Arcapta Neohaler

Generic Name: indacaterol (Inhalation route)

in-da-KAT-er-ol

Commonly used brand name(s)

In the U.S.

• Arcapta Neohaler

Available Dosage Forms:

• Capsule

Therapeutic Class: Bronchodilator

Pharmacologic Class: Beta-2 Adrenergic Agonist

Uses For Arcapta Neohaler

Indacaterol is used to treat air flow blockage and prevent worsening of chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. COPD is a long-term lung disease that causes bronchospasm (wheezing or difficulty with breathing).

Indacaterol is a long-acting bronchodilator. Bronchodilators are medicines that are breathed in through the mouth to open up the bronchial tubes (air passages) in the lungs. They relieve cough, wheezing, shortness of breath, and troubled breathing by increasing the flow of air through the bronchial tubes.

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

Before Using Arcapta Neohaler

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

Indacaterol is not indicated for use in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of indacaterol in the elderly.

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 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.

• Acebutolol


• Alprenolol


• Amitriptyline


• Amoxapine


• Arotinolol


• Atenolol


• Befunolol


• Betaxolol


• Bevantolol


• Bisoprolol


• Bopindolol


• Brofaromine


• Bucindolol


• Bupranolol


• Carteolol


• Carvedilol


• Celiprolol


• Clomipramine


• Clorgyline


• Desipramine


• Dilevalol


• Dothiepin


• Doxepin


• Esmolol


• Furazolidone


• Imipramine


• Iproniazid


• Isocarboxazid


• Labetalol


• Landiolol


• Lazabemide


• Levobetaxolol


• Levobunolol


• Linezolid


• Lofepramine


• Mepindolol


• Metipranolol


• Metoprolol


• Moclobemide


• Nadolol


• Nebivolol


• Nialamide


• Nipradilol


• Nortriptyline


• Opipramol


• Oxprenolol


• Pargyline


• Penbutolol


• Phenelzine


• Pindolol


• Procarbazine


• Propranolol


• Protriptyline


• Rasagiline


• Selegiline


• Sotalol


• Talinolol


• Tertatolol


• Timolol


• Toloxatone


• Tranylcypromine


• Trimipramine

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:

• Allergy to milk proteins—Use with caution. This medicine contains lactose (milk sugar) and milk proteins.

• Asthma—Do not use this medicine if you have this condition. Some people with asthma have had more severe asthma attacks when they used this medicine.

• COPD attack, severe—Should not be used if you are having a severe COPD attack, or if symptoms of COPD attack has already started. Your doctor may prescribe another medicine for you to use in case of an acute COPD attack.

• Diabetes or


• Heart or blood vessel disease or


• Heart rhythm problems (e.g., QT prolongation) or


• Hypertension (high blood pressure) or


• Hyperthyroidism (overactive thyroid) or


• Hypokalemia (low potassium in the blood) or


• Ketoacidosis (high ketones in the blood) or


• Seizures, history of—Use with caution. May make these conditions worse.

Proper Use of Arcapta Neohaler

Use this medicine only as directed by your doctor. Do not use more of it and do not use it more often than recommended on the label, unless otherwise directed by your doctor. Using the medicine more often may increase the chance of serious unwanted effects.

In order for this medicine to help prevent COPD attacks, it must be used once a day at the same time each day as ordered by your doctor.

Indacaterol inhalation powder is used with a special inhaler (Neohaler™) and usually comes with a Medication Guide and patient directions. Read the directions carefully before using this medicine. If you do not understand the directions or you are not sure how to use the inhaler, ask your doctor to show you what to do. Also, ask your doctor to check how you use the inhaler to make sure you are using it properly.

To use indacaterol inhalation powder with the Neohaler™:

• Dry your hands before handling this medicine.


• Open a blister card of capsules. Do not remove a capsule until you are ready for a dose.


• Open the base of inhaler firmly and tilt the mouthpiece to open the inhaler.


• Place the capsule only in the capsule-chamber in the base of the inhaler. Do not swallow the capsule and do not place a capsule directly into the mouthpiece.


• Hold the mouthpiece of the inhaler upright and press both buttons at the same time. Press the buttons only once. You should hear a click as the capsule is being pierced.


• Breathe out fully. Do not exhale into the mouthpiece.


• Place the mouthpiece in your mouth then close your lips around the mouthpiece.


• Breathe in quickly and deeply.


• Remove the inhaler from your mouth. Hold your breath as long as you can and then exhale.


• Open the inhaler after using it, and remove and discard the empty capsule. Do not leave the used capsule inside the chamber.


• Close the mouthpiece and then replace the cover.


• Do not wash the inhaler. Keep it dry.


• You may reuse your inhaler. But use a new inhaler with each refill of your medicine.


• Do not use the inhaler for this medicine with any other medicine.

Dosing

The dose of this medicine 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 this medicine. 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 inhalation powder dosage form (used with Neohaler™):
  
  • For maintenance treatment of COPD:
    
    • Adults—75 micrograms (mcg) (1 capsule) by oral inhalation once a day.
    
    
    • Children—Use is not recommended.
    
    
  
  

Missed Dose

If you miss a dose of this medicine, 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.

Do not use this medicine more than one time every 24 hours.

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 Arcapta Neohaler

If you will be using this medicine for a long time, it is very important that your doctor check you at regular visits. This will allow your doctor to see if the medicine is working properly and to check for any unwanted effects.

Tell your doctor if you are also using other medicines for your COPD. Your doctor may want you to stop using the other medicine and use it only during a severe COPD attack. Follow your doctor's instructions on how you should take your medicine.

