Sunday 29 April 2012

Teveten


Generic Name: eprosartan (EP roe SAR tan)

Brand Names: Teveten


What is Teveten (eprosartan)?

Eprosartan is in a group of drugs called angiotensin II receptor antagonists. Eprosartan keeps blood vessels from narrowing, which lowers blood pressure and improves blood flow.


Eprosartan is used to treat high blood pressure (hypertension). It is sometimes given together with other blood pressure medications.


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


What is the most important information I should know about Teveten (eprosartan)?


Stop using this medication and tell your doctor right away if you become pregnant. Eprosartan can cause injury or death to the unborn baby if you take the medicine during your second or third trimester. You should not use this medication if you are allergic to eprosartan. Drinking alcohol can further lower your blood pressure and may increase certain side effects of eprosartan. Do not use potassium supplements or salt substitutes while you are taking eprosartan, unless your doctor has told you to.

Your blood pressure will need to be checked often. Visit your doctor regularly.


Keep using this medicine as directed, even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medication for the rest of your life.


In rare cases, eprosartan can cause a condition that results in the breakdown of skeletal muscle tissue, leading to kidney failure. Call your doctor right away if you have unexplained muscle pain, tenderness, or weakness especially if you also have fever, unusual tiredness, and dark colored urine.

What should I discuss with my healthcare provider before taking Teveten (eprosartan)?


You should not use this medication if you are allergic to eprosartan.

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


  • kidney disease;

  • liver disease;


  • congestive heart failure; or




  • if you are dehydrated.




FDA pregnancy category D. Do not use eprosartan if you are pregnant. Stop using this medication and tell your doctor right away if you become pregnant. Eprosartan can cause injury or death to the unborn baby if you take the medicine during your second or third trimester. Use effective birth control while taking eprosartan. It is not known whether eprosartan passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I take Teveten (eprosartan)?


Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.


Your doctor may occasionally change your dose to make sure you get the best results.


You may take eprosartan with or without food.


Conditions that may cause very low blood pressure include: vomiting, diarrhea, heavy sweating, heart disease, dialysis, a low salt diet, or taking diuretics (water pills). Follow your doctor's instructions about the type and amount of liquids you should drink while taking eprosartan. Tell your doctor if you have a prolonged illness that causes diarrhea or vomiting.

Your blood pressure will need to be checked often. Visit your doctor regularly.


It may take 2 to 3 weeks of using this medicine before your blood pressure is under control. For best results, keep using the medication as directed. Talk with your doctor if your symptoms do not improve after 3 weeks of treatment.

Keep using this medicine as directed, even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medication for the rest of your life.


Store eprosartan at room temperature away from moisture and heat.

What happens if I miss a dose?


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


What happens if I overdose?


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

Overdose symptoms may include dizziness or feeling like you might pass out.


What should I avoid while taking Teveten (eprosartan)?


Drinking alcohol can further lower your blood pressure and may increase certain side effects of eprosartan. Do not use potassium supplements or salt substitutes while you are taking eprosartan, unless your doctor has told you to.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.


Teveten (eprosartan) side effects


Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat. In rare cases, eprosartan can cause a condition that results in the breakdown of skeletal muscle tissue, leading to kidney failure. Call your doctor right away if you have unexplained muscle pain, tenderness, or weakness especially if you also have fever, unusual tiredness, and dark colored urine. Call your doctor at once if you have a serious side effect such as:

  • feeling like you might pass out;




  • urinating less than usual or not at all;




  • chest pain, fast heart rate; or




  • swelling in your hands or feet.



Less serious side effects may include:



  • runny or stuffy nose, sore throat, cough;




  • joint pain;




  • nausea, stomach pain, diarrhea;




  • headache, dizziness; or




  • tired feeling.



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 Teveten (eprosartan)?


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



  • a diuretic (water pill); or




  • an NSAID (non-steroidal anti-inflammatory drug) such as ibuprofen (Advil, Motrin), naproxen (Aleve, Naprosyn, Naprelan, Treximet), celecoxib (Celebrex), diclofenac (Arthrotec, Cambia, Cataflam, Voltaren, Flector Patch, Pennsaid, Solareze), indomethacin (Indocin), meloxicam (Mobic), and others.



This list is not complete and other drugs may interact with eprosartan. 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 Teveten resources


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


  • Teveten Prescribing Information (FDA)

  • Teveten MedFacts Consumer Leaflet (Wolters Kluwer)

  • Teveten Monograph (AHFS DI)

  • Teveten Advanced Consumer (Micromedex) - Includes Dosage Information

  • Eprosartan Prescribing Information (FDA)



Compare Teveten with other medications


  • High Blood Pressure


Where can I get more information?


  • Your pharmacist can provide more information about eprosartan.

See also: Teveten side effects (in more detail)


Activase


Generic Name: alteplase, recombinant (Intravenous route)


AL-te-plase, ree-KOM-bi-nant


Commonly used brand name(s)

In the U.S.


  • Activase

  • Cathflo Activase

Available Dosage Forms:


  • Powder for Solution

Therapeutic Class: Thrombolytic


Pharmacologic Class: Tissue Plasminogen Activator


Uses For Activase


Alteplase is used to dissolve blood clots that have formed in the blood vessels. It is used immediately after symptoms of a heart attack occur to improve patient survival. It is also used after symptoms of a stroke and to treat blood clots in the lungs (pulmonary embolism) .


Alteplase is used to dissolve blood clots in tubes (catheters) that are placed in large blood vessels (central venous access devices) .


This medicine is available only with your doctor's prescription .


Before Using Activase


In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:


Allergies


Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.


Pediatric


Heart attack, stroke, pulmonary embolism—Appropriate studies have not been performed on the relationship of age to the effects of alteplase in the pediatric population. Safety and efficacy have not been established .


Central venous access devices—Appropriate studies performed to date have not demonstrated pediatrics-specific problems that would limit the usefulness of alteplase in children .


Geriatric


Heart attack, stroke, pulmonary embolism—No information is available on the relationship of age to the effects of alteplase in geriatric patients .


Central venous access devices—Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of alteplase in the elderly .


Pregnancy








Pregnancy CategoryExplanation
All TrimestersCAnimal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding


There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.


Interactions with Medicines


Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are receiving this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.


Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.


  • Abciximab

  • Acenocoumarol

  • Alteplase, Recombinant

  • Anistreplase

  • Ardeparin

  • Argatroban

  • Aspirin

  • Benazepril

  • Bivalirudin

  • Captopril

  • Certoparin

  • Cilostazol

  • Clopidogrel

  • Dabigatran Etexilate

  • Dalteparin

  • Danaparoid

  • Desirudin

  • Dipyridamole

  • Drotrecogin Alfa

  • Enalapril

  • Enalaprilat

  • Enoxaparin

  • Eptifibatide

  • Fondaparinux

  • Fosinopril

  • Heparin

  • Lepirudin

  • Lisinopril

  • Moexipril

  • Nadroparin

  • Nitroglycerin

  • Parnaparin

  • Perindopril

  • Phenindione

  • Phenprocoumon

  • Prasugrel

  • Protein C, Human

  • Quinapril

  • Ramipril

  • Reteplase, Recombinant

  • Reviparin

  • Rivaroxaban

  • Streptokinase

  • Sulfinpyrazone

  • Tenecteplase

  • Ticlopidine

  • Tinzaparin

  • Tirofiban

  • Trandolapril

  • Treprostinil Sodium

  • Urokinase

  • Warfarin

Interactions with Food/Tobacco/Alcohol


Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.


Other Medical Problems


The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:


  • Bleeding problems or a history of bleeding in any part of the body or

  • Blood vessel problems (e.g., aneurysm or arteriovenous malformation) or

  • Brain disease or tumor or

  • High blood pressure, uncontrolled or

  • Stroke, history of or

  • Surgery or injury to the brain or spine, recent (within three months)—This medicine should NOT be used in these conditions .

  • Blood clots, history of or

  • Diabetic eye problems (e.g. hemorrhagic retinopathy) or

  • Heart infections (e.g., pericarditis or endocarditis) or

  • Injections into a blood vessel or

  • Kidney disease, severe or

  • Liver disease, severe or

  • Placement of any catheter (tube) into the body or

  • Surgery or injury of any kind, major and recent—The chance of serious bleeding may be increased .

  • Catheter (tube) infection or

  • Deep venous thrombosis (blood clots in the legs) or

  • High cholesterol, history of—The chance of having a serious side effect may be increased .

  • Heart rhythm problems—This condition may get worse .

Proper Use of alteplase, recombinant

This section provides information on the proper use of a number of products that contain alteplase, recombinant. It may not be specific to Activase. Please read with care.


A doctor or other trained health professional will give you this medicine. This medicine is given through a needle or tube placed into one of your blood vessels .


Precautions While Using Activase


Alteplase can cause bleeding that usually is not serious. However, serious bleeding may occur in some people. To help prevent serious bleeding, carefully follow any instructions given by your doctor. Move around as little as possible, and do not get out of bed on your own, unless your doctor tells you it is all right to do so.


Watch for any bleeding or oozing on your skin, such as around the place of injection or where blood was drawn from your arm. Also, check for blood in your urine or bowel movements. If you have any bleeding or injuries, tell your doctor or nurse right away .


Activase Side Effects


Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.


