ankles, or feet; unusual bruising or bleeding; unusual leg pain; very cold or blue fingers or toes.



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: Coreg CR side effects (in more detail)


If OVERDOSE is suspected:


Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include chest pain; fainting; seizures; severe dizziness; slow heartbeat; slow, shallow, or difficult breathing.


Proper storage of Coreg CR Extended-Release Capsules:

Store Coreg CR Extended-Release Capsules at 77 degrees F (25 degrees C). Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Coreg CR Extended-Release Capsules out of the reach of children and away from pets.


General information:


  • If you have any questions about Coreg CR Extended-Release Capsules, please talk with your doctor, pharmacist, or other health care provider.

  • Coreg CR Extended-Release Capsules are 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 Coreg CR Extended-Release Capsules. 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 Coreg CR resources


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


Compare Coreg CR with other medications


  • Angina
  • Atrial Fibrillation
  • Heart Failure
  • High Blood Pressure
  • Left Ventricular Dysfunction

fluphenazine hydrochloride


Class: Phenothiazines
Note: This monograph also contains information on fluphenazine decanoate
VA Class: CN701
CAS Number: 5002-47-1
Brands: Prolixin


Special Alerts:


[Posted 02/22/2011] ISSUE: FDA notified healthcare professionals that the Pregnancy section of drug labels for the entire class of antipsychotic drugs has been updated. The new drug labels now contain more and consistent information about the potential risk for abnormal muscle movements (extrapyramidal signs or EPS) and withdrawal symptoms in newborns whose mothers were treated with these drugs during the third trimester of pregnancy.


The symptoms of EPS and withdrawal in newborns may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty in feeding. In some newborns, the symptoms subside within hours or days and do not require specific treatment; other newborns may require longer hospital stays.


BACKGROUND: Antipsychotic drugs are used to treat symptoms of psychiatric disorders such as schizophrenia and bipolar disorder.


RECOMMENDATION: Healthcare professionals should be aware of the effects of antipsychotic medications on newborns when the medications are used during pregnancy. Patients should not stop taking these medications if they become pregnant without talking to their healthcare professional, as abruptly stopping antipsychotic medications can cause significant complications for treatment. For more information visit the FDA website at: and .


[Posted 06/16/2008] FDA notified healthcare professionals that both conventional and atypical antipsychotics are associated with an increased risk of mortality in elderly patients treated for dementia-related psychosis. In April 2005, FDA notified healthcare professionals that patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death. Since issuing that notification, FDA has reviewed additional information that indicates the risk is also associated with conventional antipsychotics. Antipsychotics are not indicated for the treatment of dementia-related psychosis. The prescribing information for all antipsychotic drugs will now include the same information about this risk in a BOXED WARNING and the WARNINGS section. For more information visit the FDA website at: , and .



Introduction

Phenothiazine antipsychotic agent.a b c d f g i


Uses for fluphenazine hydrochloride


Psychotic Disorders


Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.


Symptomatic management of psychotic disorders (i.e., schizophrenia).a b c f g i


The long-acting decanoate ester is used mainly for maintenance therapy in patients with chronic schizophrenic disorder who cannot be relied on to take oral antipsychotic drugs; do not use for acute management of severely agitated patients.a b


Mental Retardation


Efficacy not established for management of behavioral complications in mental retardation.a b c f g i


fluphenazine hydrochloride Dosage and Administration


General



  • Use shorter-acting fluphenazine hydrochloride formulations in patients with acute schizophrenic reactions so that dosage can be readily adjusted according to patient’s tolerance and therapeutic response.a b



Administration


Administer fluphenazine hydrochloride orally or IM.a b c f g i


Administer fluphenazine decanoate IM or sub-Q.a b If used outside of psychiatric institutions, administer under direction of clinician experienced in use of psychotropic drugs, particularly phenothiazine derivatives.b


Avoid skin contact with elixir, oral concentrate solution, or injection since contact dermatitis rarely occurs.a d


Oral Administration


Fluphenazine hydrochloride: Administer orally every 6–8 hours initially; maintenance therapy can often be administered as a single daily dose.a c f g


When oral concentrate solution is used, dilute dose with at least 60 mL of suitable diluent (e.g., water; uncaffeinated soft drinks [e.g., Seven-Up]; carbonated orange beverage; sodium chloride; milk; V-8; or pineapple, apricot, prune, orange, tomato, or grapefruit juice) just before administration.a f (See Compatibility under Stability.)


IM or Sub-Q Administration


Fluphenazine hydrochloride: Administer IM every 6–8 hours.a f


Fluphenazine decanoate: Administer IM or sub-Q using a dry syringe and needle of at least 21 gauge; use of a wet needle or syringe may cause solution to become cloudy.b


Dosage


Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.


Available as fluphenazine hydrochloride or fluphenazine decanoate; dosage expressed in terms of the salt.b c f g i


Carefully adjust dosage according to individual requirements and response, using lowest possible effective dosage.a c f g


Because of risk of adverse reactions associated with cumulative effects of phenothiazines, periodically evaluate patients with a history of long-term therapy with fluphenazine and/or other antipsychotic agents to determine whether maintenance dosage may be decreased or drug therapy discontinued.a


Conversion from oral fluphenazine hydrochloride to long-acting decanoate injection may be indicated for psychotic patients stabilized on a fixed daily oral dosage.a c f g In patients without a history of therapy with phenothiazines, administer shorter-acting form for several weeks prior to instituting therapy with fluphenazine decanoate in order to determine patient’s approximate dosage requirements and susceptibility to adverse effects.a b


Precise formula for converting therapy from fluphenazine hydrochloride to fluphenazine decanoate not established.a An approximate conversion ratio of 12.5 mg every 3 weeks of fluphenazine decanoate for every 10 mg daily of fluphenazine hydrochloride has been used.a


Adults


Psychotic Disorders

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.


Oral

Fluphenazine hydrochloride: Initially, 2.5–10 mg daily given in divided doses every 6–8 hours.a c f g Dosage may be gradually increased, if necessary, until desired clinical effects are obtained.a c f g


Optimum therapeutic effect often occurs with oral fluphenazine hydrochloride dosages <20 mg daily.a c f g Dosages up to 40 mg may be required in severely disturbed patients, but safety of prolonged administration of such dosages not established.a c f g Use dosages >20 mg daily with caution.a


After maximum response attained, reduce fluphenazine hydrochloride dosage gradually to maintenance dosage of 1–5 mg daily, often as a single dose.a c f g To avoid recurrence of psychotic symptoms, continued therapy is required following optimum therapeutic response.a


IM

Fluphenazine hydrochloride: Generally, IM dose is approximately one-third to one-half the oral dose.a i


Usual initial fluphenazine hydrochloride dose is 1.25 mg.a i Depending on severity and duration of symptoms, initial total IM dosage may range from 2.5–10 mg daily given in divided doses every 6–8 hours; may gradually increase dosage if necessary, until symptoms are controlled.a i


Use fluphenazine hydrochloride dosages >10 mg daily with caution.a i


After symptoms are controlled, oral therapy generally should replace parenteral therapy.a i