This medicine should not be used if you are having a severe COPD attack, or if symptoms of COPD attack has already started. Your doctor may prescribe another medicine for you to use in case of an acute COPD attack. If the other medicine does not work as well, tell your doctor right away.

Talk to your doctor or get medical care right away:

• Your symptoms do not improve after using this medicine within a few days or if they become worse.


• Your short-acting inhaler does not seem to be working as well as usual and you need to use it more often.

This medicine should not be used together with similar inhaled medicines such as arformoterol (Brovana™), budesonide/formoterol (Symbicort®), formoterol (Foradil®, Perforomist™), salmeterol (Serevent®), or salmeterol/fluticasone (Advair®).

This medicine may cause paradoxical bronchospasm, which means your breathing or wheezing will get worse. Paradoxical bronchospasm may be life-threatening. Stop using this medicine and check with your doctor right away if you are having a cough, difficulty with breathing, shortness of breath, or wheezing after using this medicine.

Hypokalemia (low potassium in the blood) may occur while you are using this medicine. Check with your doctor right away if you have more than one of the following symptoms: decreased urine; dry mouth; increased thirst; loss of appetite; mood changes; muscle pain or cramps; nausea or vomiting; numbness or tingling in the hands, feet, or lips; seizures; shortness of breath; uneven heartbeat; or unusual tiredness or weakness.

This medicine may affect blood sugar levels. If you are diabetic and notice a change in the results of your blood or urine sugar tests, check with your doctor.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Arcapta Neohaler 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

• Arm, back, or jaw pain


• chest pain or discomfort


• chest tightness or heaviness


• cough


• dizziness


• fainting


• fast or irregular heartbeat


• fever or chills


• nausea


• shortness of breath


• sneezing


• sore throat


• sweating


• tightness in the chest


• troubled breathing


• wheezing

Less common

• Abdominal or stomach pain


• bloating or swelling of the face, arms, hands, lower legs, or feet


• blurred vision


• body aches or pain


• dry mouth


• ear congestion


• fainting


• flushed, dry skin


• fruit-like breath odor


• headache


• increased hunger


• increased thirst


• increased urination


• loss of consciousness


• loss of voice


• rapid weight gain


• runny or stuffy nose


• stomachache


• sweating


• tingling of the hands or feet


• unexplained weight loss


• unusual tiredness or weakness


• unusual weight gain or loss


• vomiting

Incidence not known

• Fast, irregular, pounding, or racing heartbeat or pulse

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:

Less common

• Muscle or bone pain


• muscle spasm


• pain or tenderness around the eyes and cheekbones

Incidence not known

• Itching skin


• rash

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: Arcapta Neohaler 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.

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More Arcapta Neohaler resources

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

• Arcapta Neohaler Prescribing Information (FDA)


• Arcapta Neohaler inhalation Concise Consumer Information (Cerner Multum)


• Arcapta Neohaler MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Arcapta Neohaler with other medications

• COPD, Maintenance

Lyme Disease Medications

Definition of Lyme Disease: Lyme disease is an acute inflammatory disease characterized by a skin rash, joint inflammation, and flu-like symptoms, caused by the bacterium More...

Drugs associated with Lyme Disease

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

See sub-topics

Topics under Lyme Disease

• Lyme Disease, Arthritis (25 drugs)

• Lyme Disease, Carditis (24 drugs)

• Lyme Disease, Erythema Chronicum Migrans (25 drugs)

• Lyme Disease, Neurologic (24 drugs)

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Medical Encyclopedia:

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• Lyme disease - chronic persistent

Harvard Health Guide:

• Symptoms and treatment for Lyme Disease

Drug List:

Ceftin

Claforan

Doryx-Delayed-Release-Capsules

Doxy-100

Doxy-200

E-E-S-Granules-Suspension

E-E-S-200

E-E-S-400

E-E-S-400-Filmtab

Ery-Tab

Eryc-Delayed-Release-Particles-Capsules

Eryped-Drops

Erythrocin

Erythromycin-Lactobionate-I-V

Erythrocin-Stearate-Filmtab

Ilosone

Monodox

Ocudox-Convenience-Kit

Oraxyl

Pce

Rocephin

Vibra-Tabs

Vibramycin

Zinacef

ketamine

Generic Name: ketamine (KET a meen)

Brand Names: Ketalar

What is ketamine?

Ketamine is an anesthetic medication.

Ketamine is used as a general anesthetic to prevent pain and discomfort during certain medical tests or procedures, or minor surgery.

Ketamine may also be used for purposes other than those listed in this medication guide.

What is the most important information I should know about ketamine?

Before you receive ketamine, tell your doctor if you are allergic to any drugs, or if you have a history of alcoholism.

It may take you longer to recover from anesthesia with ketamine if you have recently used a barbiturate such as phenobarbital (Luminal) or secobarbital (Seconal), or a narcotic medication such as fentanyl (Actiq, Duragesic), hydrocodone (Lortab, Vicodin), oxycodone (OxyContin), propoxyphene (Darvocet, Darvon), and others.

Ketamine may be harmful to an unborn baby. Before you receive ketamine, tell your doctor if you are pregnant.

You may feel strange or slightly confused when you first come out of anesthesia. Tell your caregivers if these feelings are severe or unpleasant.

Ketamine can cause side effects that may impair your thinking or reactions for 24 hours or longer. Be careful if you drive or do anything that requires you to be awake and alert. You will probably not be allowed to drive yourself home after your surgery or medical procedure.