Check with your doctor or nurse immediately if any of the following side effects occur:


More common
  • Bleeding from puncture sites and wounds

  • bleeding gums

  • coughing up blood

  • difficulty with breathing or swallowing

  • dizziness

  • headache

  • increased menstrual flow or vaginal bleeding

  • nosebleeds

  • paralysis

  • prolonged bleeding from cuts

  • red or black, tarry stools

  • red or dark brown urine

  • shortness of breath

Rare
  • Chills

  • confusion

  • fainting

  • fast heartbeat

  • fever

  • lightheadedness

  • pain in chest, groin, or legs, especially the calves

  • pain, redness, or swelling in arm or leg

  • rapid, shallow breathing

  • severe, sudden headache

  • slurred speech

  • sudden loss of coordination

  • sudden, severe weakness or numbness in arm or leg

  • sudden, unexplained shortness of breath

  • vision changes

Incidence not determined
  • Anxiety

  • blue lips and fingernails

  • blue or pale skin

  • blurred vision

  • chest pain or discomfort

  • chest pain, possibly moving to the left arm, neck, or shoulder

  • convulsions

  • cool, sweaty skin

  • cough

  • coughing that sometimes produces a pink frothy sputum

  • decreased urine output

  • dilated neck veins

  • extreme fatigue

  • hives or welts

  • hoarseness

  • increased sweating

  • itching

  • large, hive-like swelling on mouth, lips, or tongue

  • loss of bladder control

  • low blood pressure or pulse

  • muscle spasm or jerking of all extremities

  • nausea or vomiting

  • pain or discomfort in arms, jaw, back, or neck

  • puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue

  • redness of skin

  • skin rash

  • slow or irregular breathing or heartbeat

  • sudden loss of consciousness

  • sweating

  • swelling of face, fingers, feet, lower legs, or ankles

  • tightness in chest

  • troubled breathing

  • unconsciousness

  • unusual tiredness or weakness

  • weight gain

  • wheezing

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.


Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: Activase side effects (in more detail)



The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.


The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.


More Activase resources


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


  • Activase MedFacts Consumer Leaflet (Wolters Kluwer)

  • Alteplase Monograph (AHFS DI)

  • Cathflo Activase MedFacts Consumer Leaflet (Wolters Kluwer)



Compare Activase with other medications


  • Heart Attack
  • Ischemic Stroke
  • Pulmonary Embolism
  • Thrombotic/Thromboembolic Disorder

Thursday 26 April 2012

Light Anesthesia Medications


Drugs associated with Light Anesthesia

The following drugs and medications are in some way related to, or used in the treatment of Light Anesthesia. This service should be used as a supplement to, and NOT a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners.





Drug List:

Anagrelide hydrochloride


Class: Platelet-reducing Agents
VA Class: BL400
Chemical Name: 6,7-dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-one monohydrochloride monohydrate
CAS Number: 58579-51-4; 68475-42-3
Brands: Agrylin

Introduction

Platelet-reducing agent; imidazoquinazoline derivative.1 4 5 7 9 10 11 12 14 15 16 17 18 22 23 24 26 31 32


Uses for Anagrelide hydrochloride


Thrombocythemia


Reduction of elevated platelet counts and associated risk of thromboembolic and hemorrhagic events in patients with thrombocythemia secondary to essential thrombocythemia (ET) and other myeloproliferative disorders.1 3 7 13 14 15 17 18 23 Has been designated an orphan drug by FDA for the treatment of ET.2


Management of ET generally based on a risk-stratification approach.3 7 11 14 16 19 20 22 25 27 31 32 Treatment with a cytoreductive agent (e.g., anagrelide, hydroxyurea) usually reserved for patients at high risk (i.e., age >60 years, previous history of thrombosis, and/or platelet count ≥1,500,000/mm3) of developing thromboembolic and/or hemorrhagic complications.3 7 9 11 12 13 14 16 20 25 31 32 Some clinicians also recommend cytoreductive therapy in intermediate-risk ET patients (e.g., 40–60 years of age, platelet count >1,000,000/mm3, and cardiovascular risk factor [smoking, arterial hypertension, hypercholesterolemia, or diabetes mellitus] or familial thrombophilia).27 31 32


Hydroxyurea (often combined with low-dose aspirin) generally considered drug of choice in high-risk patients with ET because of proven efficacy and infrequent acute toxicity.3 6 7 11 14 17 20 21 22 25 27 30 32 However, because of potential leukemogenic effects with hydroxyurea when used long term or sequentially with other cytotoxic drugs,3 5 7 anagrelide or interferon alfa suggested as alternative therapy in high-risk patients, particularly younger patients (<40–60 years of age), and in those who do not respond to or cannot tolerate hydroxyurea.3 5 7 9 17 22 24 25 27 31 32 Consider cautious use of low-dose aspirin concomitantly with anagrelide based on relative risks of thrombosis and arterial hemorrhage in individual patients.3 5 6 11 27 31 32 (See Specific Drugs or Foods under Interactions.)


Anagrelide hydrochloride Dosage and Administration


General



  • Initiate therapy under close supervision of a clinician.1




  • Monitor platelet counts every 2 days for 1 week following initiation of therapy, then at least weekly thereafter until maintenance dosage established.1 23



Administration


Oral Administration


Administer orally without regard to meals.1


Dosage


Available as anagrelide hydrochloride; dosage expressed in terms of anagrelide.1


Pediatric Patients


Thrombocythemia

Oral

Children and adolescents 7–14 years of age: Initially, 0.5 mg daily.1 Initial dosages up to 0.5 mg 4 times daily have been used.1


Maintain initial dosage for ≥1 week, then adjust to lowest effective dosage that will maintain platelet counts <600,000/mm3 or ideally within normal range.1 17 Usual maintenance dosage is 1.5–3 mg daily.1 17 18


Increase dosage by ≤0.5 mg daily in any 1-week period.1 17


Continue therapy indefinitely if adequate response achieved.17 23


Adults


Thrombocythemia

Oral

Initially, 0.5 mg 4 times daily or 1 mg twice daily recommended by manufacturer.1 Lower dosages (e.g., 0.5 mg twice daily) have been used and may improve tolerability.5


Maintain initial dosage for ≥1 week, then adjust to lowest effective dosage that will maintain platelet counts <600,000/mm3 or ideally within normal range (e.g., 150,000–400,000/mm3).1 17 Usual maintenance dosage is 1.5–3 mg daily.1 13 17 22


Increase dosage by ≤0.5 mg daily in any 1-week period.1 17 22


Continue therapy indefinitely if adequate response achieved.17 23


Prescribing Limits


Pediatric Patients


Thrombocythemia

Oral

Children and adolescents 7–14 years of age: Maximum 10 mg daily or 2.5 mg as a single dose.1


Adults


Thrombocythemia

Oral

Maximum 10 mg daily or 2.5 mg as a single dose.1


Special Populations


Hepatic Impairment


In patients with moderate hepatic impairment, reduce initial dosage to 0.5 mg daily and maintain for ≥1 week.1 Increase dosage by ≤0.5 mg daily in any 1-week period.1 (See Hepatic Impairment under Cautions.)


Contraindicated in severe hepatic impairment.1


Renal Impairment


Dosage adjustment not required in patients with renal impairment.1


Cautions for Anagrelide hydrochloride


Contraindications


Severe hepatic impairment.1


Warnings/Precautions


Warnings


Cardiovascular Effects

Adverse cardiovascular effects (e.g., vasodilation, tachycardia, palpitations, edema, CHF) reported with usual dosages of anagrelide, including rare cases of sudden death.1 5 16 17 18 26 Assess risk versus benefits of therapy.1 16 17 Use with caution, if at all, in patients with known or suspected cardiovascular disease.1 5 13 15 16 17 18 22 23 24 Evaluate cardiac status prior to and during therapy.1 5 13 16 17 Consider reduced dosages.5 Some clinicians recommend immediate discontinuance of therapy if any evidence of cardiac dysfunction occurs.5 26


Temporary decreases in BP reported, usually during treatment initiation; BP appears to normalize during maintenance therapy.5 9 17 23 24


General Precautions


Laboratory Monitoring

Monitor CBCs, liver function tests, and renal function tests while platelet counts are being decreased, usually during first 2 weeks of therapy.1


To assess response to therapy and prevent thrombocytopenia, monitor platelet counts every 2 days for first week of therapy, then at least weekly thereafter until maintenance dosage achieved.1 23


Rebound Thrombocythemia

A rapid (e.g., within 4 days) increase in platelet count generally is observed when anagrelide is discontinued or interrupted.1 5 16 17 18 23 Continue treatment indefinitely (if adequate response achieved) to prevent rebound thrombocythemia.17 23


Anemia

Decreases in hemoglobin and hematocrit (anemia) reported, usually with long-term use.1 5 9 10 12 13 16 17 18 24 27


Bleeding Tendency

Concomitant use with aspirin may increase bleeding tendency.3 5 6 9 (See Specific Drugs and Foods under Interactions.) Use caution with such combined therapy.3 5 6 Some clinicians suggest that aspirin not be used concomitantly with anagrelide in patients with history of bleeding.3


Renal Effects

Renal impairment reported in a few patients following treatment with anagrelide; most patients had preexisting renal impairment.1 17 23 Monitor renal function while platelet counts are being decreased.1


Fetal/Neonatal Morbidity

Safety of use during pregnancy not established; embryotoxicity and fetotoxicity demonstrated in animals.1 Generally not recommended in pregnant women unless potential benefits outweigh possible risks to fetus.1 5 11 16 22 Women of childbearing potential should avoid pregnancy and use contraception during therapy.1 5


Specific Populations


Pregnancy

Category C.1


Lactation

Not known whether anagrelide is distributed into human milk.1 Discontinue nursing or drug because of potential risk in nursing infants.1 5


Pediatric Use

Evaluated in a limited number of children and adolescents 7–14 years of age with thrombocythemia secondary to myeloproliferative disorders;1 28 29 preliminary data suggest no overall differences in dosage or adverse effects relative to adults.1


Geriatric Use

Response in patients ≥65 years of age does not appear to differ from that in younger adults.1 Use with caution because of age-related decreases in hepatic, renal, and/or cardiac function.1 5 16 22


Hepatic Impairment

Extensively metabolized in liver; possible increased systemic exposure to anagrelide in patients with hepatic impairment.1 9 (See Elimination: Special Populations, under Pharmacokinetics.)