IM or Sub-Q

Fluphenazine decanoate: In patients with chronic schizophrenic disorder, usual initial dose is 12.5–25 mg.a b


Carefully adjust subsequent fluphenazine decanoate dose and dosage interval according to patient tolerance and response;a b if doses >50 mg are deemed necessary, increase the next and succeeding doses cautiously in increments of 12.5 mg, but do not exceed 100 mg.a b


When administered as maintenance therapy, a single fluphenazine decanoate injection may be effective in controlling schizophrenic symptoms for up to 4 weeks or longer; response may persist for up to 6 weeks in some patients.a b


Prescribing Limits


Adults


Psychotic Disorders

Oral

Fluphenazine hydrochloride: Safety of prolonged administration of dosages up to 40 mg daily not established.a f g Use dosages >20 mg daily with caution.a


IM

Fluphenazine hydrochloride: Use dosages >10 mg daily with caution.a i


IM or Sub-Q

Fluphenazine decanoate: Do not exceed 100 mg.b


Special Populations


Geriatric Patients


Fluphenazine hydrochloride: Initially 1–2.5 mg orally daily.a c f g Increase dosage more gradually in debilitated, emaciated, or geriatric patients.a


Cautions for fluphenazine hydrochloride


Contraindications



  • Suspected or established subcortical brain damage.b c f g i




  • Comatose or severely depressed states.b c f g i




  • Blood dyscrasia or liver damage.b c f g i




  • Concomitant therapy with large doses of hypnotics.b c f g i




  • Known hypersensitivity to fluphenazineb c f g i or other phenothiazine derivatives (unless potential benefits outweigh possible risks).d



Warnings/Precautions


Warnings


Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.


Tardive Dyskinesia

Tardive dyskinesia, a syndrome of potentially irreversible, involuntary dyskinetic movements, may develop in patients receiving antipsychotic agents, including fluphenazine.b c f g i Consider discontinuance.b c f g i


Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment, may occur in patients receiving antipsychotic agents, including fluphenazine.b c f g i


Sensitivity Reactions


Hypersensitivity

Skin disorders (e.g., pruritus, erythema, urticaria, seborrhea, photosensitivity, eczema, exfoliative dermatitis) reported with phenothiazine derivatives.b c f g i Contact dermatitis reported rarely.a


Consider possibility of anaphylactoid reactions.b c f g i


Cross-sensitivity

Possible cross-sensitivity with other phenothiazines; use with caution in patients who have developed cholestatic jaundice, dermatoses, or other allergic reactions to phenothiazine derivatives.b c f g i


General Precautions


Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.


Use phenothiazines with caution in debilitated patients, patients with renal or hepatic disease, patients with glaucoma or prostatic hypertrophy, and patients exposed to organophosphate insecticides.b c d f g i


Use phenothiazines with caution in patients with hypocalcemia, since susceptibility to dystonic reactions may be increased.d


Abrupt Withdrawal

Gastritis, nausea, vomiting, dizziness, and tremulousness reported after abrupt discontinuance of high-dose therapy; minimize symptoms by continuing concomitant antiparkinsonian agents for several weeks after phenothiazine is withdrawn.b c f g i


Cardiovascular Effects

Hypotension occurs rarely.a b f g i Patients with pheochromocytoma, cerebral or vascular insufficiency, or severe cardiac reserve deficiency (e.g., mitral insufficiency), or psychotic patients receiving large doses of phenothiazines who are undergoing surgery may be especially prone to hypotensive effects;a b c f g i closely monitor such patients during therapy.a b c f g i


Hypertension and fluctuations in BP may occur.a b c f g i


Nervous System Effects

Possible risk of seizures; phenothiazines may lower seizure threshold.d Use with caution in patients with a history of seizures or EEG abnormalities or in those receiving anticonvulsant agents.b c d f g i Maintain adequate anticonvulsant therapy.d


Drowsiness or lethargy possible; may necessitate dosage reduction.b c f g i


Because of CNS depressant effects of phenothiazines, use with caution in patients with chronic respiratory disorders (e.g., severe asthma, emphysema, acute respiratory tract infections).d


Neurologic reactions from phenothiazine therapy may be similar to CNS manifestations accompanying certain disorders (e.g., Reye’s syndrome, encephalopathy, meningitis, tetanus); diagnosis of these disorders may be obscured or disease-associated manifestations may be incorrectly diagnosed as drug induced.d


Antiemetic effect of phenothiazines may mask signs of overdosage of toxic drugs (e.g., antineoplastic agents) or may obscure cause of vomiting in various disorders (e.g., intestinal obstruction, Reye’s syndrome, brain tumor).d


Phenothiazines depress hypothalamic mechanism for body temperature regulation; use caution in patients exposed to extreme heat or cold.b c f g i


Extrapyramidal symptoms occur frequently and are usually reversible; persistent reactions can usually be controlled by concomitant therapy with an antiparkinsonian drug and subsequent dosage reduction.a b c f g i


Autonomic reactions (e.g., nausea, appetite loss, salivation, polyuria, perspiration, dry mouth, headache, constipation) may occur.a b c f g i


Hematologic Effects

Blood dyscrasias, including leukopenia, agranulocytosis, thrombocytopenic or nonthrombocytopenic purpura, eosinophilia, and pancytopenia reported with phenothiazine derivatives.b c d f g i Perform hematologic evaluations periodically.b c d f g i


If manifestations of blood dyscrasias (e.g., sore throat, fever, weakness) occur, discontinue until possibility of adverse hematologic effect is ruled out; if evidence of cellular depression (i.e., decreased leukocyte and differential counts) occurs, discontinue and institute appropriate therapy.b c d f g i


Hepatic Effects

Liver damage, manifested by cholestatic jaundice may occur, particularly during first months of therapy;b c f g i discontinue immediately if liver damage occurs.d


Consider possibility of liver damage in patients receiving prolonged therapy.b c f g i Monitor hepatic function periodically.b c f g i


Ocular Effects

Consider possibility of pigmentary retinopathy and lenticular and corneal deposits in patients receiving prolonged therapy.b c d f g i Periodic ophthalmic examinations recommended in patients receiving prolonged phenothiazine therapy with moderate to high dosages.d


Endocrine Effects

Elevated prolactin concentrations, which persist during chronic administration, possible.b c d f g i


Galactorrhea, amenorrhea, gynecomastia, and impotence reported.b c f g i


Pulmonary Effects

Clinicians should be alert to possible development of “silent pneumonias” in patients receiving phenothiazines, including fluphenazine.b c f g i


Use with caution in patients with chronic respiratory disorders (e.g., severe asthma, emphysema, acute respiratory tract infections).d


Specific Populations


Pregnancy

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.


Category C.e


Lactation

Phenothiazines are distributed into milk.d e Women receiving phenothiazines should not breast-feed.d


Pediatric Use

Insufficient experience with fluphenazine hydrochloride to establish safety and efficacy.a c f g i


Safety and efficacy of fluphenazine decanoate not established in children <12 years of age.a b


Geriatric Use

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.


