venlafaxine

ven-la-FAX-een

Oral route(Tablet;Capsule, Extended Release;Tablet, Extended Release)

Antidepressants increased the risk of suicidal thinking and behavior in children, adolescents, and young adults in short-term studies with major depressive disorder (MDD) and other psychiatric disorders. Short term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24, and there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. This risk must be balanced with the clinical need. Monitor patients closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Not approved for use in pediatric patients .

Commonly used brand name(s)

In the U.S.

• Effexor


• Effexor-XR

Available Dosage Forms:

• Capsule, Extended Release


• Tablet, Extended Release


• Tablet

Therapeutic Class: Antidepressant

Pharmacologic Class: Antidepressant, Bicyclic

Chemical Class: Phenethylamine (class)

Uses For venlafaxine

Venlafaxine is used to treat mental depression. It is also used to treat certain anxiety disorders or to relieve the symptoms of anxiety. However, it generally is not used for anxiety or tension caused by the stress of everyday life. Venlafaxine is also used to treat panic disorders .

venlafaxine is available only with your doctor's prescription .

Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although this use is not included in product labeling, venlafaxine is used in certain patients with the following medical condition:

• Hot flashes

Before Using venlafaxine

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 venlafaxine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to venlafaxine 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

Appropriate studies performed to date have not demonstrated any benefit to using venlafaxine in children with depression. Studies have shown that some children, teenagers, and young adults think about suicide or attempt suicide when taking the medicine. Because of this toxicity, use in children is not recommended .

Geriatric

Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of venlafaxine in the elderly. However, elderly patients are more likely to have age-related liver or kidney problems, which may require an adjustment in the dose for patients receiving venlafaxine .

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	C	Animal 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 taking venlafaxine, 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 venlafaxine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Furazolidone


• Iproniazid


• Isocarboxazid


• Linezolid


• Methylene Blue


• Metoclopramide


• Moclobemide


• Nialamide


• Pargyline


• Phenelzine


• Procarbazine


• Selegiline


• Toloxatone


• Tranylcypromine


• Trifluoperazine

Using venlafaxine 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.

• Acenocoumarol


• Almotriptan


• Amitriptyline


• Amoxapine


• Amoxicillin


• Anagrelide


• Ancrod


• Anisindione


• Antithrombin III Human


• Aspirin


• Atazanavir


• Bivalirudin


• Cilostazol


• Clarithromycin


• Clomipramine


• Clopidogrel


• Danaparoid


• Defibrotide


• Dermatan Sulfate


• Desipramine


• Desirudin


• Desvenlafaxine


• Dexfenfluramine


• Dextroamphetamine


• Dextromethorphan


• Dibenzepin


• Dicumarol


• Dipyridamole


• Dothiepin


• Doxepin


• Duloxetine


• Eletriptan


• Entacapone


• Epoprostenol


• Eptifibatide


• Fenfluramine


• Fluoxetine


• Fondaparinux


• Frovatriptan


• Haloperidol


• Heparin


• Iloprost


• Imipramine


• Itraconazole


• Jujube


• Lamifiban


• Lexipafant


• Milnacipran


• Mirtazapine


• Naratriptan


• Nefazodone


• Nelfinavir


• Nortriptyline


• Pentosan Polysulfate Sodium


• Phenindione


• Phenprocoumon


• Protriptyline


• Rasagiline


• Ritonavir


• Rizatriptan


• Saquinavir


• Sibrafiban


• Sibutramine


• Sulfinpyrazone


• Sulodexide


• Sumatriptan


• Tapentadol


• Telithromycin


• Ticlopidine


• Tirofiban


• Toremifene


• Tramadol


• Trazodone


• Trimipramine


• Vasopressin


• Vilazodone


• Warfarin


• Xemilofiban


• Zolmitriptan

Using venlafaxine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Aceclofenac


• Acemetacin


• Alclofenac


• Benoxaprofen


• Bromfenac


• Bufexamac


• Carprofen


• Celecoxib


• Clonixin


• Clozapine


• Dexketoprofen


• Diclofenac


• Diflunisal


• Dipyrone


• Droxicam


• Etodolac


• Etofenamate


• Etoricoxib


• Felbinac


• Fenbufen


• Fenoprofen


• Fentiazac


• Floctafenine


• Flufenamic Acid


• Flurbiprofen


• Ginkgo


• Ibuprofen


• Indomethacin


• Indoprofen


• Isoxicam


• Ketoprofen


• Ketorolac


• Lornoxicam


• Meclofenamate


• Mefenamic Acid


• Meloxicam


• Metoprolol


• Morniflumate


• Nabumetone


• Naproxen


• Niflumic Acid


• Nimesulide


• Oxaprozin


• Parecoxib


• Phenylbutazone


• Pirazolac


• Piroxicam


• Pirprofen


• Propyphenazone


• Proquazone


• Rofecoxib


• St John's Wort


• Sulindac


• Suprofen


• Tenidap


• Tenoxicam


• Tiaprofenic Acid


• Tolmetin


• Valdecoxib


• Zolpidem


• Zomepirac

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. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Other Medical Problems

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

• Bipolar disorder (mental disease with cycles of elation and depression), history of, or


• Bleeding problems or


• Glaucoma (e.g., acute narrow-angle) or


• High blood pressure or


• Hypercholesterolemia (high cholesterol in the blood) or


• Hyponatremia (low sodium in the blood) or


• Seizures (convulsions), history of—May make these conditions worse .

• Heart attack, recent or


• Heart failure or


• Hyperthyroidism (overactive thyroid)—Use with caution. May cause an increase in heart rate .

• Kidney disease or


• Liver disease (e.g., liver cirrhosis)—Use with caution. The effects may be increased because of slower removal of the medicine from the body .

• Mania or hypomania (history of)—Use of venlafaxine may activate these conditions .

Proper Use of venlafaxine

Take venlafaxine only as directed by your doctor to benefit your condition as much as possible. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered .

You may have to take venlafaxine for 4 weeks or longer before you begin to feel better. Also, you will probably need to keep taking venlafaxine for at least 6 months, even if you feel better, to help prevent your depression from returning. Your doctor should check your progress at regular visits during this time .

Venlafaxine should be taken with food or on a full stomach to lessen the chance of stomach upset. However, if your doctor tells you to take the medicine a certain way, take it exactly as directed .

If you are taking the extended-release capsule form, take it with food and swallow the capsule whole with fluid. Do not open, crush, chew, or place the capsule in a liquid .

Dosing

The dose of venlafaxine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of venlafaxine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For mental depression:
  
  • For oral dosage form (extended-release capsules):
    
    • Adults—At first, 75 milligrams (mg) a day, taken as one dose in the morning or evening. Your doctor may adjust your dose if needed. However, the dose is usually not more than 225 mg a day.
    
    
    • Children—Use and dose must be determined by your doctor .
    
    
  
  
  • For oral dosage form (tablets):
    
    • Adults—At first, a total of 75 milligrams (mg) a day, taken in smaller doses two or three times during the day. Your doctor may adjust your dose if needed. However, the dose is usually not more than 375 mg a day.
    
    
    • Children—Use and dose must be determined by your doctor .
    