Follow your doctor's instructions about any restrictions on food, beverages, or activity after you recover from anesthesia.

What should I discuss with my health care provider before receiving ketamine?

Before you receive ketamine, tell your doctor if you are allergic to any drugs, or if you have a history of alcoholism.

Ketamine may be harmful to an unborn baby. Before you receive ketamine, tell your doctor if you are pregnant.

How is ketamine given?

Ketamine is given as an injection through a needle placed into a vein or muscle. You will receive this injection in a clinic or hospital setting.

Your caregivers will monitor your heart function, blood pressure, and breathing while you are under the effects of ketamine.

You may feel strange or slightly confused when you first come out of anesthesia. Tell your caregivers if these feelings are severe or unpleasant.

What happens if I miss a dose?

Since ketamine is usually given for anesthesia, you are not likely to be on a dosing schedule.

What happens if I overdose?

An overdose of ketamine is unlikely to occur since the medication is given by a doctor. Your vital signs will be closely watched while you are under anesthesia to make sure the medication is not causing any harmful effects.

What should I avoid after receiving ketamine?

Ketamine can cause side effects that may impair your thinking or reactions for 24 hours or longer. Be careful if you drive or do anything that requires you to be awake and alert. You will probably not be allowed to drive yourself home after your surgery or medical procedure.

Follow your doctor's instructions about any restrictions on food, beverages, or activity after you recover from anesthesia.

Ketamine 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. Tell your caregivers at once if you have any of these serious side effects within 24 hours after you receive ketamine:

• 
  

  severe confusion;

  
  


• 
  

  hallucinations;

  
  


• 
  

  unusual thoughts; or

  
  


• 
  

  extreme fear.

  
  

Less serious side effects may include:

• 
  

  dream-like feeling;

  
  


• 
  

  double vision;

  
  


• 
  

  jerky muscle movements;

  
  


• 
  

  dizziness, drowsiness;

  
  


• 
  

  nausea, vomiting, loss of appetite; or

  
  


• 
  

  sleep problems (insomnia).

  
  

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

Ketamine Dosing Information

Usual Adult Dose for Anesthesia:

Parenteral:

Intravenous:

Induction: 1 to 4.5 mg/kg; alternatively, 1 to 2 mg/kg at a rate of 0.5 mg/kg/min may be used. (2 mg/kg dose provides 5 to 10 minutes of surgical anesthesia within 30 seconds following injection).

Maintenance: The maintenance dose should be adjusted according to the patient's anesthetic needs and whether an additional anesthetic is employed. Increments of one-half to the full induction dose may be repeated as needed for maintenance of anesthesia.

Intramuscular:

Induction: 6.5 to 13 mg/kg; (9 to 13 mg/kg dose provides 12 to 25 minutes of surgical anesthesia within 3 to 4 minutes following injection).

Maintenance: The maintenance dose should be adjusted according to the patient's anesthetic needs and whether an additional anesthetic is employed. Increments of one-half to the full induction dose may be repeated as needed for maintenance of anesthesia.

What other drugs will affect ketamine?

Before you receive ketamine, tell your doctor if you have recently used any of the following:

• 
  

  a barbiturate such as amobarbital (Amytal), butabarbital (Butisol), mephobarbital (Mebaral), secobarbital (Seconal), or phenobarbital (Luminal, Solfoton); or

  
  


• 
  

  narcotic medication such as fentanyl (Actiq, Duragesic, Ionsys), hydrocodone (Lortab, Vicodin), hydromorphone (Dilaudid, Palladone), methadone (Dolophine, Methadose), morphine (Kadian, MS Contin, Oramorph), oxycodone (OxyContin, Percocet, Roxicodone), propoxyphene (Darvocet, Darvon), and others.

  
  

If you are using any of these drugs, it may take you longer to recover from anesthesia with ketamine.

There may be other drugs that can affect ketamine. 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 ketamine resources

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

• Ketamine MedFacts Consumer Leaflet (Wolters Kluwer)


• Ketalar Prescribing Information (FDA)

Compare ketamine with other medications

• Anesthesia
• Pain

Where can I get more information?

• Your doctor or pharmacist can provide more information about ketamine.

See also: ketamine side effects (in more detail)

perflutren lipid microsphere Intravenous

per-FLOO-tren LIP-id MYE-kroe-sfeers

Commonly used brand name(s)

In the U.S.

• Definity

Available Dosage Forms:

• Suspension

Therapeutic Class: Radiological Non-Ionic Contrast Media

Uses For perflutren lipid microsphere

Perflutren lipid microsphere preparation is an ultrasound contrast agent. Ultrasound contrast agents are used to help provide a clear picture during ultrasound. Ultrasound is a special kind of diagnostic procedure. It uses high-frequency sound waves to create images or “pictures” of certain areas inside the body. The sound waves produced by the ultrasound equipment can be reflected (bounced off) by different parts of the body, like for example, the heart. As the sound waves return they are electronically converted into images on a television screen. Unlike x-rays, ultrasound does not involve ionizing radiation.

The perflutren lipid microspheres preparation contains very small gas-filled lipid microspheres that reflect the sound waves and help create a better picture. The lipid microsphere preparation is given by injection into a vein before ultrasound to help diagnose problems of the heart.

perflutren lipid microsphere is to be given only by or under the direct supervision of a doctor with specialized training in ultrasound procedures.