Geriatric patients appear to be particularly sensitive to adverse CNS (e.g., tardive dyskinesia, parkinsonian manifestations, akathisia, sedation), anticholinergic, and cardiovascular (e.g., orthostatic hypotension) effects of antipsychotic agents.d (See Geriatric Patients under Dosage and Administration.)


Hepatic Impairment

Use phenothiazines with caution in patients with hepatic disease.d Monitor hepatic function periodically.b c f g i


Renal Impairment

Use phenothiazines with caution in patients with renal disease.d Monitor renal function periodically; if BUN becomes abnormal, discontinue therapy.b c f g i


Common Adverse Effects


Extrapyramidal reactions (e.g., pseudo-parkinsonism, dystonia, dyskinesia, akathisia, oculogyric crises, opisthotonos, hyperreflexia), drowsiness, lethargy, weight gain.a b c d f g i


Interactions for fluphenazine hydrochloride


Specific Drugs and Laboratory Tests






























Drug or Test



Interaction



Comments



Anticonvulsants



Phenothiazines may lower seizure threshold, but CNS depressant effects do not potentiate anticonvulsant activity of anticonvulsantsd



Dosage adjustment of anticonvulsant may be necessary to maintain seizure control during concomitant used



Atropine



Possible potentiated effects of atropine in some patients receiving fluphenazine because of added anticholinergic effectsb c f g i



CNS depressants (e.g., alcohol, analgesics, antihistamines, barbiturates, general anesthetics, opiates)



Possible additive effects or potentiated action of other CNS depressantsb c d f g i



Use concomitantly with caution to avoid excessive sedation or CNS depressionb c d


During surgery in patients receiving high fluphenazine dosages, may need to reduce dosages of anesthetics or other CNS depressantsb c f g i



Epinephrine



Reversal of epinephrine actionb c f g i



Do not use epinephrine for phenothiazine-induced hypotension; further lowering of BP may resultb c f g i



Lithium



An acute encephalopathic syndrome reported occasionally, especially when high serum lithium concentrations presentd



Observe patients receiving combined therapy for evidence of adverse neurologic effects; promptly discontinue if such signs or symptoms appeard



Test for phenylketonuria (PKU)



False-positive test results may occur during phenothiazine used



Tests for pregnancy



False-positive results reported in some patients receiving phenothiazinesb c d f g i



Tests for urobilinogen, amylase, uroporphyrins, porphobilinogens, 5-hydroxyindolacetic acid



Urinary metabolites of phenothiazines may cause urine to darken and result in false-positive test resultsd


fluphenazine hydrochloride Pharmacokinetics


Absorption


Bioavailability


Rapidly absorbed from GI tract and from parenteral sites.a Peak serum concentrations were attained within 1.5–2 or 0.5 hours after IM or oral administration, respectively, of fluphenazine hydrochloride.a


Onset


Fluphenazine hydrochloride: Usually occurs within 1 hour following oral or IM administration.a


Fluphenazine decanoate: Within 24–72 hours.a b


Duration


Fluphenazine hydrochloride: 6–8 hours following oral or IM administration.a


Fluphenazine decanoate: Usually 1–6 weeks (average: 2 weeks).a


Distribution


Extent


Not fully elucidated; reportedly crosses blood-brain barrier.a


Phenothiazines cross the placenta and are distributed into milk.e


Elimination


Metabolism


Metabolic fate not fully elucidated.a


Elimination Route


Excreted in feces and urine as unchanged drug, fluphenazine sulfoxide, and 7-hydroxyfluphenazine following IM administration of fluphenazine decanoate in 1 patient studied; also excreted in urine as metabolite conjugates.a


Half-life


Fluphenazine hydrochloride: 14.7–15.3 hours following IM or oral administration.a


Fluphenazine decanoate: 6.8–9.6 days following IM administration.a


Stability


Storage


Oral


Tablets

15–30°C.c Protect from light.c Avoid excessive heat.c


Elixir

Tightly closed containers at 15–30°C, unless otherwise specified by manufacturer; a d g avoid freezing.g Protect from light.a g


Solution, concentrate

Tightly closed containers at <40°C, preferably 15–30°C, unless otherwise specified by manufacturer;a d f avoid freezing.d f Protect from light.a f


Parenteral


Injection

Fluphenazine decanoate: 15–30°C.b Avoid freezing and excessive heat.b Protect from light.b


Fluphenazine hydrochloride: 15–30°C.d i Avoid freezing.a Protect from light.a i


Compatibility


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


Oral


Do not mix oral concentrate solution with beverages containing caffeine (e.g., coffee, cola), tannic acid (e.g., tea), or pectinates (e.g., apple juice), since physical incompatibility may result.a f (See Oral Administration under Dosage and Administration.)


Parenteral


Drug Compatibility (for Fluphenazine Hydrochloride)






Syringe Compatibilityh

Compatible



Benztropine mesylate



Diphenhydramine HCl



Hydroxyzine HCl


ActionsActions



  • Precise mechanism(s) of antipsychotic action not determined but may be principally related to antidopaminergic effects.d




  • Exhibits weak anticholinergic and sedative effects and strong extrapyramidal effects; has weak antiemetic activity.a



Advice to Patients


Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.



  • Risk of drowsiness and impairment of mental and physical abilities required for driving a car or operating heavy machinery.a b c f g i




  • Importance of avoiding alcohol during fluphenazine therapy.a b c f g i




  • Importance of clinicians informing patients in whom chronic use is contemplated of risk of tardive dyskinesia, taking into account clinical circumstances and competency of patient to understand information provided.a b c f g i




  • Importance of clinicians informing patients of risk of extrapyramidal reactions and providing reassurance that these reactions usually can be controlled by administration of antiparkinsonian drugs (e.g., benztropine) and by subsequent dosage reduction.b c f g i




  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.a b c f g i




  • Importance of avoiding exposure to temperature extremes.b c d f g i




  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.a b c f g i




  • Importance of informing patients of other important precautionary information.a b c f g i (See Cautions.)



Preparations


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


















Fluphenazine Decanoate

Routes



Dosage Forms



Strengths



Brand Names



Manufacturer



Parenteral



Injection



25 mg/mL



Fluphenazine Decanoate Injection (with benzyl alcohol 1.2% in sesame oil)



Abraxis, Apotex, Bedford, Sicor



Prolixin Decanoate (with benzyl alcohol 1.2% in sesame oil)



Sandoz


* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name











































Fluphenazine Hydrochloride

Routes



Dosage Forms



Strengths



Brand Names



Manufacturer



Oral



Elixir



2.5 mg/5 mL



Fluphenazine Hydrochloride Elixir



Pharmaceutical Associates, Teva



Solution, concentrate



5 mg/mL



Fluphenazine Hydrochloride Concentrate



Pharmaceutical Associates, Teva



Tablets



1 mg*



Fluphenazine Hydrochloride Tablets



Mylan, Par, Sandoz, UDL



2.5 mg*



Fluphenazine Hydrochloride Tablets



Mylan, Par, Sandoz, UDL



5 mg*



Fluphenazine Hydrochloride Tablets



Mylan, Par, Sandoz, UDL



10 mg*



Fluphenazine Hydrochloride Tablets



Mylan, Par, Sandoz, UDL



Parenteral



Injection, for IM use only



2.5 mg/mL



Fluphenazine Hydrochloride Injection (with parabens)



Abraxis


Comparative Pricing


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


Fluphenazine Decanoate 25MG/ML Solution (APP PHARMACEUTICAL): 5/$69.99 or 10/$130


Fluphenazine HCl 1MG Tablets (SANDOZ): 90/$17.99 or 180/$23.98


Fluphenazine HCl 10MG Tablets (SANDOZ): 60/$24.99 or 180/$74.98


Fluphenazine HCl 2.5MG Tablets (MYLAN): 60/$15.99 or 180/$38.98


Fluphenazine HCl 5MG Tablets (SANDOZ): 60/$18.99 or 180/$45.98



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 March 15, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.