Weigh risks of therapy against potential benefits in patients with mild to moderate hepatic impairment.1 Reduce dosage and carefully monitor for adverse cardiovascular effects or other manifestations of toxicity.1 17 22 23 (See Hepatic Impairment under Dosage and Administration and see Cardiovascular Effects under Cautions.)


Contraindicated in patients with severe hepatic impairment.1


Renal Impairment

Closely monitor patients with known or suspected renal impairment for cardiovascular effects or other manifestations of toxicity.1 17 23


Common Adverse Effects


Headache,1 3 5 7 9 10 16 17 18 23 24 palpitations,1 3 5 7 9 10 16 17 18 23 24 diarrhea,1 3 5 7 9 10 17 18 23 24 asthenia,1 9 23 edema,1 5 9 10 16 17 18 23 24 nausea,1 7 9 18 23 24 abdominal pain,1 9 17 18 23 24 dizziness,1 9 16 18 23 24 pain,1 9 dyspnea,1 9 flatulence,1 9 18 vomiting,1 9 23 fever,1 9 peripheral edema,1 9 rash,1 9 chest pain,1 23 anorexia,1 9 tachycardia,1 7 9 16 18 23 24 pharyngitis,1 9 malaise,1 9 23 cough,1 9 paresthesia,1 9 back pain,1 pruritus,1 9 dyspepsia.1 9


Interactions for Anagrelide hydrochloride


Metabolized partially by CYP1A2; inhibits CYP1A2 to a limited extent.1


Inhibits phosphodiesterase (PDE) type 3.1 4 5 9 10 11 16 18 22 23


Drugs Affecting Hepatic Microsomal Enzymes


Inhibitors of CYP1A2: Potential pharmacokinetic interaction (decreased clearance of anagrelide).1 9 22


Drugs Metabolized by Hepatic Microsomal Enzymes


CYP1A2 substrates: Potential pharmacokinetic interaction (decreased clearance of substrate).1 22


Specific Drugs or Foods

































Drug or Food



Interaction



Comments



Aspirin



No clinically important interaction observed in vivo;1 however, potential for increased risk of bleeding due to additive platelet inhibition3 5 9 10 11 14 22 27



Use concomitantly with caution, considering individual risks of thrombosis and bleeding; carefully monitor for bleeding3 5 11 27



Digoxin



Pharmacokinetic interaction unlikely1 9 22



Fluvoxamine



Possible decreased clearance of anagrelide1 9 22



Grapefruit juice



Possible decreased clearance of anagrelide 9 22



Omeprazole



Possible decreased clerance of anagrelide 22



PDE type 3 inhibitors (e.g., amrinone, cilostazol, milrinone)



Possible additive pharmacologic effects1 9 22



Use with caution22



Sucralfate



Possible decreased absorption of anagrelide1



Theophylline



Possible decreased clearance of theophylline 1 9 22



Warfarin



Pharmacokinetic interaction unlikely1 9 22


Anagrelide hydrochloride Pharmacokinetics


Absorption


Bioavailability


Well absorbed following oral administration. 9


Following oral administration, peak plasma concentrations attained within 1–2 hours.5 9 22 23 24


No evidence of drug accumulation following multiple dosing.1 9 29


Onset


Platelet counts usually begin to decrease within 7–14 days.1 5 9 10 17 22 Complete response (e.g., platelet count ≤600,000/mm3) generally achieved within 4–12 weeks.1


Food


Food decreases peak plasma concentrations by 14% and increases AUC by 20%; not clinically important.1 5 9


Special Populations


In children and adolescents 7–14 years of age, AUC and peak plasma anagrelide concentrations lower than those in adults 16–86 years of age.1


Distribution


Extent


Distributes extensively into large peripheral compartment.24


Crosses placenta.5


Elimination


Metabolism


Extensively metabolized in liver to at least 4 metabolites, including an active hydroxylated derivative (3-hydroxyanagrelide).1 4 5 9 16 17 22 23 24


Undergoes first-pass metabolism by CYP1A2 to 3-hydroxyanagrelide.9


Elimination Route


Excreted principally in urine as metabolites (>70%) and unchanged drug (<1%).5 9 16 17 22 23 24 Approximately 10% excreted in feces through bile.5 24


Half-life


Anagrelide: Approximately 1.3 hours after a single 0.5-mg dose under fasting conditions.1 17 29


3-Hydroxyanagrelide: Approximately 3 hours.29


Special Populations


Systemic exposure increased eightfold in patients with moderate hepatic impairment compared with that in healthy individuals.1 9


Severe renal impairment (Clcr <30 mL/minute) does not appear to affect pharmacokinetics of anagrelide.1 9


Possible decreased clearance and prolonged half-life in geriatric patients.5


Stability


Storage


Oral


Tablets

25°C in light-resistant container; may be exposed to 15–30°C.1


ActionsActions



  • Exact mechanism of action not fully elucidated;1 4 9 12 17 22 23 thought to reduce platelet counts in a dose-related manner by selectively inhibiting megakaryocyte maturation during postmitotic stage of development.1 4 6 9 10 12 13 14 15 16 17 18 19 22 23 23 24 Reduces size and ploidy of megakaryocytes, but does not appear to affect platelet function or bleeding time.1 5 9 15 16 17 19 22 24 23




  • Acts selectively on megakaryocytes with minimal or no effect on other blood-cell precursors.3 4 5 11 13 14 17 18 23 24 Current data suggest no long-term leukemogenicity.3 5 17 23




  • Inhibits phospholipase A2 and phosphodiesterase (PDE) type 3 activity in platelets; results in increased concentrations of cyclic adenosine monophosphate (cAMP).1 4 5 9 10 11 16 18 22 23 24 29 Such increases in cAMP may produce an anti-aggregating effect on platelets at dosages substantially higher than those required to cause thrombocytopenia.1 3 4 5 6 8 9 11 15 16 17 18 23 24




  • Exerts positive inotropic and vasodilatory effects through inhibition of cAMP PDE type 3 in myocardium;5 9 11 16 17 18 22 23 24 26 such actions may result in adverse cardiovascular effects.9 10 16 17 23 26



Advice to Patients



  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. 1 Advise women of childbearing potential to avoid pregnancy and use effective contraception while taking anagrelide.1 If pregnancy occurs, apprise patient of potential risk to fetus.1




  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., liver disease).1




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



Preparations


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


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




























Anagrelide Hydrochloride

Routes



Dosage Forms



Strengths



Brand Names



Manufacturer



Oral



Capsules



0.5 mg (of anagrelide)*



Agrylin



Shire



Anagrelide Hydrochloride Capsules



Barr, Mylan, Sandoz, Teva



1 mg (of anagrelide)*



Agrylin



Shire



Anagrelide Hydrochloride Capsules



Barr, Mylan, Sandoz, Teva


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.


Agrylin 0.5MG Capsules (SHIRE US INC.): 50/$329.97 or 150/$970.02


Agrylin 1MG Capsules (SHIRE US INC.): 50/$545.99 or 150/$1621.95


Anagrelide HCl 0.5MG Capsules (IVAX PHARMACEUTICALS INC.): 30/$79.98 or 90/$235.97


Anagrelide HCl 1MG Capsules (IVAX PHARMACEUTICALS INC.): 50/$109.99 or 150/$310.02



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 September 01, 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.




References



1. Shire. Agrylin (anagrelide hydrochloride) capsules prescribing information. Wayne, PA; 2004 Dec.



2. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD. From FDA web site. Accessed 2007 Nov 30.



3. Steurer M, Gastl G, Jedrzejczak WW et al. Anagrelide for thrombocytosis in myeloproliferative disorders: a prospective study to assess efficacy and adverse event profile. Cancer. 2004; 101:2239-46. [PubMed 15476273]



4. Wang G, Franklin R, Hong Y et al. Comparison of the biological activities of anagrelide and its major metabolites in haematopoietic cell cultures. Br J Pharmacol. 2005; 146:324-32. [PubMed 16041400]



5. Petrides PE. Anagrelide: a decade of clinical experience with its use for the treatment of primary thrombocythaemia. Expert Opin Pharmacother. 2004; 5:1781-98. [PubMed 15264993]



6. Harrison CN, Campbell PJ, Buck G et al for the United Kingdom Medical Research Council Primary Thrombocythemia 1 Study. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med. 2005; 353:33-45. [PubMed 16000354]



7. Penninga EI, Bjerrum OW. Polycythaemia vera and essential thrombocythaemia: current treatment strategies. Drugs. 2006; 66:2173-87. [PubMed 17137402]



8. Petrides PE. Anagrelide: What was new in 2004 and 2005? Semin Thromb Hemost. 2006; 32:399-408.



9. Wagstaff AJ, Keating GM. Anagrelide: a review of its use in the management of essential thrombocythaemia. Drugs. 2006; 66:111-31. [PubMed 16398570]



10. Birgegard G. Anagrelide treatment in myeloproliferative disorders. Semin Thromb Hemost. 2006; 32:260-6. [PubMed 16673280]



11. Campbell PJ, Green AR. Management of polycythemia vera and essential thrombocythemia. Hematology Am Soc Hematol Educ Program. 2005; 201-8.