    
  
  

• For anxiety:
  
  • For oral dosage form (extended-release capsules):
    
    • Adults—At first, 75 milligrams (mg) a day, taken as one dose in the morning or evening. Your doctor may adjust your dose if needed. However, the dose is usually not more than 225 mg a day.
    
    
    • Children—Use and dose must be determined by your doctor .
    
    
  
  


• For panic disorder:
  
  • For oral dosage form (extended-release capsules):
    
    • Adults—At first, 37.5 milligrams (mg) a day, taken as one dose in the morning or evening for 7 days. Your doctor may adjust your dose if needed. However, the dose is usually not more than 225 mg a day.
    
    
    • Children—Use and dose must be determined by your doctor .
    
    
  
  

Missed Dose

If you miss a dose of venlafaxine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using venlafaxine

It is important that your doctor check your progress at regular visits, to allow for changes in your dose and to help reduce any side effects .

Venlafaxine may cause some people to be agitated, irritable, or display other abnormal behaviors. It may also cause some people to have suicidal thoughts and tendencies or to become more depressed. If you, your child, or your caregiver notice any of these side effects, tell your doctor or your child's doctor right away .

Do not stop taking venlafaxine without first checking with your doctor. Your doctor may want you to gradually reduce the amount you are taking before stopping completely. This is to decrease the chance of side effects .

Do not take venlafaxine within 2 weeks (14 days) of taking a monoamine oxidase (MAO) inhibitor (e.g., isocarboxazid [Marplan®], phenelzine [Nardil®], selegiline [Eldepryl®], or tranylcypromine [Parnate®]), and do not take an MAO inhibitor for at least 7 days after taking venlafaxine. If you do, you may develop serious side effects such as seizures .

Make sure your doctor knows about all the other medicines you are using. Venlafaxine may cause a serious condition called serotonin syndrome when taken with certain medicines such as linezolid [e.g., Zyvox®], lithium, tryptophan, St. John's Wort, or some pain or migraine medicines (e.g., tramadol [Ultram®], sumatriptan [Imitrex®], zolmitriptan [Zomig®], or rizatriptan [Maxalt®]). Check with your doctor first before taking any other medicines .

It is not known how venlafaxine will interact with alcohol and other central nervous system (CNS) depressants (medicines that may make you drowsy or less alert). Some examples of CNS depressants are antihistamines or medicine for hay fever, other allergies, or colds; sedatives, tranquilizers, or sleeping medicine; prescription pain medicine or narcotics; barbiturates; medicine for seizures; muscle relaxants; or anesthetics, including some dental anesthetics. Check with your doctor before taking any of these medicines while you are using venlafaxine .

Venlafaxine may cause some people to become drowsy or have blurred vision. Make sure you know how you react to venlafaxine before you drive, use machines, or do anything else that could be dangerous if you are not alert or able to see clearly .

Dizziness, light-headedness, or fainting may occur with venlafaxine, especially when you get up quickly from a lying or sitting position. Getting up slowly may help. If this problem continues or gets worse, check with your doctor .

venlafaxine 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 immediately if any of the following side effects occur:

More common

• Changes in vision, such as blurred vision


• headache


• high blood pressure

Less common

• Chest pain


• fast or irregular heartbeat


• mood or mental changes


• ringing or buzzing in the ears

Rare

• Convulsions (seizures)


• itching or skin rash


• light-headedness or fainting, especially when getting up suddenly from a sitting or lying position


• menstrual changes


• problems in urinating or in holding urine


• swelling


• talking, feeling, and acting with excitement that you cannot control


• trouble with breathing

Incidence not known

• Abdominal or stomach pain


• agitation


• black, tarry stools


• bleeding gums


• blistering, peeling, loosening of skin


• bloating of the abdomen


• blood in eye


• bloody urine


• bloody, black, or tarry stools


• blue-green to black skin


• chest pain or discomfort


• confusion


• confusion as to time, place, or person


• cough or hoarseness


• coughing up blood


• dark urine


• decreased awareness or responsiveness


• decreased frequency or amount of urine


• depression


• difficulty with breathing or swallowing


• doing the opposite of what one is requested to do


• dry cough


• extra heartbeats


• eye pain


• fast, pounding, slow, or irregular heartbeat or pulse


• fever with or without chills


• general feeling of tiredness or weakness


• hallucinations


• hearing loss


• high fever


• hives


• holding false beliefs that can not be changed by fact


• hostility


• increased menstrual flow or vaginal bleeding


• increased thirst


• indigestion


• involuntary movements


• irregular heartbeats


• irritability


• joint or muscle pain


• lethargy


• light-colored stools


• lip smacking or puckering


• loss of consciousness or coma


• low blood pressure


• lower back or side pain


• mimicry of speech or movements


• muscle cramps or spasms


• muscle pain or stiffness


• muscle twitching


• nosebleeds


• overactive reflexes


• pain, redness, or swelling in the arm or leg


• painful or difficult urination


• pains in stomach, side, or abdomen, possibly radiating to the back


• palpitations


• panic


• paralysis


• peculiar postures or movements, mannerisms, or grimacing


• poor coordination


• pounding or rapid pulse


• prolonged bleeding from cuts


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


• puffing of cheeks


• rapid breathing


• rapid or worm-like movements of the tongue


• rapid weight gain


• rash


• recurrent fainting


• red or dark brown urine


• red skin lesions, often with a purple center


• red, irritated eyes


• redness in the whites of the eyes


• restlessness


• severe muscle stiffness


• severe sleepiness


• shivering


• shock-like electrical sensations


• sore throat


• sores, ulcers, or white spots in the mouth or on the lips


• stupor


• sweating


• swelling of the face, lower legs, ankles, hands, or fingers


• swollen or painful glands


• tightness in the chest


• tiredness


• twitching, twisting, uncontrolled repetitive movements of the tongue, lips, face, arms, or legs


• unable or unwilling to speak


• uncontrolled chewing movements


• uncontrolled movements of the arms and legs


• unexplained bleeding or bruising


• unpleasant breath odor


• unusual excitement, nervousness, or restlessness


• unusually pale skin


• vomiting of blood or material that looks like coffee grounds


• weight gain


• wheezing


• yellow eyes or skin

Get emergency help immediately if any of the following symptoms of overdose occur:

Symptoms of overdose

• Agitation


• convulsions (seizures)


• drowsiness


• extreme tiredness or weakness


• fast heartbeat


• tingling, burning, or prickling sensations


• trembling or shaking

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Abnormal dreams


• anxiety or nervousness


• chills


• constipation


• decrease in sexual desire or ability


• diarrhea


• dizziness


• drowsiness


• dry mouth


• heartburn


• increased sweating


• loss of appetite


• nausea


• stomach pain or gas


• stuffy or runny nose


• tingling, burning, or prickly sensations


• trembling or shaking


• trouble with sleeping


• unusual tiredness or weakness


• vomiting


• weight loss

Less common

• Change in sense of taste


• muscle tension


• yawning

Incidence not known

• Night sweats

After you stop using venlafaxine, it may still produce some side effects that need attention. During this period of time, check with your doctor immediately if you notice the following side effects:

• Actions that are out of control


• anxiety


• changes in dreaming


• continuing ringing or buzzing or other unexplained noise in the ears


• convulsions (seizures)