References



a. AHFS drug information 2004. McEvoy GK, ed. Fluphenazine. Bethesda, MD: American Society of Health-System Pharmacists; 2004:2314-5.



b. Gensia Sicor Pharmaceuticals, Inc. Fluphenazine decanoate injection prescribing information. Irvine, CA; 1998 Aug.



c. Par Pharmaceutical, Inc. Fluphenazine hydrochloride tablets prescribing information. Spring Valley, NY; 2003 Jul.



d. AHFS drug information 2004. McEvoy GK, ed. Phenothiazines general statement. Bethesda, MD: American Society of Health-System Pharmacists; 2004: 2301-11.



e. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 6th ed. Baltimore, MD: Williams & Wilkins; 2002:574-5.



f. Pharmaceutical Associates, Inc. Fluphenazine hydrochloride oral solution prescribing information. Greenville, SC; 2000 Oct.



g. Pharmaceutical Associates, Inc. Fluphenazine hydrochloride elixir prescribing information. Greenville, SC; 2002 Nov.



h. Trissel LA. Handbook on injectable drugs. 12th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2003:622-3.



i. American Pharmaceutical Partners. Fluphenazine hydrochloride injection prescribing information. Schaumburg, IL; 2002 Jul.



More fluphenazine hydrochloride resources


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


  • Fluphenazine Professional Patient Advice (Wolters Kluwer)

  • Fluphenazine MedFacts Consumer Leaflet (Wolters Kluwer)

  • Prolixin Prescribing Information (FDA)

  • Prolixin Concise Consumer Information (Cerner Multum)

  • Prolixin Decanoate Prescribing Information (FDA)

  • fluphenazine Concise Consumer Information (Cerner Multum)



Compare fluphenazine hydrochloride with other medications


  • Psychosis

Thursday, 3 May 2012

Integrilin





Dosage Form: injection
Integrilin® (eptifibatide) Injection

For Intravenous Administration



Integrilin Description


Eptifibatide is a cyclic heptapeptide containing 6 amino acids and 1 mercaptopropionyl (des-amino cysteinyl) residue. An interchain disulfide bridge is formed between the cysteine amide and the mercaptopropionyl moieties. Chemically it is N6 - (aminoiminomethyl) - N2 - (3 - mercapto - 1 - oxopropyl - L - lysylglycyl - L - α - aspartyl - L - tryptophyl - L - prolyl - L - cysteinamide, cyclic (1→6)-disulfide. Eptifibatide binds to the platelet receptor glycoprotein (GP) IIb/IIIa of human platelets and inhibits platelet aggregation.


The eptifibatide peptide is produced by solution-phase peptide synthesis, and is purified by preparative reverse-phase liquid chromatography and lyophilized. The structural formula is:



Integrilin® (eptifibatide) Injection is a clear, colorless, sterile, non-pyrogenic solution for intravenous (IV) use with an empirical formula of C35H49N11O9S2 and a molecular weight of 831.96. Each 10-mL vial contains 2 mg/mL of eptifibatide and each 100-mL vial contains either 0.75 mg/mL of eptifibatide or 2 mg/mL of eptifibatide. Each vial of either size also contains 5.25 mg/mL citric acid and sodium hydroxide to adjust the pH to 5.35.



Integrilin - Clinical Pharmacology



Mechanism of Action


Eptifibatide reversibly inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive ligands to GP IIb/IIIa. When administered intravenously, eptifibatide inhibits ex vivo platelet aggregation in a dose- and concentration-dependent manner. Platelet aggregation inhibition is reversible following cessation of the eptifibatide infusion; this is thought to result from dissociation of eptifibatide from the platelet.



Pharmacodynamics


Infusion of eptifibatide into baboons caused a dose-dependent inhibition of ex vivo platelet aggregation, with complete inhibition of aggregation achieved at infusion rates greater than 5.0 mcg/kg/min. In a baboon model that is refractory to aspirin and heparin, doses of eptifibatide that inhibit aggregation prevented acute thrombosis with only a modest prolongation (2- to 3-fold) of the bleeding time. Platelet aggregation in dogs was also inhibited by infusions of eptifibatide, with complete inhibition at 2.0 mcg/kg/min. This infusion dose completely inhibited canine coronary thrombosis induced by coronary artery injury (Folts model).


Human pharmacodynamic data were obtained in healthy subjects and in patients presenting with unstable angina (UA) or non-ST-segment elevation myocardial infarction (NSTEMI) and/or undergoing percutaneous coronary interventions. Studies in healthy subjects enrolled only males; patient studies enrolled approximately one-third women. In these studies, eptifibatide inhibited ex vivo platelet aggregation induced by adenosine diphosphate (ADP) and other agonists in a dose- and concentration-dependent manner. The effect of eptifibatide was observed immediately after administration of a 180-mcg/kg intravenous bolus. Table 1 shows the effects of dosing regimens of eptifibatide used in the IMPACT II and PURSUIT studies on ex vivo platelet aggregation induced by 20 µM ADP in PPACK-anticoagulated platelet-rich plasma and on bleeding time. The effects of the dosing regimen used in ESPRIT on platelet aggregation have not been studied.






















Table 1 Platelet Inhibition and Bleeding Time
IMPACT II 135/0.5*PURSUIT 180/2.0

*

135-mcg/kg bolus followed by a continuous infusion of 0.5 mcg/kg/min.


180-mcg/kg bolus followed by a continuous infusion of 2.0 mcg/kg/min.

Inhibition of platelet aggregation 15 min after bolus69%84%
Inhibition of platelet aggregation at steady state40–50%>90%
Bleeding-time prolongation at steady state<5×<5×
Inhibition of platelet aggregation 4h after infusion discontinuation<30%<50%
Bleeding-time prolongation 6h after infusion discontinuation1.4×

The eptifibatide dosing regimen used in the ESPRIT study included two 180-mcg/kg bolus doses given 10 minutes apart combined with a continuous 2.0-mcg/kg/min infusion.


When administered alone, eptifibatide has no measurable effect on prothrombin time (PT) or activated partial thromboplastin time (aPTT) (see also PRECAUTIONS, Drug Interactions section).


There were no important differences between men and women or between age groups in the pharmacodynamic properties of eptifibatide. Differences among ethnic groups have not been assessed.