Before Using perflutren lipid microsphere

In deciding to use a diagnostic test, any risks of the test must be weighed against the good it will do. This is a decision you and your doctor will make. Also, other things may affect test results. For this test, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to perflutren lipid microsphere 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 have not been performed on the relationship of age to the effects of perflutren lipid microsphere injection in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of perflutren lipid microsphere injection in the elderly.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	B	Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate studies in pregnant women OR animal studies have shown an adverse effect, but adequate studies in pregnant women have failed to demonstrate a risk to the fetus.

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 diagnostic test, 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.

Receiving this diagnostic test with any of the following medicines is not recommended. Your doctor may decide not to use this diagnostic test or change some of the other medicines you take.

• Cisapride


• Dronedarone


• Mesoridazine


• Pimozide


• Sparfloxacin


• Thioridazine

Receiving this diagnostic test 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.

• Alfuzosin


• Amiodarone


• Amitriptyline


• Amoxapine


• Apomorphine


• Arsenic Trioxide


• Asenapine


• Astemizole


• Azithromycin


• Chloroquine


• Chlorpromazine


• Ciprofloxacin


• Citalopram


• Clarithromycin


• Clomipramine


• Clozapine


• Crizotinib


• Dasatinib


• Desipramine


• Disopyramide


• Dofetilide


• Dolasetron


• Droperidol


• Erythromycin


• Flecainide


• Fluconazole


• Gatifloxacin


• Gemifloxacin


• Granisetron


• Halofantrine


• Haloperidol


• Ibutilide


• Iloperidone


• Imipramine


• Lapatinib


• Levofloxacin


• Lopinavir


• Lumefantrine


• Mefloquine


• Methadone


• Moxifloxacin


• Nilotinib


• Norfloxacin


• Nortriptyline


• Octreotide


• Ofloxacin


• Ondansetron


• Paliperidone


• Pazopanib


• Posaconazole


• Procainamide


• Prochlorperazine


• Promethazine


• Propafenone


• Protriptyline


• Quetiapine


• Quinidine


• Quinine


• Ranolazine


• Salmeterol


• Saquinavir


• Sodium Phosphate


• Sodium Phosphate, Dibasic


• Sodium Phosphate, Monobasic


• Solifenacin


• Sorafenib


• Sotalol


• Sunitinib


• Telavancin


• Telithromycin


• Terfenadine


• Tetrabenazine


• Toremifene


• Trazodone


• Trifluoperazine


• Trimipramine


• Vandetanib


• Vardenafil


• Vemurafenib


• Voriconazole


• Ziprasidone

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 diagnostic test. Make sure you tell your doctor if you have any other medical problems, especially:

• Congestive heart failure or


• Heart attack or


• Heart disease (e.g., coronary artery syndrome) or


• Heart rhythm problems (e.g., ventricular arrhythmia) or


• Respiratory distress syndrome—May increase risk for more serious side effects.

• Heart rhythm problems (e.g., QT prolongation)—Use with caution. May make this condition worse.

• Heart shunt, right-to-left, bi-directional, or transient right-to-left—Should not be used in patients with this condition.

Proper Use of perflutren lipid microsphere

A doctor or other trained health professional will give you perflutren lipid microsphere. perflutren lipid microsphere is given through a needle placed in one of your veins before ultrasound.

Your doctor may have special instructions for you in preparation for your test. If you do not understand the instructions you receive or if you have not received such instructions, check with your doctor in advance.

Precautions While Using perflutren lipid microsphere

It is very important that your doctor check your progress very closely while you are receiving perflutren lipid microsphere. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to receive it.

perflutren lipid microsphere may cause a serious type of allergic reaction called anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Tell your doctor right away if you have a rash; itching; hoarseness; trouble breathing; trouble swallowing; or any swelling of your hands, face, or mouth after receiving perflutren lipid microsphere.

Tell your doctor right away if you have a chest pain; fast, slow, pounding, or irregular heartbeat; lightheadedness, dizziness, or fainting; shortness of breath; or troubled breathing. These may be symptoms of heart or lung problems.

perflutren lipid microsphere 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:

Rare

• Black, tarry stools


• blurred vision


• chest pain


• chills


• difficulty with breathing


• dizziness, severe or continuing


• fast, pounding, or irregular heartbeat or pulse


• hives


• itching


• lightheadedness when getting up from a lying or sitting position


• shortness of breath


• skin rash


• slow or irregular heartbeat


• swollen glands


• unusual bleeding or bruising

Incidence not known

• Cough


• difficulty swallowing


• dizziness


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


• tightness in the chest


• unusual tiredness or weakness


• wheezing

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:

Less common

• Back pain


• feeling of warmth on the skin


• headache


• nausea


• redness of the face, neck, arms, and occasionally, upper chest

Rare

• Acid or sour stomach


• bruising


• diarrhea


• difficulty with moving


• dizziness


• dryness of the mouth


• feeling of constant movement of self or surroundings


• fever


• heartburn


• indigestion


• leg cramps


• muscle stiffness or tension


• pain at the injection site


• pain or swelling in the joints


• prickly or tingling sensation


• sneezing or runny nose


• stomach upset or pain

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.

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.

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Leucovorin Injection

Dosage Form: injection, powder, lyophilized, for solution
Leucovorin Calcium For Injection

Rx only

Leucovorin Injection Description

Leucovorin is one of several active, chemically reduced derivatives of folic acid.  It is useful as an antidote to drugs which act as folic acid antagonists.