• crying


• depersonalization


• diarrhea


• difficulty with coordination


• dizziness


• dry mouth


• dysphoria


• euphoria


• fear


• feeling of constant movement of self or surroundings


• feeling unwell or unhappy


• headache


• hearing loss


• hyperventilation


• increased sweating


• irregular heartbeats


• irritability


• light-headedness


• loss of appetite


• loss of bladder control


• mental depression


• mood or mental changes


• muscle spasm or jerking of all extremities


• nausea


• nervousness


• nightmares


• paranoia


• quick to react or overreact emotionally


• rapidly changing moods


• restlessness


• sensation of spinning


• sensory disturbances (including shock-like electrical sensations)


• shakiness in legs, arms, hands, or feet


• shaking


• shortness of breath


• sleeping or unusual drowsiness


• sudden loss of consciousness


• talking, feeling, and acting with excitement


• trembling or shaking of hands or feet


• trouble with sleeping


• twitches of the muscles under the skin


• unusual drowsiness, dullness, or the feeling of sluggishness


• unusual tiredness or weakness


• vomiting


• weight loss

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: venlafaxine side effects (in more detail)

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More venlafaxine resources

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

• Venlafaxine Prescribing Information (FDA)


• Venlafaxine MedFacts Consumer Leaflet (Wolters Kluwer)


• Effexor Prescribing Information (FDA)


• Effexor Consumer Overview


• Effexor XR Prescribing Information (FDA)


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


• Venlafaxine Hydrochloride Monograph (AHFS DI)

Compare venlafaxine with other medications

• Anxiety
• Anxiety and Stress
• Autism
• Bipolar Disorder
• Bulimia
• Cataplexy
• Depression
• Fibromyalgia
• Generalized Anxiety Disorder
• Hot Flashes
• Irritable Bowel Syndrome
• Obsessive Compulsive Disorder
• Panic Disorder
• Postpartum Depression
• Premenstrual Dysphoric Disorder
• Social Anxiety Disorder
• Vulvodynia

Micardis 20mg Tablets

Micardis 20 mg tablets

Telmisartan

Read all of this leaflet carefully before you start taking this medicine.

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


• If you have any further questions, ask your doctor or pharmacist.


• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.


• 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 Micardis is and what it is used for


• 2. Before you take Micardis


• 3. How to take Micardis


• 4. Possible side effects


• 5. How to store Micardis


• 6. Further information

What Micardis Is And What It Is Used For

Micardis belongs to a class of medicines known as angiotensin II receptor antagonists. Angiotensin II is a substance produced in your body which causes your blood vessels to narrow, thus increasing your blood pressure. Micardis blocks the effect of angiotensin II so that the blood vessels relax, and your blood pressure is lowered.

Micardis is used to treat essential hypertension (high blood pressure). ‘Essential’ means that the high blood pressure is not caused by any other condition.

High blood pressure, if not treated, can damage blood vessels in several organs, which could lead sometimes to heart attack, heart or kidney failure, stroke, or blindness. There are usually no symptoms of high blood pressure before damage occurs. Thus it is important to regularly measure blood pressure to verify if it is within the normal range.

Micardis is also used to reduce cardiovascular events (i.e. heart attack or stroke) in patients who are at risk because they have a reduced or blocked blood supply to the heart or legs, or have had a stroke or have high risk diabetes. Your doctor can tell you if you are at high risk for such events.

Before You Take Micardis

Do not take Micardis

• if you are allergic (hypersensitive) to telmisartan or any other ingredients included in Micardis tablets (see section Further information for a list of other ingredients).


• if you are more than 3 months pregnant. (It is also better to avoid Micardis in early pregnancy – see pregnancy section.)


• if you have severe liver problems such as cholestasis or biliary obstruction (problems with the drainage of the bile from the liver and gall bladder) or any other severe liver disease.

If any of the above applies to you, tell your doctor or pharmacist before taking Micardis.

Take special care with Micardis

Please tell your doctor if you are suffering or have ever suffered from any of the following conditions or illnesses:

• Kidney disease or kidney transplant.


• Renal artery stenosis (narrowing of the blood vessels to one or both kidneys).


• Liver disease.


• Heart trouble.


• Raised aldosterone levels (water and salt retention in the body along with imbalance of various blood minerals).


• Low blood pressure (hypotension), likely to occur if you are dehydrated (excessive loss of body water) or have salt deficiency due to diuretic therapy (‘water tablets’), low-salt diet, diarrhoea, or vomiting.


• Elevated potassium levels in your blood.


• Diabetes.

You must tell your doctor if you think you are (or might become) pregnant. Micardis is not recommended in early pregnancy, and must not be taken if you are more than 3 months pregnant, as it may cause serious harm to your baby if used at that stage (see pregnancy section).

In case of surgery or anaesthesia, you should tell your doctor that you are taking Micardis.

The use of Micardis in children and adolescents up to the age of 18 years is not recommended.

As with all other angiotensin II receptor antagonists, Micardis may be less effective in lowering the blood pressure in black patients.

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. Your doctor may need to change the dose of these other medicines or take other precautions. In some cases you may have to stop taking one of the medicines. This applies especially to the medicines listed below taken at the same time with Micardis:

• Lithium containing medicines to treat some types of depression.


• Medicines that may increase blood potassium levels such as salt substitutes containing potassium, potassium-sparing diuretics (certain ‘water tablets’), ACE inhibitors, angiotensin II receptor antagonists, NSAIDs (non steroidal anti-inflammatory medicines, e.g. aspirin or ibuprofen), heparin, immunosuppressives (e.g. cyclosporin or tacrolimus), and the antibiotic trimethoprim.


• Diuretics (‘water tablets’), especially if taken in high doses together with Micardis, may lead to excessive loss of body water and low blood pressure (hypotension).

As with other blood pressure lowering medicines, the effect of Micardis may be reduced when you take NSAIDs (non steroidal anti-inflammatory medicines, e.g. aspirin or ibuprofen) or corticosteroids.

Micardis may increase the blood pressure lowering effect of other medicines used to treat high blood pressure.

Taking Micardis with food and drink

You can take Micardis with or without food.

Pregnancy and breast-feeding

Pregnancy

You must tell your doctor if you think you are (or might become) pregnant. Your doctor will normally advise you to stop taking Micardis before you become pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of Micardis. Micardis is not recommended in early pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious harm to your baby if used after the third month of pregnancy.

Breast-feeding

Tell your doctor if you are breast-feeding or about to start breast-feeding. Micardis is not recommended for mothers who are breast-feeding, and your doctor may choose another treatment for you if you wish to breast-feed, especially if your baby is newborn, or was born prematurely.

Driving and using machines

No information is available on the effect of Micardis on the ability to drive or operate machinery. Some people feel dizzy or tired when they are treated for high blood pressure. If you feel dizzy or tired, do not drive or operate machinery.

Important information about some of the ingredients of Micardis

Micardis contains sorbitol.

If you are intolerant to some sugars, consult your doctor before taking Micardis.

How To Take Micardis

Always take Micardis exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.