Pharmacokinetics


The pharmacokinetics of eptifibatide are linear and dose-proportional for bolus doses ranging from 90 to 250 mcg/kg and infusion rates from 0.5 to 3.0 mcg/kg/min. Plasma elimination half-life is approximately 2.5 hours. Administration of a single 180-mcg/kg bolus combined with an infusion produces an early peak level, followed by a small decline prior to attaining steady state (within 4–6 hours). This decline can be prevented by administering a second 180-mcg/kg bolus 10 minutes after the first. The extent of eptifibatide binding to human plasma protein is about 25%. Clearance in patients with coronary artery disease is about 55 mL/kg/h. In healthy subjects, renal clearance accounts for approximately 50% of total body clearance, with the majority of the drug excreted in the urine as eptifibatide, deaminated eptifibatide, and other, more polar metabolites. No major metabolites have been detected in human plasma.


In patients with moderate to severe renal insufficiency (creatinine clearance <50 mL/min using the Cockcroft-Gault equation), the clearance of eptifibatide is reduced by approximately 50% and steady-state plasma levels approximately doubled (see WARNINGS and DOSAGE AND ADMINISTRATION).



Special Populations


Patients in clinical studies were older (range: 20–94 years) than those in the clinical pharmacology studies. Elderly patients with coronary artery disease demonstrated higher plasma levels and lower total body clearance of eptifibatide when given the same dose as younger patients. Limited data are available on lighter weight (<50 kg) patients over 75 years of age.


No studies have been conducted in patients with hepatic impairment.


Males and females have not demonstrated any clinically significant differences in the pharmacokinetics of eptifibatide.



Clinical Studies


Eptifibatide was studied in 3 placebo-controlled, randomized studies. PURSUIT evaluated patients with acute coronary syndromes: unstable angina (UA) or non-ST-segment elevation MI (NSTEMI). Two other studies, ESPRIT and IMPACT II, evaluated patients about to undergo a percutaneous coronary intervention (PCI). Patients underwent primarily balloon angioplasty in IMPACT II and intracoronary stent placement, with or without angioplasty, in ESPRIT.



Non-ST-segment Elevation Acute Coronary Syndrome


Non-ST-segment elevation acute coronary syndrome is defined as prolonged (≥10 minutes) symptoms of cardiac ischemia within the previous 24 hours associated with either ST-segment changes (elevations between 0.6 mm and 1mm or depression >0.5 mm), T-wave inversion (>1 mm), or positive CK-MB. This definition includes "unstable angina" and "NSTEMI" but excludes myocardial infarction that is associated with Q waves or greater degrees of ST-segment elevation.



PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy)


PURSUIT was a 726-center, 27-country, double-blind, randomized, placebo-controlled study in 10,948 patients presenting with UA or NSTEMI. Patients could be enrolled only if they had experienced cardiac ischemia at rest (≥10 minutes) within the previous 24 hours and had either ST-segment changes (elevations between 0.6 mm and 1 mm or depression >0.5 mm), T-wave inversion (>1 mm), or increased CK-MB. Important exclusion criteria included a history of bleeding diathesis, evidence of abnormal bleeding within the previous 30 days, uncontrolled hypertension, major surgery within the previous 6 weeks, stroke within the previous 30 days, any history of hemorrhagic stroke, serum creatinine >2.0 mg/dL, dependency on renal dialysis, or platelet count <100,000/mm3.


Patients were randomized to either placebo, eptifibatide 180-mcg/kg bolus followed by a-2.0 mcg/kg/min infusion (180/2.0), or eptifibatide 180-mcg/kg bolus followed by a 1.3-mcg/kg/min infusion (180/1.3). The infusion was continued for 72 hours, until hospital discharge, or until the time of coronary artery bypass grafting (CABG), whichever occurred first, except that if PCI was performed, the eptifibatide infusion was continued for 24 hours after the procedure, allowing for a duration of infusion up to 96 hours.


The lower-infusion-rate arm was stopped after the first interim analysis when the 2 active-treatment arms appeared to have the same incidence of bleeding.


Patient age ranged from 20 to 94 (mean 63) years, and 65% were male. The patients were 89% Caucasian, 6% Hispanic, and 5% Black, recruited in the United States and Canada (40%), Western Europe (39%), Eastern Europe (16%), and Latin America (5%).


This was a "real world" study; each patient was managed according to the usual standards of the investigational site; frequencies of angiography, PCI, and CABG therefore differed widely from site to site and from country to country. Of the patients in PURSUIT, 13% were managed with PCI during drug infusion, of whom 50% received intracoronary stents; 87% were managed medically (without PCI during drug infusion).


The majority of patients received aspirin (75–325 mg once daily). Heparin was administered intravenously or subcutaneously, at the physician's discretion, most commonly as an intravenous bolus of 5000 U followed by a continuous infusion of 1000 U/h. For patients weighing less than 70 kg, the recommended heparin bolus dose was 60 U/kg followed by a continuous infusion of 12 U/kg/h. A target aPTT of 50 to 70 seconds was recommended. A total of 1250 patients underwent PCI within 72 hours after randomization, in which case they received intravenous heparin to maintain an activated clotting time (ACT) of 300 to 350 seconds.


The primary endpoint of the study was the occurrence of death from any cause or new myocardial infarction (MI) (evaluated by a blinded Clinical Endpoints Committee) within 30 days of randomization.


Compared to placebo, eptifibatide administered as a 180-mcg/kg bolus followed by a 2.0-mcg/kg/min infusion significantly (P=0.042) reduced the incidence of endpoint events (see Table 2). The reduction in the incidence of endpoint events in patients receiving eptifibatide was evident early during treatment, and this reduction was maintained through at least 30 days (see Figure 1). Table 2 also shows the incidence of the components of the primary endpoint, death (whether or not preceded by an MI) and new MI in surviving patients at 30 days.












































Table 2 Clinical Events in the PURSUIT Study
Death or MIPlacebo

(n = 4739)

n
Eptifibatide (180/2.0)

(n = 4722)

(%)
P-value
3 days359(7.6%)279(5.9%)0.001
7 days552(11.6%)477(10.1%)0.016
30 days
  Death or MI (primary endpoint)745(15.7%)672(14.2%)0.042
    Death177(3.7%)165(3.5%)
    Nonfatal MI568(12.0%)507(10.7%)


Figure 1: Kaplan-Meier Plot of Time to Death or Myocardial Infarction Within 30 Days of Randomization

Treatment with eptifibatide prior to determination of patient management strategy reduced clinical events regardless of whether patients ultimately underwent diagnostic catheterization, revascularization (i.e., PCI or CABG surgery) or continued to receive medical management alone. Table 3 shows the incidence of death or MI within 72 hours.



