Also known as folinic acid, Citrovorum factor, or 5-formyl-5,6,7,8-tetrahydrofolic acid, this compound has the chemical designation of Calcium N - [p - [[[(6RS) - 2 - amino - 5 - formyl - 5,6,7,8 - tetrahydro - 4 - hydroxy - 6 - pteridinyl]methyl]amino]benzoyl] - L - glutamate (1:1). The structural formula of leucovorin calcium is:

 

C20H21CaN7O7                                                                                                M.W. 511.51

Leucovorin Calcium for Injection is a sterile product indicated for intramuscular (IM) or intravenous (IV) administration and is supplied in 200 mg and 500 mg vials.

Each 200 mg vial of Leucovorin Calcium for Injection, when reconstituted with 20 mL of sterile diluent, contains leucovorin (as the calcium salt) 10 mg/mL.

Each 500 mg vial of Leucovorin Calcium for Injection, when reconstituted with 50 mL of sterile diluent, contains leucovorin (as the calcium salt) 10 mg/mL.

In each dosage form, one milligram of leucovorin calcium contains 0.002 mmol of leucovorin and 0.002 mmol of calcium.

These lyophilized products contain no preservative.  The inactive ingredient is sodium chloride added to adjust tonicity.  Reconstitute with Bacteriostatic Water for Injection, USP, which contains benzyl alcohol (see WARNINGS), or with Sterile Water for Injection, USP.

The inactive ingredient is sodium chloride 180 mg/vial for the 200 mg and 450 mg/vial for the 500 mg.  Sodium hydroxide and/or hydrochloric acid may be added for pH adjustment.  pH adjusted to approximately 7.8.

There is 0.004 mEq of calcium per mg of leucovorin.  Solution contains no bacteriostat or antimicrobial agents.

Leucovorin Injection - Clinical Pharmacology

Leucovorin is a mixture of the diastereoisomers of the 5-formyl derivative of tetrahydrofolic acid (THF). The biologically active compound of the mixture is the (-)-I-isomer, known as Citrovorum factor or (-)-folinic acid.  Leucovorin does not require reduction by the enzyme dihydrofolate reductase in order to participate in reactions utilizing folates as a source of “one-carbon” moieties.

I-Leucovorin (I-5-formyltetrahydrofolate) is rapidly metabolized (via 5, 10-methenyltetrahydrofolate then 5, 10-methylenetetrahydrofolate) to I,5-methyltetrahydrofolate. I,5-Methyltetrahydrofolate can in turn be metabolized via other pathways back to 5,10-methylenetetrahydrofolate, which is converted to 5-methyltetrahydrofolate by an irreversible, enzyme catalyzed reduction using the cofactors FADH2 and NADPH.

Administration of leucovorin can counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase.

In contrast, leucovorin can enhance the therapeutic and toxic effects of fluoropyrimidines used in cancer therapy, such as 5-fluorouracil.  Concurrent administration of leucovorin does not appear to alter the plasma pharmacokinetics of 5-fluorouracil. 5-Fluorouracil is metabolized to fluorodeoxyuridylic acid, which binds to and inhibits the enzyme thymidylate synthase (an enzyme important in DNA repair and replication).

Leucovorin is readily converted to another reduced folate, 5,10-methylenetetrahydrofolate, which acts to stabilize the binding of fluorodeoxyridylic acid to thymidylate synthase and thereby enhances the inhibition of this enzyme.

The pharmacokinetics after intravenous, intramuscular and oral administration of a 25 mg dose of leucovorin were studied in male volunteers.  After intravenous administration, serum total reduced folates (as measured by Lactobacillus casei assay) reached a mean peak of 1259 ng/mL (range 897 to 1625). The mean time to peak was 10 minutes.  This initial rise in total reduced folates was primarily due to the parent compound 5-formyl-THF (measured by Streptococcus faecalis assay) which rose to 1206 ng/mL at 10 minutes.  A sharp drop in parent compound followed and coincided with the appearance of the active metabolite 5-methyl-THF which became the predominant circulating form of the drug.

The mean peak of 5-methyl-THF was 258 ng/mL and occurred at 1.3 hours.  The terminal half-life for total reduced folates was 6.2 hours.  The area under the concentration versus time curves (AUCs) for I-leucovorin, d-leucovorin and 5-methyltetrahydrofolate were 28.4 ± 3.5, 956 ± 97 and 129 ± 12 (mg/min/L ± S.E.).  When a higher dose of d,I-leucovorin (200 mg/m2) was used, similar results were obtained.  The d-isomer persisted in plasma at concentrations greatly exceeding those of the I-isomer.

After intramuscular injection, the mean peak of serum total reduced folates was 436 ng/mL (range 240 to 725) and occurred at 52 minutes.  Similar to IV administration, the initial sharp rise was due to the parent compound.  The mean peak of 5-formyl-THF was 360 ng/mL and occurred at 28 minutes.  The level of the metabolite 5-methyl-THF increased subsequently over time until at 1.5 hours it represented 50% of the circulating total folates.  The mean peak of 5-methyl-THF was 226 ng/mL at 2.8 hours.  The terminal half-life of total reduced folates was 6.2 hours.  There was no difference of statistical significance between IM and IV administration in the AUC for total reduced folates, 5-formyl-THF, or 5-methyl-THF.

After oral administration of leucovorin reconstituted with aromatic elixir, the mean peak concentration of serum total reduced folates was 393 ng/mL (range 160 to 550).  The mean time to peak was 2.3 hours and the terminal half-life was 5.7 hours. The major component was the metabolite 5-methyltetrahydrofolate to which leucovorin is primarily converted in the intestinal mucosa.  The mean peak of 5-methyl-THF was 367 ng/mL at 2.4 hours. The peak level of the parent compound was 51 ng/mL at 1.2 hours.  The AUC of total reduced folates after oral administration of the 25 mg dose was 92% of the AUC after intravenous administration.