The usual dose of Micardis is one tablet a day. Try to take the tablet at the same time each day. You can take Micardis with or without food. The tablets should be swallowed with some water or other non-alcoholic drink. It is important that you take Micardis every day until your doctor tells you otherwise. If you have the impression that the effect of Micardis is too strong or too weak, talk to your doctor or pharmacist.

For treatment of high blood pressure, the usual dose of Micardis for most patients is one 40 mg tablet once a day to control blood pressure over the 24-hour period. Your doctor has recommended a lower dose of one 20 mg tablet daily. Micardis may also be used in combination with diuretics (‘water tablets’) such as hydrochlorothiazide which has been
shown to have an additive blood pressure lowering effect with Micardis.

For reduction of cardiovascular events, the usual dose of Micardis is one 80 mg tablet once a day. At the beginning of the preventive therapy with Micardis 80mg, blood pressure should be frequently monitored.

If your liver is not working properly, the usual dose should not exceed 40 mg once daily.

If you take more Micardis than you should

If you accidentally take too many tablets, contact your doctor, pharmacist, or your nearest hospital emergency department immediately.

If you forget to take Micardis

If you forget to take a dose, do not worry. Take it as soon as you remember then carry on as before. If you do not take your tablet on one day, take your normal dose on the next day. Do not take a double dose to make up for forgotten individual doses.

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

Possible Side Effects

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

These side effects may occur with certain frequencies, which are defined as follows:

• very common: affects more than 1 user in 10


• common: affects 1 to 10 users in 100


• uncommon: affects 1 to 10 users in 1,000


• rare: affects 1 to 10 users in 10,000


• very rare: affects less than 1 user in 10,000


• not known: frequency cannot be estimated from the available data.

Common side effects may include:

Low blood pressure (hypotension) in users treated for reduction of cardiovascular events.

Uncommon side effects may include:

Upper respiratory tract infections (e.g. sore throat, inflamed sinuses, common cold), urinary tract infections, deficiency in red blood cells (anaemia), high potassium levels, feeling sad (depression), fainting (syncope), difficulty falling asleep, feeling of spinning (vertigo), slow heart rate (bradycardia), low blood pressure (hypotension) in users treated for high blood pressure, dizziness on standing up (orthostatic hypotension), shortness of breath, abdominal pain, diarrhoea, discomfort in the abdomen, bloating, vomiting, increased sweating, itching, drug rash, muscle pain (myalgia), back pain, muscle cramps, kidney impairment including acute kidney failure, pain in the chest, feeling of weakness,
and increased level of creatinine in the blood.

Rare side effects may include:

Low platelet count (thrombocytopenia), allergic reaction (e.g. rash, itching, difficulty breathing, wheezing, swelling of the face or low blood pressure), feeling anxious, impaired vision, fast heart beat (tachycardia), upset stomach, dry mouth, abnormal liver function, severe drug rash, redness of skin, rapid swelling of the skin and mucosa (angioedema), eczema (a skin disorder), joint pain (arthralgia), pain in extremity, flu-like-illness, increased levels of uric acid, hepatic enzymes or creatine phosphokinase in the blood, and decreased haemoglobin (a blood protein).

Side effects of unknown frequency may include:

Increase in certain white blood cells (eosinophilia), severe allergic reaction (anaphylactic reaction), hives (urticaria), tendon pain, and. sepsis* (often called “blood poisoning”, is a severe infection with whole-body inflammatory response which can lead to death).

*In a long-term study involving more than 20,000 patients, more patients treated with telmisartan experienced sepsis compared with patients who received no telmisartan. The event may have happened by chance or could be related to a mechanism currently not known.

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.

How To Store Micardis

Keep out of the reach and sight of children.

Do not use Micardis after the expiry date which is stated on the carton after “EXP”. The expiry date refers to the last day of that month.

This medicine does not require any special storage conditions. You should store your medicine in the original package in order to protect the tablets from moisture.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Further Information

What Micardis contains

The active substance is telmisartan. Each tablet contains 20 mg telmisartan.

The other ingredients are povidone, meglumine, sodium hydroxide, sorbitol (E420) and magnesium stearate.

What Micardis looks like and contents of the pack

Micardis 20 mg tablets are white, round and engraved with the code number ‘50H’ on one side and the company logo on the other side.

Micardis is available in blister packs containing 14, 28, 56, or 98 tablets.

Not all pack sizes may be marketed in your country.

Marketing Authorisation Holder

Boehringer Ingelheim International GmbH

Binger Str. 173

D-55216 Ingelheim am Rhein

Germany

Manufacturer

Boehringer Ingelheim Pharma GmbH & Co. KG

Binger Str. 173

D-55216 Ingelheim am Rhein

Germany

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder.

United Kingdom

Boehringer Ingelheim Ltd.

Tel:+44 1344 424 600

This leaflet was last approved in 11/2009

Detailed information on this medicine is available on the European Medicines Agency (EMEA) web site: http://www.emea.europa.eu/.

28553419-14

Azelastine Ophthalmic Solution

Dosage Form: ophthalmic solution
Azelastine Hydrochloride Ophthalmic Solution, 0.05%

Azelastine Ophthalmic Solution Description

Azelastine Hydrochloride Ophthalmic Solution, 0.05% is a sterile ophthalmic solution containing azelastine hydrochloride, a relatively selective H1-receptor antagonist for topical administration to the eyes. Azelastine hydrochloride is a white crystalline powder with a molecular weight of 418.37. Azelastine hydrochloride is sparingly soluble in water, methanol and propylene glycol, and slightly soluble in ethanol, octanol, and glycerine. Azelastine hydrochloride is a racemic mixture with a melting point of 225°C. The chemical name for azelastine hydrochloride is (±)-1-(2H)-phthalazinone,4-[(4-chlorophenyl) methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-, monohydrochloride and is represented by the following chemical structure:

Each mL of azelastine hydrochloride ophthalmic solution contains: Active: 0.5 mg azelastine hydrochloride, equivalent to 0.457 mg of azelastine base; Preservative: 0.125 mg benzalkonium chloride; Inactives: disodium edetate dihydrate, hydroxypropylmethylcellulose, sodium hydroxide, sorbitol solution and water for injection. It has a pH of approximately 5.0 to 6.5 and an osmolality of approximately 271 to 312 mOsmol/L.

Azelastine Ophthalmic Solution - Clinical Pharmacology

Azelastine hydrochloride is a relatively selective histamine H1 antagonist and an inhibitor of the release of histamine and other mediators from cells (e.g. mast cells) involved in the allergic response. Based on in vitro studies using human cell lines, inhibition of other mediators involved in allergic reactions (e.g. leukotrienes and PAF) has been demonstrated with azelastine hydrochloride. Decreased chemotaxis and activation of eosinophils has also been demonstrated.

Pharmacokinetics and Metabolism

Absorption of azelastine following ocular administration was relatively low. A study in symptomatic patients receiving one drop of azelastine hydrochloride ophthalmic solution in each eye two to four times a day (0.06 to 0.12 mg azelastine hydrochloride) demonstrated plasma concentrations of azelastine hydrochloride to generally be between 0.02 and 0.25 ng/mL after 56 days of treatment. Three of nineteen patients had quantifiable amounts of N-desmethylazelastine that ranged from 0.25 - 0.87 ng/mL at Day 56.