Table 3 Clinical Events (Death or MI) in the PURSUIT Study Within 72 Hours of Randomization
PlaceboEptifibatide 180/2.0
Overall patient populationn=4739n=4722
  – At 72 hours7.6%5.9%
Patients undergoing early PCIn=631n=619
  – Pre-procedure (nonfatal MI only)5.5%1.8%
  – At 72 hours14.4%9.0%
Patients not undergoing early PCIn=4108n=4103
  – At 72 hours6.5%5.4%

All of the effect of eptifibatide was established within 72 hours (during the period of drug infusion), regardless of management strategy. Moreover, for patients undergoing early PCI, a reduction in events was evident prior to the procedure.


An analysis of the results by sex suggests that women who would not routinely be expected to undergo percutaneous coronary intervention (PCI) receive less benefit from eptifibatide (95% confidence limits for relative risk of 0.94– 1.28) than do men (0.72– 0.90). This difference may be a true treatment difference, the effect of other differences in these subgroups, or a statistical anomaly. No differential outcomes were seen between male and female patients undergoing PCI (see results for ESPRIT).


Follow-up data were available through 165 days for 10,611 patients enrolled in the PURSUIT trial (96.9%of the initial enrollment). This follow-up included 4566 patients who received eptifibatide at the 180/2.0 dose. As reported by the investigators, the occurrence of death from any cause or new myocardial infarction for patients followed for at least 165 days was reduced from 13.6% with placebo to 12.1% with eptifibatide 180/2.0.



Percutaneous Coronary Intervention


IMPACT II (Integrilin to Minimize Platelet Aggregation and Prevent Coronary Thrombosis II)

IMPACT II was a multicenter, double-blind, randomized, placebo-controlled study conducted in the United States in 4010 patients undergoing PCI. Major exclusion criteria included a history of bleeding diathesis, major surgery within 6 weeks of treatment, gastrointestinal bleeding within 30 days, any stroke or structural CNS abnormality, uncontrolled hypertension, PT >1.2 times control, hematocrit <30%, platelet count <100,000/mm3, and pregnancy.


Patient age ranged from 24 to 89 (mean 60) years, and 75% were male. The patients were 92% Caucasian, 5% Black, and 3% Hispanic. Forty-one percent of the patients underwent PCI for ongoing ACS. Patients were randomly assigned to 1 of 3 treatment regimens, each incorporating a bolus dose initiated immediately prior to PCI followed by a continuous infusion lasting 20 to 24 hours: 1) 135-mcg/kg bolus followed by a continuous infusion of 0.5 mcg/kg/min of eptifibatide (135/0.5); 2) 135-mcg/kg bolus followed by a continuous infusion of 0.75-mcg/kg/min of eptifibatide (135/0.75); or 3) a matching placebo bolus followed by a matching placebo continuous infusion. Each patient received aspirin and an intravenous heparin bolus of 100 U/kg, with additional bolus infusions of up to 2000 additional units of heparin every 15 minutes to maintain an activated clotting time (ACT) of 300 to 350 seconds.


The primary endpoint was the composite of death, MI, or urgent revascularization, analyzed at 30 days after randomization in all patients who received at least 1 dose of study drug.


As shown in Table 4, each eptifibatide regimen reduced the rate of death, MI, or urgent intervention, although at 30 days, this finding was statistically significant only in the lower-dose eptifibatide group. As in the PURSUIT study, the effects of eptifibatide were seen early and persisted throughout the 30-day period.








































































Table 4 Clinical Events in the IMPACT II Study
PlaceboEptifibatide (135/0.5)Eptifibatide (135/0.75)
n (%)n (%)n (%)

*

Kaplan-Meier estimate of event rate.

Patients128513001286
Abrupt Closure65 (5.1%)36 (2.8%)43 (3.3%)
  P-value vs. placebo0.0030.030
Death, MI, or Urgent Intervention
  24 hours123 (9.6%)86 (6.6%)89 (6.9%)
    P-value vs. placebo0.0060.014
  48 hours131 (10.2%)99 (7.6%)102 (7.9%)
    P-value vs. placebo0.0210.045
  30 days (primary endpoint)149 (11.6%)118 (9.1%)128 (10.0%)
    P-value vs. placebo0.0350.179
Death or MI
  30 days110 (8.6%)89 (6.8%)95 (7.4%)
    P-value vs. placebo0.1020.272
  6 months151 (11.9%)*136 (10.6%)*130 (10.3%)*
    P-value vs. placebo0.2970.182
ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy)

The ESPRIT study was a multicenter, double-blind, randomized, placebo-controlled study conducted in the United States and Canada that enrolled 2064 patients undergoing elective or urgent PCI with intended intracoronary stent placement. Exclusion criteria included MI within the previous 24 hours, ongoing chest pain, administration of any oral antiplatelet or oral anticoagulant other than aspirin within 30 days of PCI (although loading doses of thienopyridine on the day of PCI were encouraged), planned PCI of a saphenous vein graft or subsequent "staged" PCI, prior stent placement in the target lesion, PCI within the previous 90 days, a history of bleeding diathesis, major surgery within 6 weeks of treatment, gastrointestinal bleeding within 30 days, any stroke or structural CNS abnormality, uncontrolled hypertension, PT >1.2 times control, hematocrit <30%, platelet count <100,000/mm3, and pregnancy.


Patient age ranged from 24 to 93 (mean 62) years and 73% of patients were male. The study enrolled 90% Caucasian, 5% African American, 2% Hispanic, and 1% Asian patients. Patients received a wide variety of stents. Patients were randomized either to placebo or eptifibatide administered as an intravenous bolus of 180 mcg/kg followed immediately by a continuous infusion of 2.0 mcg/kg/min, and a second bolus of 180 mcg/kg administered 10 minutes later (180/2.0/180). Eptifibatide infusion was continued for 18 to 24 hours after PCI or until hospital discharge, whichever came first. Each patient received at least 1 dose of aspirin (162–325 mg) and 60 U/kg of heparin as a bolus (not to exceed 6000 U) if not already receiving a heparin infusion. Additional boluses of heparin (10–40 U/kg) could be administered in order to reach a target ACT between 200 and 300 seconds.


The primary endpoint of the ESPRIT study was the composite of death, MI, urgent target vessel revascularization (UTVR), and "bailout" to open-label eptifibatide due to a thrombotic complication of PCI (TBO) (e.g., visible thrombus, "no reflow," or abrupt closure) at 48 hours. MI, UTVR, and TBO were evaluated by a blinded Clinical Events Committee.


As shown in Table 5, the incidence of the primary endpoint and selected secondary endpoints was significantly reduced in patients who received eptifibatide. A treatment benefit in patients who received eptifibatide was seen by 48 hours and at the end of the 30-day observation period.





















































Table 5 Clinical Events in the ESPRIT Study
Placebo

(n=1024)
Eptifibatide 180/2.0/180

(n=1040)
Relative Risk

(95% CI)
P-value
Death, MI, Urgent Target Vessel Revascularization, or Thrombotic "Bailout"
  48 hours (primary endpoint)108 (10.5%)69 (6.6%)0.629 (0.471, 0.840)0.0015
  30 days120 (11.7%)78 (7.5%)0.640 (0.488, 0.840)0.0011
Death, MI, or Urgent Target Vessel Revascularization
  48 hours95 (9.3%)62 (6.0%)0.643 (0.472, 0.875)0.0045
  30 days (key secondary endpoint)107 (10.4%)71 (6.8%)0.653 (0.490, 0.871)0.0034
Death or MI
  48 hours94 (9.2%)57 (5.5%)0.597 (0.435, 0.820)0.0013
  30 days104 (10.2%)66 (6.3%)0.625 ( 0.465, 0.840)0.0016

The need for thrombotic "bailout" was significantly reduced with eptifibatide at 48 hours (2.1% for placebo, 1.0% for eptifibatide; P=0.029). Consistent with previous studies of GP IIb/IIIa inhibitors, most of the benefit achieved acutely with eptifibatide was in the reduction of MI. Eptifibatide reduced the occurrence of MI at 48 hours from 9.0% for placebo to 5.4% (P=0.0015) and maintained that effect with significance at 30 days.