12. Storen EC, Tefferi A. Long-term use of anagrelide in young patients with essential thrombocythemia. Blood. 2001; 97:863-6. [PubMed 11159509]



13. Mazzucconi MG, Redi R, Bernasconi S et al. A long-term study of young patients with essential thrombocythemia treated with anagrelide. Haematologica. 2004; 89:1306-13. [PubMed 15531452]



14. Barbui T, Finazzi G. When and how to treat essential thrombocythemia. N Engl J Med. 2005; 353:85-6. [PubMed 16000360]



15. Laguna MS, Kornblihtt LI, Marta RF et al. Effectiveness of anagrelide in the treatment of symptomatic patients with essential thrombocythemia. Clin Appl Thromb Hemost. 2000; 6:157-61. [PubMed 10898276]



16. Brooks WG, Stanley DD, Goode JV. Role of anagrelide in the treatment of thrombocytosis. Ann Pharmacother. 1999; 33:1116-8. [PubMed 10534225]



17. Oertel MD. Anagrelide, a selective thrombocytopenic agent. Am J HealthSyst Pharm. 1998; 55:1979-86.



18. Anagrelide Study Group. Anagrelide, a therapy for thrombocythemic states: experience in 577 patients. Am J Med. 1992; 92:69-76. [PubMed 1731512]



19. Thiele J, Kvasnicka HM, Schmitt-Graeff A. Effects of anagrelide on megakaryopoiesis and platelet production. Semin Thromb Hemost. 2006; 32:352-61. [PubMed 16810611]



20. Tefferi A. Essential thrombocythemia: scientific advances and current practice. Curr Opin Hematol. 2006; 13:93-8. [PubMed 16456375]



21. American Society of Hematology. Old treatment remains best option for patients with blood disorder [Abstract 6]. Washington, DC; 2004 Dec 5. Press release.



22. Harrison CN. Anagrelide for control of thrombocytosis due to myeloproliferative disorders. Future Oncol. 2005; 1:609-18. [PubMed 16556037]



23. Pescatore SL, Lindley C. Anagrelide: a novel agent for the treatment of myeloproliferative disorders. Expert Opin Pharmacother. 2000; 1:537-46. [PubMed 11249536]



24. Spencer CM, Brogden RN. Anagrelide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in the treatment of thrombocythaemia. Drugs. 1994; 47:809-22. [PubMed 7520859]



25. Finazzi G, Barbui T. Expertise-based management in essential thrombocythemia and polycythemia vera. Cancer J. 2007; 13:372-6. [PubMed 18032974]



26. Engel PJ, Johnson H, Baughman RP et al. High-output heart failure associated with anagrelide therapy for essential thrombocytosis. Ann Intern Med. 2005; 143:311-3. [PubMed 16103481]



27. Gisslinger H. Update on diagnosis and management of essential thrombocythemia. Semin Thromb Hemost. 2006; 32:430-6. [PubMed 16810619]



28. Chintagumpala MM, Kennedy LL, Steuber CP. Treatment of essential thrombocythemia with anagrelide. J Pediatr. 1995; 127:495-8. [PubMed 7658287]



29. Shire, Wayne, PA: Personal communication.



30. Barosi G, Besses C, Birgegard G et al. A unified definition of clinical resistance/intolerance to hydroxyurea in essential thrombocythemia: results of a consensus process by an international working group. Leukemia. 2007; 21:277-80. [PubMed 17251900]



31. Briere JB. Essential thrombocythemia. Orphanet J Rare Dis.. 2007; 2:3. Available from website. Accessed 2008 Jan 2.



32. Barbui T, Barosi G, Grossi A et al. Practice guidelines for the therapy of essential thrombocythemia. A statement from the Italian Society of Hematology, the Italian Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation. Haematologica. 2004; 89:215-32. [PubMed 15003898]



More Anagrelide hydrochloride resources


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


  • Anagrelide Professional Patient Advice (Wolters Kluwer)

  • Anagrelide Prescribing Information (FDA)

  • Agrylin Prescribing Information (FDA)

  • Agrylin Concise Consumer Information (Cerner Multum)

  • Agrylin Advanced Consumer (Micromedex) - Includes Dosage Information

  • Agrylin MedFacts Consumer Leaflet (Wolters Kluwer)



Compare Anagrelide hydrochloride with other medications


  • Chronic Myelogenous Leukemia
  • Thrombocythemia

Zone-A Forte


Generic Name: hydrocortisone and pramoxine topical (HYE droe KOR ti sone and pra MOX een)

Brand Names: Analpram E, Analpram-HC, Epifoam, HC Pramoxine, Hydropram, Novacort, Pramosone, Proctofoam HC, Rectocort HC, ZyPram


What is Zone-A Forte (hydrocortisone and pramoxine topical)?

Pramoxine is an anesthetic. It works by interfering with pain signals sent from the nerves to the brain.


Hydrocortisone is a steroid. It reduces the actions of chemicals in the body that cause inflammation, redness, and swelling.


The combination of hydrocortisone and pramoxine topical is used to treat pain, itching, or inflammation of the skin caused by a number of conditions such as allergic reactions, eczema, psoriasis, insect bites, and minor burns or scrapes. This medication is also used on the rectal area to treat itching and inflammation caused by hemorrhoids, anal fissures, or other rectal irritation.


Hydrocortisone and pramoxine topical may also be used for other purposes not listed in this medication guide.


What is the most important information I should know about Zone-A Forte (hydrocortisone and pramoxine topical)?


You should not use this medication if you are allergic to hydrocortisone or pramoxine, or if you have chickenpox or measles.

Before using hydrocortisone and pramoxine topical, tell your doctor if you are allergic to any drugs or any other anesthetics or "numbing medicines."


Hydrocortisone and pramoxine topical will not treat a bacterial, fungal, or viral skin infection. If you have a skin infection, you should not use this medication until your infection is treated and clears up.


Avoid using this medication on your face, near your eyes, or on body areas where you have skin folds or thin skin.


Do not use this medication on a child without a doctor's advice. Children are more sensitive to the effects of topical hydrocortisone. Do not cover treated skin areas with a bandage or other covering unless your doctor has told you to. If you are treating the diaper area of a baby, do not use plastic pants or tight-fitting diapers. Covering the skin that is treated with hydrocortisone topical can increase the amount of the drug your skin absorbs, which may lead to unwanted side effects. Follow your doctor's instructions. Contact your doctor if your condition does not improve or if it gets worse after using this medication for several days.

Do not use hydrocortisone and pramoxine topical for any condition that has not been checked by a doctor.


What should I discuss with my health care provider before using Zone-A Forte (hydrocortisone and pramoxine topical)?


You should not use this medication if you are allergic to hydrocortisone or pramoxine, or if you have chickenpox or measles.

Before using hydrocortisone and pramoxine topical, tell your doctor if you are allergic to any drugs or any other anesthetics or "numbing medicines." Also tell your doctor if you have:



  • liver disease;




  • diabetes;




  • problems with your eyes;




  • a stomach or intestinal disorder;




  • a rectal sore or infection; or




  • if you use any drugs that weaken the immune system, including steroids.



Hydrocortisone and pramoxine topical will not treat a bacterial, fungal, or viral skin infection. If you have a skin infection, you should not use this medication until your infection is treated and clears up.


FDA pregnancy category C. It is not known whether this medication is harmful to an unborn baby. Before using hydrocortisone and pramoxine topical, tell your doctor if you are pregnant or plan to become pregnant during treatment. It is not known whether hydrocortisone and pramoxine topical passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby. Do not use this medication on a child without a doctor's advice. Children are more sensitive to the effects of topical hydrocortisone.

How should I use Zone-A Forte (hydrocortisone and pramoxine topical)?


Use this medication exactly as directed on the label, or as prescribed by your doctor. Do not use it in larger amounts or for longer than recommended. Follow the directions on your prescription label.


Hydrocortisone and pramoxine topical is usually applied 3 or more times daily, depending on which form of this medication you use. Follow the label directions or your doctor's instructions about how much of this medication to use and how often. Do not use hydrocortisone and pramoxine topical for any condition that has not been checked by a doctor.


Wash your hands before and after applying this medication, unless you are using hydrocortisone and pramoxine topical to treat a hand condition.

When using this medication on the skin, apply just enough of the medication to cover the area to be treated. Rub in gently.


Avoid using this medication on your face, near your eyes or mouth, or on body areas where you have skin folds or thin skin.


Do not cover treated skin areas with a bandage or other covering unless your doctor has told you to. If you are treating the diaper area of a baby, do not use plastic pants or tight-fitting diapers. Covering the skin that is treated with hydrocortisone topical can increase the amount of the drug your skin absorbs, which may lead to unwanted side effects. Follow your doctor's instructions.

Before apply the rectal form of this medication (cream, lotion, or foam), clean the rectal area with mild soap and pat dry.


Use only a small amount of medicine when applying hydrocortisone and pramoxine around the outside of the rectum. You may first place the medicine onto a clean tissue and then wipe it gently onto your rectum.


When using this medication inside the rectum, insert only the applicator tip of the medicine tube or foam can into the anus, no deeper than 1 inch.


Shake the hydrocortisone and pramoxine rectal foam before each use. Contact your doctor if your condition does not improve or if it gets worse after using this medication for several days, or if your condition clears up and then comes back. Do not stop using hydrocortisone and pramoxine topical suddenly after long-term use, or you could have unpleasant withdrawal symptoms. Talk to your doctor about how to avoid withdrawal symptoms when you stop using the medication. Store this medication at room temperature away from moisture and heat. Keep the rectal foam canister away from open flame or high heat. The canister may explode if it gets too hot. Do not puncture or burn an empty canister.

What happens if I miss a dose?


Use the medication as soon as you remember. If it is almost time for the next dose, skip the missed dose and use the medicine at the next regularly scheduled time. Do not use 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 hydrocortisone and pramoxine topical is not expected to produce life-threatening symptoms. However, long-term use of high steroid doses can lead to symptoms such as thinning skin, easy bruising, changes in the shape or location of body fat (especially in your face, neck, back, and waist), increased acne or facial hair, menstrual problems, impotence, or loss of interest in sex.


What should I avoid while using Zone-A Forte (hydrocortisone and pramoxine topical)?


Avoid using this medication on your face, near your eyes, or on body areas where you have skin folds or thin skin. If it does get into any of these areas, wash with water. Do not use hydrocortisone and pramoxine topical on deep skin wounds, blistered skin, severe burns, irritated skin, or large skin areas. Also avoid using this medication in open wounds.