Following oral administration, leucovorin is rapidly absorbed and expands the serum pool of reduced folates.  At a dose of 25 mg, almost 100% of the I-isomer but only 20% of the d-isomer is absorbed.  Oral absorption of leucovorin is saturable at doses above 25 mg.  The apparent bioavailability of leucovorin was 97% for 25 mg, 75% for 50 mg, and 37% for 100 mg.

In a randomized clinical study conducted by the Mayo Clinic and the North Central Cancer Treatment Group (Mayo/NCCTG) in patients with advanced metastatic colorectal cancer three treatment regimens were compared: Leucovorin (LV) 200 mg/m2 and 5-fluorouracil (5-FU) 370 mg/m2 versus LV 20 mg/m2 and 5-FU 425 mg/m2 versus 5-FU 500 mg/m2.  All drugs were administered by slow intravenous infusion daily for 5 days repeated every 28 to 35 days.  Response rates were 26% (p=0.04 versus 5-FU alone), 43% (p=0.001 versus 5-FU alone) and 10% for the high dose leucovorin, low dose leucovorin and 5-FU alone groups respectively.  Respective median survival times were 12.2 months (p=0.037), 12 months (p=0.05), and 7.7 months.  The low dose LV regimen gave a statistically significant improvement in weight gain of more than 5%, relief of symptoms, and improvement in performance status.  The high dose LV regimen gave a statistically significant improvement in performance status and trended toward improvement in weight gain and in relief of symptoms but these were not statistically significant.1

In a second Mayo/NCCTG randomized clinical study the 5-FU alone arm was replaced by a regimen of sequentially administered methotrexate (MTX), 5-FU, and LV.  Response rates with LV 200 mg/m2 and 5-FU 370 mg/m2 versus LV 20 mg/m2 and 5-FU 425 mg/m2 versus sequential MTX and 5-FU and LV were respectively 31% (p=<.01), 42% (p=<.01), and 14%. Respective median survival times were 12.7 months (p=<.04), 12.7 months (p=<.01), and 8.4 months.  No statistically significant difference in weight gain of more than 5% or in improvement in performance status was seen between the treatment arms.2

Indications and Usage for Leucovorin Injection

Leucovorin calcium rescue is indicated after high dose methotrexate therapy in osteosarcoma.   Leucovorin calcium is also indicated to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosages of folic acid antagonists.

Leucovorin calcium is indicated in the treatment of megaloblastic anemias due to folic acid deficiency when oral therapy is not feasible.

Leucovorin is also indicated for use in combination with 5-fluorouracil to prolong survival in the palliative treatment of patients with advanced colorectal cancer. Leucovorin should not be mixed in the same infusion as 5-fluorouracil because a precipitate may form.

Contraindications

Leucovorin is improper therapy for pernicious anemia and other megaloblastic anemias secondary to the lack of vitamin B12. A hematologic remission may occur while neurologic manifestations continue to progress.

Warnings

In the treatment of accidental overdosages of folic acid antagonists, intravenous leucovorin should be administered as promptly as possible.  As the time interval between antifolate administration (e.g., methotrexate) and leucovorin rescue increases, leucovorin's effectiveness in counteracting toxicity decreases.  In the treatment of accidental overdosages of intrathecally administered folic acid antagonists, do not administer leucovorin intrathecally.  LEUCOVORIN MAY BE HARMFUL OR FATAL IF GIVEN INTRATHECALLY.

Monitoring of the serum methotrexate concentration is essential in determining the optimal dose and duration of treatment with leucovorin.

Delayed methotrexate excretion may be caused by a third space fluid accumulation (i.e., ascites, pleural effusion), renal insufficiency, or inadequate hydration.  Under such circumstances, higher doses of leucovorin or prolonged administration may be indicated. Doses higher than those recommended for oral use must be given intravenously.

Because of the benzyl alcohol contained in certain diluents used for reconstituting Leucovorin Calcium for Injection, when doses greater than 10 mg/m2 are administered, Leucovorin Calcium for Injection should be reconstituted with Sterile Water for Injection, USP, and used immediately (see DOSAGE AND ADMINISTRATION).

Because of the calcium content of the leucovorin solution, no more than 160 mg of leucovorin should be injected intravenously per minute (16 mL of a 10 mg/mL, or 8 mL of a 20 mg/mL solution per minute).

Leucovorin enhances the toxicity of 5-fluorouracil.  When these drugs are administered concurrently in the palliative therapy of advanced colorectal cancer, the dosage of 5-fluorouracil must be lower than usually administered.  Although the toxicities observed in patients treated with the combination of leucovorin plus 5-fluorouracil are qualitatively similar to those observed in patients treated with 5-fluorouracil alone, gastrointestinal toxicities (particularly stomatitis and diarrhea) are observed more commonly and may be more severe and of prolonged duration in patients treated with the combination.