There was no treatment difference with respect to sex in ESPRIT. Eptifibatide reduced the incidence of the primary endpoint in both men (95% confidence limits for relative risk: 0.54, 1.07) and women (0.24, 0.72) at 48 hours.


Follow-up (12-month) mortality data were available for 2024 patients (1017 on eptifibatide) enrolled in the ESPRIT trial (98.1% of the initial enrollment). Twelve-month clinical event data were available for 1964 patients (988 on eptifibatide), representing 95.2% of the initial enrollment. As shown in Table 6, the treatment effect of eptifibatide seen at 48 hours and 30 days appeared preserved at 6 months and 1 year. Most of the benefit was in reduction of MI.
































Table 6 Clinical Events at 6 Months and 1 Year in the ESPRIT Study
Placebo

(n=1024)
Eptifibatide 180/2.0/180

(n=1040)
Hazard Ratio

(95% CI)
Percentages are Kaplan-Meier event rates.
Death, MI, or Target Vessel Revascularization
  6 Months187 (18.5%)146 (14.3%)0.744 (0.599, 0.924)
  1 Year222 (22.1%)178 (17.5%)0.762 (0.626, 0.929)
Death, MI
  6 Months117 (11.5%)77 (7.4%)0.631 (0.473, 0.841)
  1 Year126 (12.4%)83 (8.0%)0.630 (0.478, 0.832)

Indications and Usage for Integrilin


Integrilin is indicated:


  • For the treatment of patients with acute coronary syndrome (unstable angina/non-ST- segment elevation myocardial infarction), including patients who are to be managed medically and those undergoing percutaneous coronary intervention (PCI). In this setting, Integrilin has been shown to decrease the rate of a combined endpoint of death or new myocardial infarction.

  • For the treatment of patients undergoing PCI, including those undergoing intracoronary stenting. In this setting, Integrilin has been shown to decrease the rate of a combined endpoint of death, new myocardial infarction, or need for urgent intervention.

In the IMPACT II, PURSUIT, and ESPRIT studies of eptifibatide, most patients received heparin and aspirin (see CLINICAL STUDIES).



Contraindications


Treatment with eptifibatide is contraindicated in patients with:


  • A history of bleeding diathesis, or evidence of active abnormal bleeding within the previous 30 days.

  • Severe hypertension (systolic blood pressure >200 mm Hg or diastolic blood pressure >110 mm Hg) not adequately controlled on antihypertensive therapy.

  • Major surgery within the preceding 6 weeks.

  • History of stroke within 30 days or any history of hemorrhagic stroke.

  • Current or planned administration of another parenteral GP IIb/IIIa inhibitor.

  • Dependency on renal dialysis. (See WARNINGS, Renal Insufficiency.)

  • Known hypersensitivity to any component of the product.


Warnings



Bleeding


Bleeding is the most common complication encountered during eptifibatide therapy. Administration of eptifibatide is associated with an increase in major and minor bleeding, as classified by the criteria of the Thrombolysis in Myocardial Infarction Study group (TIMI) (see ADVERSE REACTIONS). Most major bleeding associated with eptifibatide has been at the arterial access site for cardiac catheterization or from the gastrointestinal or genitourinary tract.


In patients undergoing percutaneous coronary interventions, patients receiving eptifibatide experience an increased incidence of major bleeding compared to those receiving placebo without a significant increase in transfusion requirement. Special care should be employed to minimize the risk of bleeding among these patients (see PRECAUTIONS). If bleeding cannot be controlled with pressure, infusion of eptifibatide and concomitant heparin should be stopped immediately.



Renal Insufficiency


Approximately 50% of eptifibatide is cleared by the kidney in patients with normal renal function. Total drug clearance is decreased by approximately 50% and steady-state plasma eptifibatide concentrations are doubled in patients with an estimated creatinine clearance <50 mL/min (using the Cockcroft-Gault equation). Therefore, the infusion dose should be reduced to 1 mcg/kg/min in such patients (see DOSAGE AND ADMINISTRATION). The safety and efficacy of eptifibatide in patients dependent on dialysis has not been established.



Thrombocytopenia


In the event of acute profound thrombocytopenia or a confirmed platelet decrease to <100,000/mm3, discontinue Integrilin and heparin (unfractionated or low-molecular-weight). Monitor serial platelet counts, assess the presence of drug-dependent antibodies, and treat as appropriate (see ADVERSE REACTIONS, Immunogenicity).


There has been no clinical experience with eptifibatide initiated in patients with a baseline platelet count <100,000/mm3. If a patient with low platelet counts is receiving Integrilin, their platelet count should be monitored closely.



Precautions



Bleeding Precautions


Care of the Femoral Artery Access Site in Patients Undergoing Percutaneous Coronary Intervention (PCI)

In patients undergoing PCI, treatment with eptifibatide is associated with an increase in major and minor bleeding at the site of arterial sheath placement. After PCI, eptifibatide infusion should be continued until hospital discharge or up to 18 to 24 hours, whichever comes first. Heparin use is discouraged after the PCI procedure. Early sheath removal is encouraged while eptifibatide is being infused. Prior to removing the sheath, it is recommended that heparin be discontinued for 3 to 4 hours and an aPTT of <45 seconds or ACT <150 seconds be achieved. In any case, both heparin and eptifibatide should be discontinued and sheath hemostasis should be achieved at least 2 to 4 hours before hospital discharge.



Use of Thrombolytics, Anticoagulants, and Other Antiplatelet Agents


In the IMPACT II, PURSUIT, and ESPRIT studies, eptifibatide was used concomitantly with unfractionated heparin and aspirin (see CLINICAL STUDIES). In the ESPRIT study, clopidogrel or ticlopidine were used routinely starting the day of PCI. Because eptifibatide inhibits platelet aggregation, caution should be employed when it is used with other drugs that affect hemostasis, including thrombolytics, oral anticoagulants, nonsteroidal anti-inflammatory drugs, and dipyridamole. To avoid potentially additive pharmacologic effects, concomitant treatment with other inhibitors of platelet receptor GP IIb/IIIa should be avoided.