Based on intravenous and oral administration, the elimination half-life, steady-state volume of distribution and plasma clearance were 22 hours, 14.5 L/kg and 0.5 L/h/kg, respectively. Approximately 75% of an oral dose of radiolabeled azelastine hydrochloride was excreted in the feces with less than 10% as unchanged azelastine. Azelastine hydrochloride is oxidatively metabolized to the principal metabolite, N-desmethylazelastine, by the cytochrome P450 enzyme system. In vitro studies in human plasma indicate that the plasma protein binding of azelastine and N-desmethylazelastine are approximately 88% and 97% respectively.

Clinical Trials

In a conjunctival antigen challenge study, azelastine hydrochloride ophthalmic solution was more effective than its vehicle in preventing itching associated with allergic conjunctivitis. Azelastine hydrochloride ophthalmic solution had a rapid (within 3 minutes) onset of effect and a duration of effect of approximately 8 hours for the prevention of itching.

In environmental studies, adult and pediatric, patients with seasonal allergic conjunctivitis were treated with azelastine hydrochloride ophthalmic solution for two to eight weeks. In these studies, azelastine hydrochloride ophthalmic solution was more effective than its vehicle in relieving itching associated with allergic conjunctivitis.

Indications and Usage for Azelastine Ophthalmic Solution

Azelastine hydrochloride ophthalmic solution is indicated for the treatment of itching of the eye associated with allergic conjunctivitis.

Contraindications

Azelastine hydrochloride ophthalmic solution is contraindicated in persons with known or suspected hypersensitivity to any of its components.

Warnings

Azelastine hydrochloride ophthalmic solution is for ocular use only and not for injection or oral use.

Precautions

Information for Patients

To prevent contaminating the dropper tip and solution, care should be taken not to touch any surface, the eyelids, or surrounding areas with the dropper tip of the bottle. Keep bottle tightly closed when not in use. This product is sterile when packaged.

Patients should be advised not to wear a contact lens if their eye is red. Azelastine hydrochloride ophthalmic solution should not be used to treat contact lens related irritation. The preservative in azelastine hydrochloride ophthalmic solution, benzalkonium chloride, may be absorbed by soft contact lenses. Patients who wear soft contact lenses and whose eyes are not red, should be instructed to wait at least ten minutes after instilling azelastine hydrochloride ophthalmic solution before they insert their contact lenses.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Azelastine hydrochloride administered orally for 24 months was not carcinogenic in rats and mice at doses up to 30 mg/kg/day and 25 mg/kg/day, respectively. Based on a 30 µL drop size, these doses were approximately 25,000 and 21,000 times higher than the maximum recommended ocular human use level of 0.001 mg/kg/day for a 50 kg adult.

Azelastine hydrochloride showed no genotoxic effects in the Ames test, DNA repair test, mouse lymphoma forward mutation assay, mouse micronucleus test, or chromosomal aberration test in rat bone marrow. Reproduction and fertility studies in rats showed no effects on male or female fertility at oral doses of up to 25,000 times the maximum recommended ocular human use level. At 68.6 mg/kg/day (57,000 times the maximum recommended ocular human use level), the duration of the estrous cycle was prolonged and copulatory activity and the number of pregnancies were decreased. The numbers of corpora lutea and implantations were decreased; however, the implantation ratio was not affected.

Pregnancy

Teratogenic Effects: Pregnancy Category C.

Azelastine hydrochloride has been shown to be embryotoxic, fetotoxic, and teratogenic (external and skeletal abnormalities) in mice at an oral dose of 68.6 mg/kg/day (57,000 times the recommended ocular human use level). At an oral dose of 30 mg/kg/day (25,000 times the recommended ocular human use level), delayed ossification (undeveloped metacarpus), and the incidence of 14th rib were increased in rats. At 68.6 mg/kg/day (57,000 times the maximum recommended ocular human use level) azelastine hydrochloride caused resorption and fetotoxic effects in rats. The relevance to humans of these skeletal findings noted at only high drug exposure levels in unknown.

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

Nursing Mothers

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

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 3 years have not been established.

Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and younger adult patients.

Adverse Reactions

In controlled multiple-dose studies where patients were treated for up to 56 days, the most frequently reported adverse reactions were transient eye burning/stinging (approximately 30%), headaches (approximately 15%) and bitter taste (approximately 10%). The occurrence of these events was generally mild.

The following events were reported in 1 - 10% of patients: asthma, conjunctivitis, dyspnea, eye pain, fatigue, influenza-like symptoms, pharyngitis, pruritus, rhinitis and temporary blurring. Some of these events were similar to the underlying disease being studied.

Azelastine Ophthalmic Solution Dosage and Administration

The recommended dose is one drop instilled into each affected eye twice a day.

How is Azelastine Ophthalmic Solution Supplied

Azelastine Hydrochloride Ophthalmic Solution, 0.05% is supplied as follows: 6 mL (NDC# 60505-0578-4) solution in a translucent 11 mL HDPE container with a LDPE dropper tip, and a white HDPE screw cap.

Storage

Store UPRIGHT at 20º-25ºC (68º-77ºF) [See USP Controlled Room Temperature].

Manufactured by:                                  Manufactured for:

Apotex Inc.                                            Apotex Corp.

Toronto, Ontario                                    Weston, FL

Canada  M9L 1T9                                  33326

251457                                                                                                                     August 2009

PRINCIPAL DISPLAY PANEL - 0.05% BOTTLE LABEL

APOTEX CORP. NDC 60505-0578-4

AZELASTINE HYDROCHLORIDE OPHTHALMIC SOLUTION

0.05%

Rx only

6 mL

AZELASTINE HYDROCHLORIDE  azelastine hydrochloride  solution/ drops

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 60505-0578 Route of Administration INTRAOCULAR DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength AZELASTINE HYDROCHLORIDE (AZELASTINE) AZELASTINE HYDROCHLORIDE 0.5 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength BENZALKONIUM CHLORIDE 0.125 mg  in 1 mL EDETATE DISODIUM   HYPROMELLOSES   SODIUM HYDROXIDE   SORBITOL   WATER

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 60505-0578-4 1 BOTTLE In 1 CARTON contains a BOTTLE, PLASTIC 1 6 mL In 1 BOTTLE, PLASTIC This package is contained within the CARTON (60505-0578-4)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA078621	12/01/2009

Labeler - Apotex Corp. (845263701)

Revised: 05/2011Apotex Corp.

More Azelastine Ophthalmic Solution resources

• Azelastine Ophthalmic Solution Use in Pregnancy & Breastfeeding
• Azelastine Ophthalmic Solution Drug Interactions
• Azelastine Ophthalmic Solution Support Group
• 1 Review for Azelastine Ophthalmic - Add your own review/rating

Compare Azelastine Ophthalmic Solution with other medications

• Conjunctivitis, Allergic

Zofran Syrup

1. Name Of The Medicinal Product

Zofran™ Syrup

2. Qualitative And Quantitative Composition

Sugar-free strawberry flavoured liquid.

Each 5ml contains 4mg of ondansetron as the hydrochloride dihydrate.

3. Pharmaceutical Form

Oral solution.