In the first Mayo/NCCTG controlled trial, toxicity, primarily gastrointestinal, resulted in 7% of patients requiring hospitalization when treated with 5-fluorouracil alone or 5-fluorouracil in combination with 200 mg/m2 of leucovorin and 20% when treated with 5-fluorouracil in combination with 20 mg/m2 of leucovorin. In the second Mayo/NCCTG trial, hospitalizations related to treatment toxicity also appeared to occur more often in patients treated with the low dose leucovorin/5-fluorouracil combination than in patients treated with the high dose combination — 11% versus 3%.  Therapy with leucovorin and 5-fluorouracil must not be initiated or continued in patients who have symptoms of gastrointestinal toxicity of any severity, until those symptoms have completely resolved.  Patients with diarrhea must be monitored with particular care until the diarrhea has resolved, as rapid clinical deterioration leading to death can occur.  In an additional study utilizing higher weekly doses of 5-fluorouracil and leucovorin, elderly and/or debilitated patients were found to be at greater risk for severe gastrointestinal toxicity.3

Seizures and/or syncope have been reported rarely in cancer patients receiving leucovorin, usually in association with fluoropyrimidine administration, and most commonly in those with CNS metastases or other predisposing factors, however, a causal relationship has not been established.5

The concomitant use of leucovorin with trimethoprim-sulfamethoxazole for the acute treatment of Pneumocystis carinii pneumonia in patients with HIV infection was associated with increased rates of treatment failure and morbidity in a placebo-controlled study.

Precautions

General

Parenteral administration is preferable to oral dosing if there is a possibility that the patient may vomit and not absorb the leucovorin.  Leucovorin has no effect on non-hematologic toxicities of methotrexate such as the nephrotoxicity resulting from drug and/or metabolite precipitation in the kidney.

Since leucovorin enhances the toxicity of fluorouracil, leucovorin/5-fluorouracil combination therapy for advanced colorectal cancer should be administered under the supervision of a physician experienced in the use of antimetabolite cancer chemotherapy.  Particular care should be taken in the treatment of elderly or debilitated colorectal cancer patients, as these patients may be at increased risk of severe toxicity.

Laboratory Tests

Patients being treated with the leucovorin/5-fluorouracil combination should have a CBC with differential and platelets prior to each treatment.  During the first two courses a CBC with differential and platelets has to be repeated weekly and thereafter once each cycle at the time of anticipated WBC nadir.  Electrolytes and liver function tests should be performed prior to each treatment for the first three cycles then prior to every other cycle.  Dosage modifications of fluorouracil should be instituted as follows, based on the most severe toxicities:

Diarrhea and/or Stomatitis	WBC/mm3 Nadir	Platelets/mm3 Nadir	5-FU Dose
Moderate Severe	1,000 to 1,900 <1,000	25 to 75,000 <25,000	decrease 20% decrease 30%

If no toxicity occurs, the 5-fluorouracil dose may increase 10%. Treatment should be deferred until WBCs are 4,000/mm3 and platelets 130,000/mm3.  If blood counts do not reach these levels within two weeks, treatment should be discontinued.  Patients should be followed up with physical examination prior to each treatment course and appropriate radiological examination as needed.  Treatment should be discontinued when there is clear evidence of tumor progression.

Drug Interactions

Folic acid in large amounts may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone, and increase the frequency of seizures in susceptible pediatric patients.

Preliminary animal and human studies have shown that small quantities of systemically administered leucovorin enter the CSF primarily as 5-methyltetrahydrofolate and, in humans, remain 1 to 3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration.  However, high doses of leucovorin may reduce the efficacy of intrathecally administered methotrexate.

Leucovorin may enhance the toxicity of 5-fluorouracil (see WARNINGS).

Pregnancy

Teratogenic Effects: Pregnancy Category C.

Adequate animal reproduction studies have not been conducted with leucovorin.  It is also not known whether leucovorin can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.  Leucovorin should be given to a pregnant woman only if clearly needed.

Nursing Mothers

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

Pediatric Use

See PRECAUTIONS, Drug Interactions.

Adverse Reactions

Allergic sensitization, including anaphylactoid reactions and urticaria, has been reported following the administration of both oral and parenteral leucovorin.  No other adverse reactions have been attributed to the use of leucovorin per se.

The following table summarizes significant adverse events occurring in 316 patients treated with the leucovorin/5-fluorouracil combinations compared against 70 patients treated with 5-fluorouracil alone for advanced colorectal carcinoma.  These data are taken from the Mayo/NCCTG large multicenter prospective trial evaluating the efficacy and safety of the combination regimen.

PERCENTAGE OF PATIENTS TREATED WITH LEUCOVORIN/FLUOROURACIL FOR ADVANCED COLORECTAL CARCINOMA REPORTING ADVERSE EXPERIENCES OR HOSPITALIZED FOR TOXICITY

	(High LV) /5-FU (N=155)		(Low LV) /5-FU (N=161)		5-FU Alone (N=70)
	Any (%)	Grade 3+ (%)	Any (%)	Grade 3+ (%)	Any (%)	Grade 3+ (%)
Leukopenia	69	14	83	23	93	48
Thrombocytopenia	8	2	8	1	18	3
Infection	8	1	3	1	7	2
Nausea	74	10	80	9	60	6
Vomiting	46	8	44	9	40	7
Diarrhea	66	18	67	14	43	11
Stomatitis	75	27	84	29	59	16
Constipation	3	0	4	0	1	-
Lethargy/Malaise/Fatigue	13	3	12	2	6	3
Alopecia	42	5	43	6	37	7
Dermatitis	21	2	25	1	13	-
Anorexia	14	1	22	4	14	-
Hospitalization for Toxicity	5%		15%		7%
High LV = Leucovorin 200 mg/m2, Low LV = Leucovorin 20 mg/m2 Any = percentage of patients reporting toxicity of any severity Grade 3+ = percentage of patients reporting toxicity Grade 3 or higher

Overdosage

Excessive amounts of leucovorin may nullify the chemotherapeutic effect of folic acid antagonists.