Avoid applying other skin medications on the same treatment area with hydrocortisone and pramoxine topical, unless your doctor has told you to.


Using a steroid can lower the blood cells that help your body fight infections. This can make it easier for you to get sick from being around others who are ill. Call your doctor for preventive treatment if you are exposed to chicken pox or measles. These conditions can be serious or even fatal in people who are using steroid medicines.


Hydrocortisone pramoxine topical 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 any of these serious side effects:

  • blurred vision, or seeing halos around lights;




  • uneven heartbeats;




  • sleep problems (insomnia);




  • ongoing headache;




  • weight gain, puffiness in your face;




  • increased thirst or urination, weight loss, unusual weakness;




  • fever, sore throat, tired feeling;




  • severe pain, burning, or irritation of treated skin;




  • rectal bleeding;




  • any new redness or swelling where the medicine was applied; or




  • itching, oozing, or other signs of infection.



Less serious side effects may include:



  • mild skin redness, burning, itching, dryness, or peeling;




  • acne;




  • changes in the color of treated skin;




  • thinning of your skin;




  • blistering skin; or




  • stretch marks.



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 Zone-A Forte (hydrocortisone and pramoxine topical)?


It is not likely that other drugs you take orally or inject will have an effect on topically applied hydrocortisone and pramoxine. But many drugs can interact with each other. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.



More Zone-A Forte resources


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


  • Analpram-HC Cream MedFacts Consumer Leaflet (Wolters Kluwer)

  • Epifoam Prescribing Information (FDA)

  • Epifoam Foam MedFacts Consumer Leaflet (Wolters Kluwer)

  • Novacort MedFacts Consumer Leaflet (Wolters Kluwer)

  • Pramosone Prescribing Information (FDA)

  • Pramosone Lotion MedFacts Consumer Leaflet (Wolters Kluwer)

  • Proctocream HC Prescribing Information (FDA)

  • Proctofoam HC Prescribing Information (FDA)

  • Proctofoam HC Foam MedFacts Consumer Leaflet (Wolters Kluwer)



Compare Zone-A Forte with other medications


  • Dermatitis
  • Dermatological Disorders
  • Hemorrhoids
  • Psoriasis


Where can I get more information?


  • Your pharmacist can provide more information about hydrocortisone and pramoxine topical.

See also: Zone-A Forte side effects (in more detail)


Lipobase





Lipobase cream





Read all of this leaflet carefully because it contains important information for you.



This medicine is available without prescription. However, you still need to use Lipobase carefully to get the best results from it.



  • Keep this leaflet. You may need to read it again.

  • Ask your pharmacist if you need more information or advice.

  • You must contact a doctor if your symptoms worsen or do not improve.

  • If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.




In this leaflet:



  • 1. What Lipobase is and what it is used for

  • 2. Before you use Lipobase

  • 3. How to use Lipobase

  • 4. Possible side effects

  • 5. How to store Lipobase

  • 6. Further information





What Lipobase Is And What It Is Used For



Lipobase is an emollient cream which restores the physiological balance of the skin.



It enhances the hydration of the outer layer of the skin (epidermis), reduces dryness, prevents scaling and protects the skin from harm.



The cream is an oil-in-water emulsion with a high lipid content (70%). It does not contain perfume. The components of the cream are selected to minimise the risk of allergy.



Lipobase cream is indicated for the treatment of dry, sensitive and dehydrated skin. You may also use it against skin irritations caused by water or detergents and for maintaining improvement. You can use Lipobase cream alternately with creams or ointments containing corticosteroids. The cream may be used by adults and children.





Before You Use Lipobase




Do not use Lipobase



  • if you are allergic (hypersensitive) to any of the ingredients of Lipobase.




Take special care with Lipobase



You may apply Lipobase to your face. It does not stain your clothing and can easily be washed off with water.





Pregnancy and breast-feeding



You may use Lipobase if you are pregnant or if you breast feed.





Important information about some of the ingredients of Lipobase



Lipobase contains methyl parahydroxybenzoate. This may cause allergic reactions (possibly delayed).



Lipobase contains cetostearyl alcohol. This may cause local skin reactions (e.g. contact dermatitis).






How To Use Lipobase



If your doctor advised you to use this cream, use it exactly as your doctor has instructed you.



Apply a thin layer of cream to the skin one to three times per day, or more often if necessary. You can use the cream more often on places where the cream is likely to be removed by washing or rubbing.



The duration of treatment depends on the condition of the skin. There is no maximum duration.



If you have any further questions on the use of this product, ask your doctor or pharmacist.





Lipobase Side Effects



Like all medicines, Lipobase can cause side effects, although not everybody gets them.




Lipobase may cause allergic reactions of the skin.



For any possible undesirable effects or unusual reactions associated with this preparation, please consult your doctor.





How To Store Lipobase



Do not store above 25°C.



Keep out of the reach and sight of children.



Do not use Lipobase after the expiry date which is stated on the package. The expiry date refers to the last day of that month.





Further Information




What Lipobase contains



Lipobase contains: sodium citrate, citric acid, methyl parahydroxybenzoate, Macrogol (25) cetostearyl ether, cetostearyl alcohol, light liquid paraffin, white soft paraffin, purified water.





What Lipobase looks like and contents of the pack



Lipobase is a white cream.



It is available in aluminium tubes, containing 50 g cream.





Marketing Authorisation Holder and Manufacturer



Marketing Authorisation Holder:




Astellas Pharma Ltd

Lovett House

Lovett Road

Staines

TW18 3AZ

UK



Manufacturer:




Temmler Italie S.r.l.

Via Delle Industrie 2

20061 Carugate (MI)

Italy





This leaflet was last approved in May 2008





© 1999 Astellas Pharma Ltd.



125685





Ambien




Generic Name: zolpidem tartrate

Dosage Form: tablet, film coated
FULL PRESCRIBING INFORMATION

Indications and Usage for Ambien


Ambien (zolpidem tartrate) is indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation. Ambien has been shown to decrease sleep latency for up to 35 days in controlled clinical studies [see Clinical Studies (14)].


The clinical trials performed in support of efficacy were 4–5 weeks in duration with the final formal assessments of sleep latency performed at the end of treatment.



Ambien Dosage and Administration


The dose of Ambien should be individualized.



Dosage in adults


The recommended dose for adults is 10 mg once daily immediately before bedtime. The total Ambien dose should not exceed 10 mg per day.



Special populations


Elderly or debilitated patients may be especially sensitive to the effects of zolpidem tartrate. Patients with hepatic insufficiency do not clear the drug as rapidly as normal subjects. The recommended dose of Ambien in both of these patient populations is 5 mg once daily immediately before bedtime [see Warnings and Precautions (5.6)].



Use with CNS depressants


Dosage adjustment may be necessary when Ambien is combined with other CNS depressant drugs because of the potentially additive effects [see Warnings and Precautions (5.5)].



Administration


The effect of Ambien may be slowed by ingestion with or immediately after a meal.



Dosage Forms and Strengths


Ambien is available in 5 mg and 10 mg strength tablets for oral administration. Tablets are not scored.


Ambien 5 mg tablets are capsule-shaped, pink, film coated, with AMB 5 debossed on one side and 5401 on the other.


Ambien 10 mg tablets are capsule-shaped, white, film coated, with AMB 10 debossed on one side and 5421 on the other.



Contraindications


Ambien is contraindicated in patients with known hypersensitivity to zolpidem tartrate or to any of the inactive ingredients in the formulation. Observed reactions include anaphylaxis and angioedema [see Warnings and Precautions (5.2)].



Warnings and Precautions



Need to evaluate for co-morbid diagnoses


Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Worsening of insomnia or the emergence of new thinking or behavior abnormalities may be the consequence of an unrecognized psychiatric or physical disorder. Such findings have emerged during the course of treatment with sedative/hypnotic drugs, including zolpidem.



Severe anaphylactic and anaphylactoid reactions


Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of sedative-hypnotics, including zolpidem. Some patients have had additional symptoms such as dyspnea, throat closing or nausea and vomiting that suggest anaphylaxis. Some patients have required medical therapy in the emergency department. If angioedema involves the throat, glottis or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with zolpidem should not be rechallenged with the drug.



Abnormal thinking and behavioral changes


A variety of abnormal thinking and behavior changes have been reported to occur in association with the use of sedative/hypnotics. Some of these changes may be characterized by decreased inhibition (e.g., aggressiveness and extroversion that seemed out of character), similar to effects produced by alcohol and other CNS depressants. Visual and auditory hallucinations have been reported as well as behavioral changes such as bizarre behavior, agitation and depersonalization. In controlled trials, < 1% of adults with insomnia who received zolpidem reported hallucinations. In a clinical trial, 7.4% of pediatric patients with insomnia associated with attention-deficit/hyperactivity disorder (ADHD), who received zolpidem reported hallucinations [see Use in Specific Populations (8.4)].


Complex behaviors such as "sleep-driving" (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported with sedative-hypnotics, including zolpidem. These events can occur in sedative-hypnotic-naive as well as in sedative-hypnotic-experienced persons. Although behaviors such as "sleep-driving" may occur with Ambien alone at therapeutic doses, the use of alcohol and other CNS depressants with Ambien appears to increase the risk of such behaviors, as does the use of Ambien at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of Ambien should be strongly considered for patients who report a "sleep-driving" episode. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with "sleep-driving", patients usually do not remember these events. Amnesia, anxiety and other neuro-psychiatric symptoms may occur unpredictably.


In primarily depressed patients, worsening of depression, including suicidal thoughts and actions (including completed suicides), has been reported in association with the use of sedative/hypnotics.


It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above is drug induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.



Withdrawal effects


Following the rapid dose decrease or abrupt discontinuation of sedative/hypnotics, there have been reports of signs and symptoms similar to those associated with withdrawal from other CNS-depressant drugs [see Drug Abuse and Dependence (9)].