4. Clinical Particulars

4.1 Therapeutic Indications

Adults:

Zofran is indicated for the management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy. Zofran is indicated for the prevention of post-operative nausea and vomiting (PONV).

Paediatric Population:

Zofran is indicated for the management of chemotherapy-induced nausea and vomiting (CINV) in children aged

4.2 Posology And Method Of Administration

Chemotherapy and radiotherapy induced nausea and vomiting (CINV).

Adults (including the elderly):

The emetogenic potential of cancer treatment varies according to the doses and combinations of chemotherapy and radiotherapy regimens used. The route of administration and dose of Zofran should be flexible and selected as shown below.

Emetogenic chemotherapy and radiotherapy: Zofran can be given either by rectal, oral (tablets or syrup), intravenous or intramuscular administration.

For oral administration: 8mg 1-2 hours before treatment, followed by 8mg 12 hours later.

To protect against delayed or prolonged emesis after the first 24 hours, oral or rectal treatment with Zofran should be continued for up to 5 days after a course of treatment.

The recommended dose for oral administration is 8mg twice daily.

Highly emetogenic chemotherapy (e.g. high dose cisplatin): Zofran can be given either by oral, rectal, intravenous or intramuscular administration.

The recommended oral dose is 24 mg taken together with oral dexamethasone sodium phosphate 12 mg, 1 to 2 hours before treatment.

To protect against delayed or prolonged emesis after the first 24 hours, oral or rectal treatment with Zofran should be continued for up to 5 days after a course of treatment.

The recommended dose for oral administration is 8mg twice daily.

Paediatric Population:

CINV in children aged

The dose for CINV can be calculated based on body surface area (BSA) or weight – see below. Weight-based dosing results in higher total daily doses compared to BSA-based dosing (sections 4.4.and 5.1).

Zofran injection should be diluted in 5% dextrose or 0.9% sodium chloride or other compatible infusion fluid (see section 6.6) and infused intravenously over not less than 15 minutes.

There are no data from controlled clinical trials on the use of Zofran in the prevention of delayed or prolonged CINV. There are no data from controlled clinical trials on the use of Zofran for radiotherapy-induced nausea and vomiting in children.

Dosing by BSA:

Zofran should be administered immediately before chemotherapy as a single intravenous dose of 5 mg/m². The intravenous dose must not exceed 8 mg.

Oral dosing can commence twelve hours later and may be continued for up to 5 days (Table 1).

The total daily dose must not exceed adult dose of 32 mg.

Table 1: BSA-based dosing for Chemotherapy - Children aged

BSA	Day 1 (a,b)	Days 2-6(b)
< 0.6 m2	5 mg/m2 i.v. plus 2 mg syrup after 12 hrs	2 mg syrup every 12 hrs
0.6 m2	5 mg/m2 i.v. plus 4 mg syrup or tablet after 12 hrs	4 mg syrup or tablet every 12 hrs

a The intravenous dose must not exceed 8mg.

b The total daily dose must not exceed adult dose of 32 mg

Dosing by bodyweight:

Weight-based dosing results in higher total daily doses compared to BSA-based dosing (sections 4.4. and 5.1).

Zofran should be administered immediately before chemotherapy as a single intravenous dose of 0.15 mg/kg. The intravenous dose must not exceed 8 mg.

Two further intravenous doses may be given in 4-hourly intervals. The total daily dose must not exceed adult dose of 32 mg.

Oral dosing can commence twelve hours later and may be continued for up to 5 days (Table 2).

Table 2: Weight-based dosing for Chemotherapy - Children aged

Weight	Day 1 (a,b)	Days 2-6(b)
	Up to 3 doses of 0.15 mg/kg every 4 hrs	2 mg syrup every 12 hrs
> 10 kg	Up to 3 doses of 0.15 mg/kg every 4 hrs	4 mg syrup or tablet every 12 hrs

a The intravenous dose must not exceed 8mg.

b The total daily dose must not exceed adult dose of 32 mg.

Post operative nausea and vomiting (PONV).

Adults:

For the prevention of PONV: Zofran can be administered orally or by intravenous or intramuscular injection.

For oral administration: 16mg one hour prior to anaesthesia. Alternatively, 8mg one hour prior to anaesthesia followed by two further doses of 8mg at eight hourly intervals.

For the treatment of established PONV: Intravenous or intramuscular administration is recommended.

Paediatric population

PONV in children aged

Oral formulation:

No studies have been conducted on the use of orally administered ondansetron in the prevention or treatment of post-operative nausea and vomiting; slow i.v. injection is recommended for this purpose.

Injection:

For prevention of PONV in paediatric patients having surgery performed under general anaesthesia, a single dose of ondansetron may be administered by slow intravenous injection (not less than 30 seconds) at a dose of 0.1mg/kg up to a maximum of 4mg either prior to, at or after induction of anaesthesia.

For the treatment of PONV after surgery in paediatric patients having surgery performed under general anaesthesia, a single dose of Zofran may be administered by slow intravenous injection (not less than 30 seconds) at a dose of 0.1mg/kg up to a maximum of 4mg.

There are no data on the use of Zofran in the treatment of PONV in children below 2 years of age.

Elderly:

There is limited experience in the use of Zofran in the prevention and treatment of PONV in the elderly, however Zofran is well tolerated in patients over 65 years receiving chemotherapy.

For both indications

Patients with Renal impairment:

No special requirements.

Patients with Hepatic impairment:

Clearance of Zofran is significantly reduced and serum half life significantly prolonged in subjects with moderate or severe impairment of hepatic function. In such patients a total daily dose of 8mg should not be exceeded and therefore parenteral or oral administration is recommended.

Patients with poor Sparteine/Debrisoquine Metabolism:

The elimination half-life of ondansetron is not altered in subjects classified as poor metabolisers of sparteine and debrisoquine. Consequently in such patients repeat dosing will give drug exposure levels no different from those of the general population. No alteration of daily dosage or frequency of dosing are required.

4.3 Contraindications

Hypersensitivity to any ingredient.

4.4 Special Warnings And Precautions For Use

Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity to other selective 5HT₃ receptor antagonists. Respiratory events should be treated symptomatically and clinicians should pay particular attention to them as precursors of hypersensitivity reactions.

Very rarely and predominantly with intravenous Zofran, transient ECG changes including QT interval prolongation have been reported. Therefore caution should be exercised in patients with cardiac rhythm or conduction disturbances, in patients treated with anti-arrhythmic agents or beta-adrenergic blocking agents and in patients with significant electrolyte disturbances.

As ondansetron is known to increase large bowel transit time, patients with signs of subacute intestinal obstruction should be monitored following administration.

In patients with adenotonsillar surgery prevention of nausea and vomiting with ondansetron may mask occult bleeding. Therefore, such patients should be followed carefully after ondansetron.

Paediatric Population:

Paediatric patients receiving ondansetron with hepatotoxic chemotherapeutic agents should be monitored closely for impaired hepatic function.