There is only a small experience with concomitant use of eptifibatide and thrombolytics. In a study of 180 patients with acute myocardial infarction (AMI), eptifibatide (in regimens up to a bolus of 180 mcg/kg followed by a continuous infusion of 0.75 mcg/kg/min for 24 hours) was administered concomitantly with the approved "accelerated" regimen of alteplase, a thrombolytic agent. The studied regimens of eptifibatide did not increase the incidence of major bleeding or transfusion compared to the incidence seen when alteplase was given alone.


In the IMPACT II study, 15 patients received a thrombolytic agent in conjunction with the 135/0.5 dosing regimen, 2 of whom experienced a major bleed. In the PURSUIT study, 40 patients who received eptifibatide at the 180/2.0 dosing regimen received a thrombolytic agent, 10 of whom experienced a major bleed.


In another AMI study involving 181 patients, eptifibatide (in regimens up to a bolus of 180 mcg/kg followed by a continuous infusion of up to 2.0 mcg/kg/min for up to 72 hours) was administered concomitantly with streptokinase (1.5 million U over 60 minutes), another thrombolytic agent. At the highest studied infusion rates (1.3 mcg/kg/min and 2.0 mcg/kg/min), eptifibatide was associated with an increase in the incidence of bleeding and transfusions compared to the incidence seen when streptokinase was given alone.


These limited data on the use of eptifibatide in patients receiving thrombolytic agents do not allow an estimate of the bleeding risk associated with concomitant use of thrombolytics. Systemic thrombolytic therapy should be used with caution in patients who have received eptifibatide.



Minimization of Vascular and Other Trauma


Arterial and venous punctures, intramuscular injections, and the use of urinary catheters, nasotracheal intubation, and nasogastric tubes should be minimized. When obtaining intravenous access, noncompressible sites (e.g., subclavian or jugular veins) should be avoided.



Laboratory Tests


Before infusion of eptifibatide, the following laboratory tests should be performed to identify preexisting hemostatic abnormalities: hematocrit or hemoglobin, platelet count, serum creatinine, and PT/aPTT. In patients undergoing PCI, the activated clotting time (ACT) should also be measured.



Maintaining Target aPTT and ACT


The aPTT should be maintained between 50 and 70 seconds unless PCI is to be performed. In patients treated with heparin, bleeding can be minimized by close monitoring of the aPTT. Table 7 displays the risk of major bleeding according to the maximum aPTT attained within 72 hours in the PURSUIT study.
























Table 7 Major Bleeding by Maximal aPTT Within 72 Hours in the PURSUIT Study
Placebo

n (%)
Eptifibatide 180/1.3*

n (%)
Eptifibatide 180/2.0

n (%)

*

Administered only until the first interim analysis.

Maximum aPTT (seconds)
<5044/721 (6.1%)21/244 (8.6%)44/743 (5.9%)
50 to 70 (recommended)92/908 (10.1%)28/259 (10.8%)99/883 (11.2%)
>70281/2786 (10.1%)99/891 (11.1%)345/2811 (12.3%)

The ESPRIT study stipulated a target ACT of 200 to 300 seconds during PCI. Patients receiving eptifibatide 180/2.0/180 (mean ACT: 284 seconds) experienced an increased incidence of bleeding relative to placebo (mean ACT: 276 seconds), primarily at the femoral artery access site. At these lower ACTs, bleeding was less than previously reported with eptifibatide in the PURSUIT and IMPACT II studies.


The aPTT or ACT should be checked prior to arterial sheath removal. The sheath should not be removed unless the aPTT is <45 seconds or the ACT is <150 seconds.



Drug Interactions


Enoxaparin dosed as a 1.0-mg/kg subcutaneous injection q12h for 4 doses did not alter the pharmacokinetics of eptifibatide or the level of platelet aggregation in healthy adults.



Geriatric Use


The PURSUIT and IMPACT II clinical studies enrolled patients up to the age of 94 years (45% were age 65 and over; 12% were age 75 and older). There was no apparent difference in efficacy between older and younger patients treated with eptifibatide. The incidence of bleeding complications was higher in the elderly in both placebo and eptifibatide groups, and the incremental risk of eptifibatide-associated bleeding was greater in the older patients. No dose adjustment was made for elderly patients, but patients over 75 years of age had to weigh at least 50 kg to be enrolled in the PURSUIT study; no such limitation was stipulated in the ESPRIT study (see also ADVERSE REACTIONS).



Carcinogenesis, Mutagenesis, Impairment of Fertility


No long-term studies in animals have been performed to evaluate the carcinogenic potential of eptifibatide. Eptifibatide was not genotoxic in the Ames test, the mouse lymphoma cell (L 5178Y, TK+/-) forward mutation test, the human lymphocyte chromosome aberration test, or the mouse micronucleus test. Administered by continuous intravenous infusion at total daily doses up to 72 mg/kg/day (about 4 times the recommended maximum daily human dose on a body surface area basis), eptifibatide had no effect on fertility and reproductive performance of male and female rats.



Pregnancy


Pregnancy Category B

Teratology studies have been performed by continuous intravenous infusion of eptifibatide in pregnant rats at total daily doses of up to 72 mg/kg/day (about 4 times the recommended maximum daily human dose on a body surface area basis) and in pregnant rabbits at total daily doses of up to 36 mg/kg/day (also about 4 times the recommended maximum daily human dose on a body surface area basis). These studies revealed no evidence of harm to the fetus due to eptifibatide. There are, however, no adequate and well-controlled studies in pregnant women with eptifibatide. Because animal reproduction studies are not always predictive of human response, eptifibatide should be used during pregnancy only if clearly needed.



Pediatric Use


Safety and effectiveness of eptifibatide in pediatric patients have not been studied.



Nursing Mothers


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



Adverse Reactions


A total of 16,782 patients were treated in the Phase III clinical trials (PURSUIT, ESPRIT, and IMPACT II). These 16,782 patients had a mean age of 62 years (range: 20–94 years). Eighty-nine percent of the patients were Caucasian, with the remainder being predominantly Black (5%) and Hispanic (5%). Sixty-eight percent were men. Because of the different regimens used in PURSUIT, IMPACT II, and ESPRIT, data from the 3 studies were not pooled.



Bleeding


The incidences of bleeding events and transfusions in the PURSUIT, IMPACT II, and ESPRIT studies are shown in Table 8. Bleeding was classified as major or minor by the criteria of the TIMI study group. Major bleeding events consisted of intracranial hemorrhage and other bleeding that led to decreases in hemoglobin greater than 5 g/dL. Minor bleeding events included spontaneous gross hematuria, spontaneous hematemesis, other observed blood loss with a hemoglobin decrease of more than 3 g/dL, and other hemoglobin decreases that were greater than 4 g/dL but less than 5 g/dL. In patients who received transfusions, the corresponding loss in hemoglobin was estimated through an adaptation of the method of Landefeld et al.









Table 8 Bleeding Events and Transfusions in the PURSUIT, ESPRIT, and IMPACT II Studies
PURSUIT
Placebo

n (%)
Eptifibatide 180/1.3*

n (%)
Eptifibatide 180/2.0

n (%)
Note: Denominator is based on patients for whom data are available.

*

Administered only until the first interim analysis.


For major and minor bleeding, patients are counted only once according to the most s