CNS depressant effects


Ambien, like other sedative/hypnotic drugs, has CNS-depressant effects. Due to the rapid onset of action, Ambien should only be taken immediately prior to going to bed. Patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness or motor coordination such as operating machinery or driving a motor vehicle after ingesting the drug, including potential impairment of the performance of such activities that may occur the day following ingestion of Ambien. Ambien showed additive effects when combined with alcohol and should not be taken with alcohol. Patients should also be cautioned about possible combined effects with other CNS-depressant drugs. Dosage adjustments may be necessary when Ambien is administered with such agents because of the potentially additive effects.



Special populations



Use in the elderly and/or debilitated patients: Impaired motor and/or cognitive performance after repeated exposure or unusual sensitivity to sedative/hypnotic drugs is a concern in the treatment of elderly and/or debilitated patients. Therefore, the recommended Ambien dosage is 5 mg in such patients to decrease the possibility of side effects [see Dosage and Administration (2.2)]. These patients should be closely monitored.



Use in patients with concomitant illness: Clinical experience with Ambien (zolpidem tartrate) in patients with concomitant systemic illness is limited. Caution is advisable in using Ambien in patients with diseases or conditions that could affect metabolism or hemodynamic responses.


Although studies did not reveal respiratory depressant effects at hypnotic doses of zolpidem in normal subjects or in patients with mild to moderate chronic obstructive pulmonary disease (COPD), a reduction in the Total Arousal Index together with a reduction in lowest oxygen saturation and increase in the times of oxygen desaturation below 80% and 90% was observed in patients with mild-to-moderate sleep apnea when treated with Ambien (10 mg) when compared to placebo. Since sedative/hypnotics have the capacity to depress respiratory drive, precautions should be taken if Ambien is prescribed to patients with compromised respiratory function. Post-marketing reports of respiratory insufficiency, most of which involved patients with pre-existing respiratory impairment, have been received. Ambien should be used with caution in patients with sleep apnea syndrome or myasthenia gravis.


Data in end-stage renal failure patients repeatedly treated with Ambien did not demonstrate drug accumulation or alterations in pharmacokinetic parameters. No dosage adjustment in renally impaired patients is required; however, these patients should be closely monitored [see Clinical Pharmacology (12.3)].


A study in subjects with hepatic impairment did reveal prolonged elimination in this group; therefore, treatment should be initiated with 5 mg in patients with hepatic compromise, and they should be closely monitored [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].



Use in patients with depression: As with other sedative/hypnotic drugs, Ambien should be administered with caution to patients exhibiting signs or symptoms of depression. Suicidal tendencies may be present in such patients and protective measures may be required. Intentional over-dosage is more common in this group of patients; therefore, the least amount of drug that is feasible should be prescribed for the patient at any one time.



Use in pediatric patients: Safety and effectiveness of zolpidem have not been established in pediatric patients. In an 8-week study in pediatric patients (aged 6–17 years) with insomnia associated with ADHD, zolpidem did not decrease sleep latency compared to placebo. Hallucinations were reported in 7.4% of the pediatric patients who received zolpidem; none of the pediatric patients who received placebo reported hallucinations [see Use in Specific Populations (8.4)].



Adverse Reactions


The following serious adverse reactions are discussed in greater detail in other sections of the labeling:


  • Serious anaphylactic and anaphylactoid reactions [see Warnings and Precautions (5.2)]

  • Abnormal thinking, behavior changes, and complex behaviors [see Warnings and Precautions (5.3)]

  • Withdrawal effects [see Warnings and Precautions (5.4)]

  • CNS-depressant effects [see Warnings and Precautions (5.5)]


Clinical trials experience



Associated with discontinuation of treatment: Approximately 4% of 1,701 patients who received zolpidem at all doses (1.25 to 90 mg) in U.S. premarketing clinical trials discontinued treatment because of an adverse reaction. Reactions most commonly associated with discontinuation from U.S. trials were daytime drowsiness (0.5%), dizziness (0.4%), headache (0.5%), nausea (0.6%), and vomiting (0.5%).


Approximately 4% of 1,959 patients who received zolpidem at all doses (1 to 50 mg) in similar foreign trials discontinued treatment because of an adverse reaction. Reactions most commonly associated with discontinuation from these trials were daytime drowsiness (1.1%), dizziness/vertigo (0.8%), amnesia (0.5%), nausea (0.5%), headache (0.4%), and falls (0.4%).


Data from a clinical study in which selective serotonin reuptake inhibitor (SSRI)-treated patients were given zolpidem revealed that four of the seven discontinuations during double-blind treatment with zolpidem (n=95) were associated with impaired concentration, continuing or aggravated depression, and manic reaction; one patient treated with placebo (n =97) was discontinued after an attempted suicide.



Most commonly observed adverse reactions in controlled trials: During short-term treatment (up to 10 nights) with Ambien at doses up to 10 mg, the most commonly observed adverse reactions associated with the use of zolpidem and seen at statistically significant differences from placebo-treated patients were drowsiness (reported by 2% of zolpidem patients), dizziness (1%), and diarrhea (1%). During longer-term treatment (28 to 35 nights) with zolpidem at doses up to 10 mg, the most commonly observed adverse reactions associated with the use of zolpidem and seen at statistically significant differences from placebo-treated patients were dizziness (5%) and drugged feelings (3%).



Adverse reactions observed at an incidence of ≥ 1% in controlled trials: The following tables enumerate treatment-emergent adverse reactions frequencies that were observed at an incidence equal to 1% or greater among patients with insomnia who received zolpidem tartrate and at a greater incidence than placebo in U.S. placebo-controlled trials. Events reported by investigators were classified utilizing a modified World Health Organization (WHO) dictionary of preferred terms for the purpose of establishing event frequencies. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice, in which patient characteristics and other factors differ from those that prevailed in these clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigators involving related drug products and uses, since each group of drug trials is conducted under a different set of conditions. However, the cited figures provide the physician with a basis for estimating the relative contribution of drug and nondrug factors to the incidence of side effects in the population studied.


The following table was derived from results of 11 placebo-controlled short-term U.S. efficacy trials involving zolpidem in doses ranging from 1.25 to 20 mg. The table is limited to data from doses up to and including 10 mg, the highest dose recommended for use.




























Incidence of Treatment-Emergent Adverse Experiences in Placebo-Controlled Clinical Trials Lasting up to 10 Nights (Percentage of patients reporting)
Body System/

Adverse Event*
Zolpidem

(≤10 mg)

(N=685)
Placebo

(N=473)

*

Reactions reported by at least 1% of patients treated with Ambien and at a greater frequency than placebo.

Central and Peripheral Nervous System
  Headache76
  Drowsiness2-
  Dizziness1-
Gastrointestinal System
  Diarrhea1-

The following table was derived from results of three placebo-controlled long-term efficacy trials involving Ambien (zolpidem tartrate). These trials involved patients with chronic insomnia who were treated for 28 to 35 nights with zolpidem at doses of 5, 10, or 15 mg. The table is limited to data from doses up to and including 10 mg, the highest dose recommended for use. The table includes only adverse events occurring at an incidence of at least 1% for zolpidem patients.













































































































Incidence of Treatment-Emergent Adverse Experiences in Placebo-Controlled Clinical Trials Lasting up to 35 Nights (Percentage of patients reporting)
Body System/

Adverse Event*
Zolpidem

(≤10 mg)

(N=152)
Placebo

(N=161)

*

Reactions reported by at least 1% of patients treated with Ambien and at a greater frequency than placebo.

Autonomic Nervous System
  Dry mouth31
Body as a Whole
  Allergy41
  Back Pain32
  Influenza-like symptoms2-
  Chest pain1-
Cardiovascular System
  Palpitation2-
Central and Peripheral Nervous System
  Drowsiness85
  Dizziness51
  Lethargy31
  Drugged feeling3-
  Lightheadedness21
  Depression21
  Abnormal dreams1-
  Amnesia1-
  Sleep disorder1-
Gastrointestinal System
  Diarrhea32
  Abdominal pain22
  Constipation21
Respiratory System
  Sinusitis42
  Pharyngitis31
Skin and Appendages
  Rash21

Dose relationship for adverse reactions: There is evidence from dose comparison trials suggesting a dose relationship for many of the adverse reactions associated with zolpidem use, particularly for certain CNS and gastrointestinal adverse events.



Adverse event incidence across the entire preapproval database: Ambien was administered to 3,660 subjects in clinical trials throughout the U.S., Canada, and Europe. Treatment-emergent adverse events associated with clinical trial participation were recorded by clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals experiencing treatment-emergent adverse events, similar types of untoward events were grouped into a smaller number of standardized event categories and classified utilizing a modified World Health Organization (WHO) dictionary of preferred terms.


The frequencies presented, therefore, represent the proportions of the 3,660 individuals exposed to zolpidem, at all doses, who experienced an event of the type cited on at least one occasion while receiving zolpidem. All reported treatment-emergent adverse events are included, except those already listed in the table above of adverse events in placebo-controlled studies, those coding terms that are so general as to be uninformative, and those events where a drug cause was remote. It is important to emphasize that, although the events reported did occur during treatment with Ambien, they were not necessarily caused by it.


Adverse events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in greater than 1/100 subjects; infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; rare events are those occurring in less than 1/1,000 patients.


Autonomic nervous system: Infrequent: increased sweating, pallor, postural hypotension, syncope. Rare: abnormal accommodation, altered saliva, flushing, glaucoma, hypotension, impotence, increased saliva, tenesmus.


Body as a whole: Frequent: asthenia. Infrequent: edema, falling, fatigue, fever, malaise, trauma. Rare: allergic reaction, allergy aggravated, anaphylactic shock, face edema, hot flashes, increased ESR, pain, restless legs, rigors, tolerance increased, weight decrease.