CINV: When calculating the dose on an mg/kg basis and administering three doses at 4-hourly intervals, the total daily dose will be higher than if one single dose of 5mg/m² followed by an oral dose is given. The comparative efficacy of these two different dosing regimens has not been investigated in clinical trials. Cross-trial comparison indicates similar efficacy for both regimens (section 5.1).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

There is no evidence that ondansetron either induces or inhibits the metabolism of other drugs commonly co-administered with it. Specific studies have shown that there are no interactions when ondansetron is administered with alcohol, temazepam, furosemide, alfentanil, tramadol morphine, lignocaine, thiopental or propofol.

Ondansetron is metabolised by multiple hepatic cytochrome P-450 enzymes: CYP3A4, CYP2D6 and CYP1A2. Due to the multiplicity of metabolic enzymes capable of metabolising ondansetron, enzyme inhibition or reduced activity of one enzyme (e.g. CYP2D6 genetic deficiency) is normally compensated by other enzymes and should result in little or no significant change in overall ondansetron clearance or dose requirement.

Phenytoin, Carbamazepine and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e. phenytoin, carbamazepine, and rifampicin), the oral clearance of ondansetron was increased and ondansetron blood concentrations were decreased.

Tramadol: Data from small studies indicate that ondansetron may reduce the analgesic effect of tramadol.

Use of Zofran with QT prolonging drugs may result in additional QT prolongation. Concomitant use of Zofran with cardiotoxic drugs (e.g. anthracyclines) may increase the risk of arrhythmias (section 4.4).

4.6 Pregnancy And Lactation

The safety of ondansetron for use in human pregnancy has not been established. Evaluation of experimental animal studies does not indicate direct or indirect harmful effects with respect to the development of the embryo, or foetus, the course of gestation and peri- and post-natal development. However as animal studies are not always predictive of human response the use of ondansetron in pregnancy is not recommended.

Tests have shown that ondansetron passes into the milk of lactating animals. It is therefore recommended that mothers receiving Zofran should not breast-feed their babies.

4.7 Effects On Ability To Drive And Use Machines

Ondansetron has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable Effects

Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (

The following frequencies are estimated at the standard recommended doses of ondansetron according to indication and formulation.

Immune system disorders
Rare:	Immediate hypersensitivity reactions sometimes severe, including anaphylaxis.
Nervous system disorders
Very common:	Headache.
Uncommon:	Seizures, movement disorders including extrapyramidal reactions such as dystonic reactions, oculogyric crisis and.(1)
Rare:	Dizziness during i.v. administration, which in most cases is prevented or resolved by lengthening the infusion period..
Eye disorders
Rare:	Transient visual disturbances (eg. blurred vision) during i.v. administration.
Very rare:	Transient blindness predominantly during intravenous administration.(2)
Cardiac disorders
Uncommon:	Arrhythmias, chest pain with or without ST segment depression, bradycardia.
Vascular disorders
Common:	Sensation of warmth or flushing.
Uncommon:	Hypotension.
Respiratory, thoracic and mediastinal disorders
Uncommon:	Hiccups.
Gastrointestinal disorders
Common:	Constipation.
Hepatobiliary disorders
Uncommon:	Asymptomatic increases in liver function tests.(3)

1. Observed without definitive evidence of persistent clinical sequelae.

2. The majority of the blindness cases reported resolved within 20 minutes.

Most patients had received chemotherapeutic agents, which included cisplatin. Some cases of transient blindness were reported as cortical in origin.

3. These events were observed commonly in patients receiving chemotherapy with cisplatin.

Paediatric population

The adverse event profile in children and adolescents was comparable to that seen in adults.

4.9 Overdose

Little is known at present about overdosage with ondansetron, however, a limited number of patients received overdoses. Manifestations that have been reported include visual disturbances, severe constipation, hypotension and a vasovagal episode with transient second degree AV block. In all instances, the events resolved completely. There is no specific antidote for ondansetron, therefore in all cases of suspected overdose, symptomatic and supportive therapy should be given as appropriate. The use of ipecacuanha to treat overdose with ondansetron is not recommended, as patients are unlikely to respond due to the anti-emetic action of ondansetron itself.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Ondansetron is a potent, highly selective 5HT3 receptor-antagonist. Its precise mode of action in the control of nausea and vomiting is not known. Chemotherapeutic agents and radiotherapy may cause release of 5HT in the small intestine initiating a vomiting reflex by activating vagal afferents via 5HT3 receptors. Ondansetron blocks the initiation of this reflex. Activation of vagal afferents may also cause a release of 5HT in the area postrema, located on the floor of the fourth ventricle, and this may also promote emesis through a central mechanism. Thus, the effect of ondansetron in the management of the nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy is probably due to antagonism of 5HT3 receptors on neurons located both in the peripheral and central nervous system. The mechanisms of action in post-operative nausea and vomiting are not known but there may be common pathways with cytotoxic induced nausea and vomiting.

Ondansetron does not alter plasma prolactin concentrations.

The role of ondansetron in opiate-induced emesis is not yet established.

Paediatric population

CINV

The efficacy of ondansetron in the control of emesis and nausea induced by cancer chemotherapy was assessed in a double-blind randomised trial in 415 patients aged 1 to 18 years (S3AB3006). On the days of chemotherapy, patients received either ondansetron 5 mg/m² intravenous + ondansetron 4 mg orally after 8-12 hrs or ondansetron 0.45 mg/kg intravenous + placebo orally after 8-12 hrs. Post-chemotherapy both groups received 4 mg ondansetron syrup twice daily for 3 days. Complete control of emesis on worst day of chemotherapy was 49% (5 mg/m² intravenous + ondansetron 4 mg orally) and 41% (0.45 mg/kg intravenous + placebo orally). Post-chemotherapy both groups received 4 mg ondansetron syrup twice daily for 3 days. There was no difference in the overall incidence or nature of adverse events between the two treatment groups.

A double-blind randomised placebo-controlled trial (S3AB4003) in 438 patients aged 1 to 17 years demonstrated complete control of emesis on worst day of chemotherapy in:

• 73% of patients when ondansetron was administered intravenously at a dose of 5 mg/m² intravenous together with 2-4 mg dexamethasone orally

• 71% of patients when ondansetron was administered as syrup at a dose of 8 mg + 2-4 mg dexamethasone orally on the days of chemotherapy.

Post-chemotherapy both groups received 4 mg ondansetron syrup twice daily for 2 days. There was no difference in the overall incidence or nature of adverse events between the two treatment groups.

The efficacy of ondansetron in 75 children aged 6 to 48 months was investigated in an open-label, non-comparative, single-arm study (S3A40320). All children received three 0.15 mg/kg doses of intravenous ondansetron, administered 30 minutes before the start of chemotherapy and then at four and eight hours after the first dose. Complete control of emesis was achieved in 56% of patients.

Another open-label, non-comparative, single-arm study (S3A239) investigated the efficacy of one intravenous dose of 0.15 mg/kg ondansetron followed by two oral ondansetron doses of 4 mg for children aged < 12 yrs and 8 mg for children aged

PONV

The efficacy of a single dose of ondansetron in the prevention of post-operative nausea and vomiting was investigated in a randomised, double-blind, placebo-controlled study in 670 children aged 1 to 24 months (post-conceptual age

Four double-blind, placebo-controlled studies have been performed in 1469 male and female patients (2 to 12 years of age) undergoing general anaesthesia. Patients were randomised to either single intravenous doses of ondansetron (0.1 mg/kg for paediatric patients weighing 40 kg or less, 4 mg for paediatric patients weighing more than 40 kg; number of patients = 735)) or placebo (number of patients = 734). Study drug was administered over at least 30 seconds, immediately prior to or following anaesthesia induction. Ondansetron was significantly more effective than placebo in preventing nausea and vomiting. The results of these studies are summarised in Table 3.