Cardiovascular system: Infrequent: cerebrovascular disorder, hypertension, tachycardia. Rare: angina pectoris, arrhythmia, arteritis, circulatory failure, extrasystoles, hypertension aggravated, myocardial infarction, phlebitis, pulmonary embolism, pulmonary edema, varicose veins, ventricular tachycardia.


Central and peripheral nervous system: Frequent: ataxia, confusion, euphoria, headache, insomnia, vertigo. Infrequent: agitation, anxiety, decreased cognition, detached, difficulty concentrating, dysarthria, emotional lability, hallucination, hypoesthesia, illusion, leg cramps, migraine, nervousness, paresthesia, sleeping (after daytime dosing), speech disorder, stupor, tremor. Rare: abnormal gait, abnormal thinking, aggressive reaction, apathy, appetite increased, decreased libido, delusion, dementia, depersonalization, dysphasia, feeling strange, hypokinesia, hypotonia, hysteria, intoxicated feeling, manic reaction, neuralgia, neuritis, neuropathy, neurosis, panic attacks, paresis, personality disorder, somnambulism, suicide attempts, tetany, yawning.


Gastrointestinal system: Frequent: dyspepsia, hiccup, nausea. Infrequent: anorexia, constipation, dysphagia, flatulence, gastroenteritis, vomiting. Rare: enteritis, eructation, esophagospasm, gastritis, hemorrhoids, intestinal obstruction, rectal hemorrhage, tooth caries.


Hematologic and lymphatic system: Rare: anemia, hyperhemoglobinemia, leukopenia, lymphadenopathy, macrocytic anemia, purpura, thrombosis.


Immunologic system: Infrequent: infection. Rare: abscess herpes simplex herpes zoster, otitis externa, otitis media.


Liver and biliary system: Infrequent: abnormal hepatic function, increased SGPT. Rare: bilirubinemia, increased SGOT.


Metabolic and nutritional: Infrequent: hyperglycemia, thirst. Rare: gout, hypercholesteremia, hyperlipidemia, increased alkaline phosphatase, increased BUN, periorbital edema.


Musculoskeletal system: Frequent: arthralgia, myalgia. Infrequent: arthritis. Rare: arthrosis, muscle weakness, sciatica, tendinitis.


Reproductive system: Infrequent: menstrual disorder, vaginitis. Rare: breast fibroadenosis, breast neoplasm, breast pain.


Respiratory system: Frequent: upper respiratory infection. Infrequent: bronchitis, coughing, dyspnea, rhinitis. Rare: bronchospasm, epistaxis, hypoxia, laryngitis, pneumonia.


Skin and appendages: Infrequent: pruritus. Rare: acne, bullous eruption, dermatitis, furunculosis, injection-site inflammation, photosensitivity reaction, urticaria.


Special senses: Frequent: diplopia, vision abnormal. Infrequent: eye irritation, eye pain, scleritis, taste perversion, tinnitus. Rare: conjunctivitis, corneal ulceration, lacrimation abnormal, parosmia, photopsia.


Urogenital system: Frequent: urinary tract infection. Infrequent: cystitis, urinary incontinence. Rare: acute renal failure, dysuria, micturition frequency, nocturia, polyuria, pyelonephritis, renal pain, urinary retention.



Drug Interactions



CNS-active drugs


Since the systematic evaluations of zolpidem in combination with other CNS-active drugs have been limited, careful consideration should be given to the pharmacology of any CNS-active drug to be used with zolpidem. Any drug with CNS-depressant effects could potentially enhance the CNS-depressant effects of zolpidem.


Ambien was evaluated in healthy subjects in single-dose interaction studies for several CNS drugs. Imipramine in combination with zolpidem produced no pharmacokinetic interaction other than a 20% decrease in peak levels of imipramine, but there was an additive effect of decreased alertness. Similarly, chlorpromazine in combination with zolpidem produced no pharmacokinetic interaction, but there was an additive effect of decreased alertness and psychomotor performance. A study involving haloperidol and zolpidem revealed no effect of haloperidol on the pharmacokinetics or pharmacodynamics of zolpidem. The lack of a drug interaction following single-dose administration does not predict a lack following chronic administration.


An additive effect on psychomotor performance between alcohol and zolpidem was demonstrated [see Warnings and Precautions (5.5)].


A single-dose interaction study with zolpidem 10 mg and fluoxetine 20 mg at steady-state levels in male volunteers did not demonstrate any clinically significant pharmacokinetic or pharmacodynamic interactions. When multiple doses of zolpidem and fluoxetine at steady-state concentrations were evaluated in healthy females, the only significant change was a 17% increase in the zolpidem half-life. There was no evidence of an additive effect in psychomotor performance.


Following five consecutive nightly doses of zolpidem 10 mg in the presence of sertraline 50 mg (17 consecutive daily doses, at 7:00 am, in healthy female volunteers), zolpidem Cmax was significantly higher (43%) and Tmax was significantly decreased (53%). Pharmacokinetics of sertraline and N-desmethylsertraline were unaffected by zolpidem.



Drugs that affect drug metabolism via cytochrome P450


Some compounds known to inhibit CYP3A may increase exposure to zolpidem. The effect of inhibitors of other P450 enzymes has not been carefully evaluated.


A randomized, double-blind, crossover interaction study in ten healthy volunteers between itraconazole (200 mg once daily for 4 days) and a single dose of zolpidem (10 mg) given 5 hours after the last dose of itraconazole resulted in a 34% increase in AUC0–∞ of zolpidem. There were no significant pharmacodynamic effects of zolpidem on subjective drowsiness, postural sway, or psychomotor performance.


A randomized, placebo-controlled, crossover interaction study in eight healthy female subjects between five consecutive daily doses of rifampin (600 mg) and a single dose of zolpidem (20 mg) given 17 hours after the last dose of rifampin showed significant reductions of the AUC (–73%), Cmax (–58%), and T1/2 (–36%) of zolpidem together with significant reductions in the pharmacodynamic effects of zolpidem.


A randomized double-blind crossover interaction study in twelve healthy subjects showed that co-administration of a single 5 mg dose of zolpidem tartrate with ketoconazole, a potent CYP3A4 inhibitor, given as 200 mg twice daily for 2 days increased Cmax of zolpidem by a factor of 1.3 and increased the total AUC of zolpidem by a factor of 1.7 compared to zolpidem alone and prolonged the elimination half-life by approximately 30% along with an increase in the pharmacodynamic effects of zolpidem. Caution should be used when ketoconazole is given with zolpidem and consideration should be given to using a lower dose of zolpidem when ketoconazole and zolpidem are given together. Patients should be advised that use of Ambien with ketoconazole may enhance the sedative effects.



Other drugs with no interaction with zolpidem


A study involving cimetidine/zolpidem and ranitidine/zolpidem combinations revealed no effect of either drug on the pharmacokinetics or pharmacodynamics of zolpidem.


Zolpidem had no effect on digoxin pharmacokinetics and did not affect prothrombin time when given with warfarin in normal subjects.



Drug-laboratory test interactions


Zolpidem is not known to interfere with commonly employed clinical laboratory tests. In addition, clinical data indicate that zolpidem does not cross-react with benzodiazepines, opiates, barbiturates, cocaine, cannabinoids, or amphetamines in two standard urine drug screens.



USE IN SPECIFIC POPULATIONS



Pregnancy



Pregnancy Category C


There are no adequate and well-controlled studies of Ambien in pregnant women. Ambien should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.


Administration of zolpidem to pregnant rats and rabbits resulted in adverse effects on offspring development at doses greater than the Ambien maximum recommended human dose (MRHD) of 10 mg/day (approximately 8 mg/day zolpidem base); however, teratogenicity was not observed.


When zolpidem was administered at oral doses of 4, 20, and 100 mg base/kg (approximately 5, 24 and 120 times the MRHD on a mg/m2 basis) to pregnant rats during the period of organogenesis, dose-related decreases in fetal skull ossification occurred at all but the lowest dose, which is approximately 5 times the MRHD on a mg/m2 basis. In rabbits treated during organogenesis with zolpidem at oral doses of 1, 4, and 16 mg base/kg (approximately 2.5, 10 and 40 times the MRHD on a mg/m2 basis), increased embryo-fetal death and incomplete fetal skeletal ossification occurred at the highest dose. The no-effect dose for embryo-fetal toxicity in rabbits is approximately 10 times the MRHD on a mg/m2 basis. Administration of zolpidem to rats at oral doses of 4, 20, and 100 mg base/kg (approximately 5, 24 and 120 times the MRHD on a mg/m2 basis) during the latter part of pregnancy and throughout lactation produced decreased offspring growth and survival at all but the lowest dose, which is approximately 5 times the MRHD on a mg/m2 basis.



Neonatal Complications


Studies in children to assess the effects of prenatal exposure to zolpidem have not been conducted; however, cases of severe neonatal respiratory depression have been reported when zolpidem was used at the end of pregnancy, especially when taken with other CNS depressants.


Children born to mothers taking sedative-hypnotic drugs may be at some risk for withdrawal symptoms during the postnatal period. Neonatal flaccidity has also been reported in infants born to mothers who received sedative-hypnotic drugs during pregnancy.



Labor and delivery


Ambien has no established use in labor and delivery [see Pregnancy (8.1)].



Nursing mothers


Zolpidem is excreted in human milk. Studies in lactating mothers indicate that the half-life of zolpidem is similar to that in non-lactating women (2.6 ± 0.3 hr). The effect of zolpidem on the nursing infant is not known. Caution should be exercised when Ambien is administered to a nursing woman.



Pediatric use


Safety and effectiveness of zolpidem have not been established in pediatric patients.