Table 3 Prevention and treatment of PONV in Paediatric Patients – Treatment response over 24 hours

Study	Endpoint	Ondansetron %	Placebo %	p value
S3A380	CR	68	39
S3GT09	CR	61	35
S3A381	CR	53	17
S3GT11	no nausea	64	51	0.004
S3GT11	no emesis	60	47	0.004

CR = no emetic episodes, rescue or withdrawal

5.2 Pharmacokinetic Properties

Following oral administration, ondansetron is passively and completely absorbed from the gastrointestinal tract and undergoes first pass metabolism. Peak plasma concentrations of about 30ng/ml are attained approximately 1.5 hours after an 8mg dose. For doses above 8mg the increase in ondansetron systemic exposure with dose is greater than proportional; this may reflect some reduction in first pass metabolism at higher oral doses. Mean bioavailability in healthy male subjects, following the oral administration of a single 8 mg tablet, is approximately 55 to 60%. Bioavailability, following oral administration, is slightly enhanced by the presence of food but unaffected by antacids. Studies in healthy elderly volunteers have shown slight, but clinically insignificant, age-related increases in both oral bioavailability (65%) and half-life (5 hours) of ondansetron. Gender differences were shown in the disposition of ondansetron, with females having a greater rate and extent of absorption following an oral dose and reduced systemic clearance and volume of distribution (adjusted for weight).

The disposition of ondansetron following oral, intramuscular(IM) and intravenous(IV) dosing is similar with a terminal half life of about 3 hours and steady state volume of distribution of about 140L. Equivalent systemic exposure is achieved after IM and IV administration of ondansetron.

A 4mg intravenous infusion of ondansetron given over 5 minutes results in peak plasma concentrations of about 65ng/ml. Following intramuscular administration of ondansetron, peak plasma concentrations of about 25ng/ml are attained within 10 minutes of injection.

Following administration of ondansetron suppository, plasma ondansetron concentrations become detectable between 15 and 60 minutes after dosing. Concentrations rise in an essentially linear fashion, until peak concentrations of 20-30 ng/ml are attained, typically 6 hours after dosing. Plasma concentrations then fall, but at a slower rate than observed following oral dosing due to continued absorption of ondansetron. The absolute bioavailability of ondansetron from the suppository is approximately 60% and is not affected by gender. The half life of the elimination phase following suppository administration is determined by the rate of ondansetron absorption, not systemic clearance and is approximately 6 hours. Females show a small, clinically insignificant, increase in half-life in comparison with males.

Ondansetron is not highly protein bound (70-76%). Ondansetron is cleared from the systemic circulation predominantly by hepatic metabolism through multiple enzymatic pathways. Less than 5% of the absorbed dose is excreted unchanged in the urine. The absence of the enzyme CYP2D6 (the debrisoquine polymorphism) has no effect on ondansetron's pharmacokinetics. The pharmacokinetic properties of ondansetron are unchanged on repeat dosing.

Special Patient Populations

Children and Adolescents (aged 1 month to 17 years)

In paediatric patients aged 1 to 4 months (n=19) undergoing surgery, weight normalised clearance was approximately 30% slower than in patients aged 5 to 24 months (n=22) but comparable to the patients aged 3 to 12 years. The half-life in the patient population aged 1 to 4 month was reported to average 6.7 hours compared to 2.9 hours for patients in the 5 to 24 month and 3 to 12 year age range. The differences in pharmacokinetic parameters in the 1 to 4 month patient population can be explained in part by the higher percentage of total body water in neonates and infants and a higher volume of distribution for water soluble drugs like ondansetron.

In paediatric patients aged 3 to 12 years undergoing elective surgery with general anaesthesia, the absolute values for both the clearance and volume of distribution of ondansetron were reduced in comparison to values with adult patients. Both parameters increased in a linear fashion with weight and by 12 years of age, the values were approaching those of young adults. When clearance and volume of distribution values were normalised by body weight, the values for these parameters were similar between the different age group populations. Use of weight-based dosing compensates for age-related changes and is effective in normalising systemic exposure in paediatric patients.

Population pharmacokinetic analysis was performed on 428 subjects (cancer patients, surgery patients and healthy volunteers) aged 1 month to 44 years following intravenous administration of ondansetron. Based on this analysis, systemic exposure (AUC) of ondansetron following oral or IV dosing in children and adolescents was comparable to adults, with the exception of infants aged 1 to 4 months. Volume was related to age and was lower in adults than in infants and children. Clearance was related to weight but not to age with the exception of infants aged 1 to 4 months. It is difficult to conclude whether there was an additional reduction in clearance related to age in infants 1 to 4 months or simply inherent variability due to the low number of subjects studied in this age group. Since patients less than 6 months of age will only receive a single dose in PONV a decreased clearance is not likely to be clinically relevant.

Renal impairment

In patients with renal impairment (creatinine clearance 15-60 ml/min), both systemic clearance and volume of distribution are reduced following IV administration of ondansetron, resulting in a slight, but clinically insignificant, increase in elimination half-life (5.4h). A study in patients with severe renal impairment who required regular haemodialysis (studied between dialyses) showed ondansetron's pharmacokinetics to be essentially unchanged following IV administration.

Elderly or renal impairment

Specific studies in the elderly or patients with renal impairment have been limited to IV and oral administration. However, it is anticipated that the half-life of ondansetron after rectal administration in these populations will be similar to that seen in healthy volunteers, since the rate of elimination of ondansetron following rectal administration is not determined by systemic clearance.

Hepatic impairment

Following oral, intravenous or intramuscular dosing in patients with severe hepatic impairment, ondansetron's systemic clearance is markedly reduced with prolonged elimination half-lives (15-32 h) and an oral bioavailability approaching 100% due to reduced pre-systemic metabolism. The pharmacokinetics of ondansetron following administration as a suppository have not been evaluated in patients with hepatic impairment.

5.3 Preclinical Safety Data

No additional data of relevance.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Citric acid

Sodium citrate dihydrate

Sodium benzoate

Sorbitol solution

Strawberry flavour

Purified water

6.2 Incompatibilities

None reported.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

Store upright below 30°C. Do not refrigerate.

6.5 Nature And Contents Of Container

60ml amber glass bottle with a child resistant cap containing 50ml of Zofran Syrup.

6.6 Special Precautions For Disposal And Other Handling

For oral administration. For detailed information see the patient information leaflet included in every pack.

Administrative Data

7. Marketing Authorisation Holder

Glaxo Wellcome UK Limited trading as GlaxoSmithKline UK

Stockley Park West

Uxbridge

Middlesex, UB11 1BT

8. Marketing Authorisation Number(S)

PL 10949/0246

9. Date Of First Authorisation/Renewal Of The Authorisation

17^th August 2001

10. Date Of Revision Of The Text

10 October 2011

11. LEGAL STATUS

POM