In an 8-week controlled study, 201 pediatric patients (aged 6–17 years) with insomnia associated with attention-deficit/hyperactivity disorder (90% of the patients were using psychoanaleptics) were treated with an oral solution of zolpidem (n=136), or placebo (n=65). Zolpidem did not significantly decrease latency to persistent sleep, compared to placebo, as measured by polysomnography after 4 weeks of treatment. Psychiatric and nervous system disorders comprised the most frequent (> 5%) treatment emergent adverse reactions observed with zolpidem versus placebo and included dizziness (23.5% vs. 1.5%), headache (12.5% vs. 9.2%), and hallucinations (7.4% vs. 0%) [see Warnings and Precautions(5.6)]. Ten patients on zolpidem (7.4%) discontinued treatment due to an adverse reaction.



Geriatric use


A total of 154 patients in U.S. controlled clinical trials and 897 patients in non-U.S. clinical trials who received zolpidem were ≥ 60 years of age. For a pool of U.S. patients receiving zolpidem at doses of ≤10 mg or placebo, there were three adverse reactions occurring at an incidence of at least 3% for zolpidem and for which the zolpidem incidence was at least twice the placebo incidence (i.e., they could be considered drug related).








Adverse EventZolpidemPlacebo
Dizziness

Drowsiness

Diarrhea
3%

5%

3%
0%

2%

1%

A total of 30/1,959 (1.5%) non-U.S. patients receiving zolpidem reported falls, including 28/30 (93%) who were ≥ 70 years of age. Of these 28 patients, 23 (82%) were receiving zolpidem doses >10 mg. A total of 24/1,959 (1.2%) non-U.S. patients receiving zolpidem reported confusion, including 18/24 (75%) who were ≥ 70 years of age. Of these 18 patients, 14 (78%) were receiving zolpidem doses >10 mg.


The dose of Ambien in elderly patients is 5 mg to minimize adverse effects related to impaired motor and/or cognitive performance and unusual sensitivity to sedative/hypnotic drugs [see Warnings and Precautions (5.6)].



Drug Abuse and Dependence



Controlled substance


Zolpidem tartrate is classified as a Schedule IV controlled substance by federal regulation.



Abuse


Abuse and addiction are separate and distinct from physical dependence and tolerance. Abuse is characterized by misuse of the drug for non-medical purposes, often in combination with other psychoactive substances. Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug effects over time. Tolerance may occur to both desired and undesired effects of drugs and may develop at different rates for different effects.


Addiction is a primary, chronic, neurobiological disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, using a multidisciplinary approach, but relapse is common.


Studies of abuse potential in former drug abusers found that the effects of single doses of zolpidem tartrate 40 mg were similar, but not identical, to diazepam 20 mg, while zolpidem tartrate 10 mg was difficult to distinguish from placebo.


Because persons with a history of addiction to, or abuse of, drugs or alcohol are at increased risk for misuse, abuse and addiction of zolpidem, they should be monitored carefully when receiving zolpidem or any other hypnotic.



Dependence


Physical dependence is a state of adaptation that is manifested by a specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.


Sedative/hypnotics have produced withdrawal signs and symptoms following abrupt discontinuation. These reported symptoms range from mild dysphoria and insomnia to a withdrawal syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremors, and convulsions. The following adverse events which are considered to meet the DSM-III-R criteria for uncomplicated sedative/hypnotic withdrawal were reported during U.S. clinical trials following placebo substitution occurring within 48 hours following last zolpidem treatment: fatigue, nausea, flushing, lightheadedness, uncontrolled crying, emesis, stomach cramps, panic attack, nervousness, and abdominal discomfort. These reported adverse events occurred at an incidence of 1% or less. However, available data cannot provide a reliable estimate of the incidence, if any, of dependence during treatment at recommended doses. Post-marketing reports of abuse, dependence and withdrawal have been received.



Overdosage



Signs and symptoms


In postmarketing experience of overdose with zolpidem tartrate alone, or in combination with CNS-depressant agents, impairment of consciousness ranging from somnolence to coma, cardiovascular and/or respiratory compromise, and fatal outcomes have been reported.



Recommended treatment


General symptomatic and supportive measures should be used along with immediate gastric lavage where appropriate. Intravenous fluids should be administered as needed. Zolpidem's sedative hypnotic effect was shown to be reduced by flumazenil and therefore may be useful; however, flumazenil administration may contribute to the appearance of neurological symptoms (convulsions). As in all cases of drug overdose, respiration, pulse, blood pressure, and other appropriate signs should be monitored and general supportive measures employed. Hypotension and CNS depression should be monitored and treated by appropriate medical intervention. Sedating drugs should be withheld following zolpidem overdosage, even if excitation occurs. The value of dialysis in the treatment of overdosage has not been determined, although hemodialysis studies in patients with renal failure receiving therapeutic doses have demonstrated that zolpidem is not dialyzable.


As with the management of all overdosage, the possibility of multiple drug ingestion should be considered. The physician may wish to consider contacting a poison control center for up-to-date information on the management of hypnotic drug product overdosage.



Ambien Description


Ambien (zolpidem tartrate) is a non-benzodiazepine hypnotic of the imidazopyridine class and is available in 5 mg and 10 mg strength tablets for oral administration.


Chemically, zolpidem is N,N,6-trimethyl-2-p-tolylimidazo[1,2-a] pyridine-3-acetamide L-(+)-tartrate (2:1). It has the following structure:



Zolpidem tartrate is a white to off-white crystalline powder that is sparingly soluble in water, alcohol, and propylene glycol. It has a molecular weight of 764.88.


Each Ambien tablet includes the following inactive ingredients: hydroxypropyl methylcellulose, lactose, magnesium stearate, micro-crystalline cellulose, polyethylene glycol, sodium starch glycolate, and titanium dioxide. The 5 mg tablet also contains FD&C Red No. 40, iron oxide colorant, and polysorbate 80.



Ambien - Clinical Pharmacology



Mechanism of action


Zolpidem, the active moiety of zolpidem tartrate, is a hypnotic agent with a chemical structure unrelated to benzodiazepines, barbiturates, or other drugs with known hypnotic properties. It interacts with a GABA-BZ receptor complex and shares some of the pharmacological properties of the benzodiazepines. In contrast to the benzodiazepines, which non-selectively bind to and activate all BZ receptor subtypes, zolpidem in vitro binds the BZ1 receptor preferentially with a high affinity ratio of the α1/α5 subunits. This selective binding of zolpidem on the BZ1 receptor is not absolute, but it may explain the relative absence of myorelaxant and anticonvulsant effects in animal studies as well as the preservation of deep sleep (stages 3 and 4) in human studies of zolpidem tartrate at hypnotic doses.



Pharmacokinetics


The pharmacokinetic profile of Ambien is characterized by rapid absorption from the gastrointestinal tract and a short elimination half-life (T1/2) in healthy subjects.


In a single-dose crossover study in 45 healthy subjects administered 5 and 10 mg zolpidem tartrate tablets, the mean peak concentrations (Cmax) were 59 (range: 29 to 113) and 121 (range: 58 to 272) ng/mL, respectively, occurring at a mean time (Tmax) of 1.6 hours for both. The mean Ambien elimination half-life was 2.6 (range: 1.4 to 4.5) and 2.5 (range: 1.4 to 3.8) hours, for the 5 and 10 mg tablets, respectively. Ambien is converted to inactive metabolites that are eliminated primarily by renal excretion. Ambien demonstrated linear kinetics in the dose range of 5 to 20 mg. Total protein binding was found to be 92.5 ± 0.1% and remained constant, independent of concentration between 40 and 790 ng/mL. Zolpidem did not accumulate in young adults following nightly dosing with 20 mg zolpidem tartrate tablets for 2 weeks.


A food-effect study in 30 healthy male subjects compared the pharmacokinetics of Ambien 10 mg when administered while fasting or 20 minutes after a meal. Results demonstrated that with food, mean AUC and Cmax were decreased by 15% and 25%, respectively, while mean Tmax was prolonged by 60% (from 1.4 to 2.2 hr). The half-life remained unchanged. These results suggest that, for faster sleep onset, Ambien should not be administered with or immediately after a meal.



Special Populations



Elderly:


In the elderly, the dose for Ambien should be 5 mg [see Warnings and Precautions (5) and Dosage and Administration (2)]. This recommendation is based on several studies in which the mean Cmax, T1/2, and AUC were significantly increased when compared to results in young adults. In one study of eight elderly subjects (> 70 years), the means for Cmax, T1/2, and AUC significantly increased by 50% (255 vs. 384 ng/mL), 32% (2.2 vs. 2.9 hr), and 64% (955 vs. 1,562 ng∙hr/mL), respectively, as compared to younger adults (20 to 40 years) following a single 20 mg oral dose. Ambien did not accumulate in elderly subjects following nightly oral dosing of 10 mg for 1 week.



Hepatic Impairment:


The pharmacokinetics of Ambien in eight patients with chronic hepatic insufficiency were compared to results in healthy subjects. Following a single 20 mg oral zolpidem tartrate dose, mean Cmax and AUC were found to be two times (250 vs. 499 ng/mL) and five times (788 vs. 4,203 ng∙hr/mL) higher, respectively, in hepatically -compromised patients. Tmax did not change. The mean half-life in cirrhotic patients of 9.9 hr (range: 4.1 to 25.8 hr) was greater than that observed in normal subjects of 2.2 hr (range: 1.6 to 2.4 hr). Dosing should be modified accordingly in patients with hepatic insufficiency [see Dosage and Administration (2.2) and Warnings and Precautions (5.6)].



Renal Impairment:


The pharmacokinetics of zolpidem tartrate were studied in 11 patients with end-stage renal failure (mean ClCr = 6.5 ± 1.5 mL/min) undergoing hemodialysis three times a week, who were dosed with zolpidem tartrate 10 mg orally each day for 14 or 21 days. No statistically significant differences were observed for Cmax, Tmax, half-life, and AUC between the first and last day of drug administration when baseline concentration adjustments were made. On day 1, Cmax was 172 ± 29 ng/mL (range: 46 to 344 ng/mL). After repeated dosing