Leucovorin Injection Dosage and Administration

Advanced Colorectal Cancer

Either of the following two regimens is recommended:

1.  Leucovorin is administered at 200 mg/m2 by slow intravenous injection over a minimum of 3 minutes, followed by 5-fluorouracil at 370 mg/m2 by intravenous injection.


2. Leucovorin is administered at 20 mg/m2 by intravenous injection followed by 5-fluorouracil at 425 mg/m2 by intravenous injection.

5-Fluorouracil and leucovorin should be administered separately to avoid the formation of a precipitate.

Treatment is repeated daily for five days.  This five-day treatment course may be repeated at 4 week (28-day) intervals, for 2 courses and then repeated at 4 to 5 week (28 to 35 day) intervals provided that the patient has completely recovered from the toxic effects of the prior treatment course.

In subsequent treatment course, the dosage of 5-fluorouracil should be adjusted based on patient tolerance of the prior treatment course.  The daily dosage of 5-fluorouracil should be reduced by 20% for patients who experienced moderate hematologic or gastrointestinal toxicity in the prior treatment course, and by 30% for patients who experienced severe toxicity (see PRECAUTIONS, Laboratory Tests).  For patients who experienced no toxicity in the prior treatment course, 5-fluorouracil dosage may be increased by 10%. Leucovorin dosages are not adjusted for toxicity.

Several other doses and schedules of leucovorin/5-fluorouracil therapy have also been evaluated in patients with advanced colorectal cancer; some of these alternative regimens may also have efficacy in the treatment of this disease.  However, further clinical research will be required to confirm the safety and effectiveness of these alternative leucovorin/5-fluorouracil treatment regimens.

Leucovorin Rescue After High-Dose Methotrexate Therapy

The recommendations for leucovorin rescue are based on a methotrexate dose of 12 to 15 grams/m2 administered by intravenous infusion over 4 hours (see methotrexate package insert for full prescribing information).4  Leucovorin rescue at a dose of 15 mg (approximately 10 mg/m2) every 6 hours for 10 doses starts 24 hours after the beginning of the methotrexate infusion.  In the presence of gastrointestinal toxicity, nausea or vomiting, leucovorin should be administered parenterally.  Do not administer leucovorin intrathecally.

Serum creatinine and methotrexate levels should be determined at least once daily. Leucovorin administration, hydration, and urinary alkalization (pH of 7.0 or greater) should be continued until the methotrexate level is below 5 x 10-8 M (0.05 micromolar).  The leucovorin dose should be adjusted or leucovorin rescue extended based on the following guidelines:

GUIDELINES FOR LEUCOVORIN DOSAGE AND ADMINISTRATION

DO NOT ADMINISTER LEUCOVORIN INTRATHECALLY

Clinical Situation	Laboratory Findings	Leucovorin Dosage and Duration
Normal Methotrexate Elimination	Serum methotrexate level approximately 10 micromolar at 24 hours after administration, 1 micromolar at 48 hours, and less than 0.2 micromolar at 72 hours.	15 mg PO, IM, or IV q 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion).
Delayed Late Methotrexate Elimination	Serum methotrexate level remaining above 0.2 micromolar at 72 hours, and more than 0.05 micromolar at 96 hours after administration.	Continue 15 mg PO, IM, or IV q 6 hours, until methotrexate level is less than 0.05 micromolar.
Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal Injury	Serum methotrexate level of 50 micromolar or more at 24 hours, or 5 micromolar or more at 48 hours after administration, OR; 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration (e.g., an increase from 0.5 mg/dL to a level of 1 mg/dL or more).	150 mg IV q 3 hours, until methotrexate level is less than 1 micromolar; then 15 mg IV q 3 hours until methotrexate level is less than 0.05 micromolar.

Patients who experience delayed early methotrexate elimination are likely to develop reversible renal failure.  In addition to appropriate leucovorin therapy, these patients require continuing hydration and urinary alkalization, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved.

Some patients will have abnormalities in methotrexate elimination or renal function following methotrexate administration, which are significant but less severe than abnormalities described in the table above.  These abnormalities may or may not be associated with significant clinical toxicity.  If significant clinical toxicity is observed, leucovorin rescue should be extended for an additional 24 hours (total of 14 doses over 84 hours) in subsequent courses of therapy.  The possibility that the patient is taking other medications which interact with methotrexate (e.g., medications which may interfere with methotrexate elimination or binding to serum albumin) should always be reconsidered when laboratory abnormalities or clinical toxicities are observed.

Impaired Methotrexate Elimination or Inadvertent Overdosage

Leucovorin rescue should begin as soon as possible after an inadvertent overdosage and within 24 hours of methotrexate administration when there is a delayed excretion (see WARNINGS).  Leucovorin 10 mg/m2 should be administered IM, IV, or PO every 6 hours until the serum methotrexate level is less than 10-8 M. In the presence of gastrointestinal toxicity, nausea, or vomiting, leucovorin should be administered parenterally.  Do not administer leucovorin intrathecally.

Serum creatinine and methotrexate levels should be determined at 24 hour intervals.  If the 24 hour serum creatinine has increased 50% over baseline or if the 24 hour methotrexate level is greater than 5 x 10-6 M or the 48 hour level is greater than 9 x 10-7 M, the dose of leucovorin should be increased to 100 mg/m2 IV every 3 hours until the methotrexate level is less than 10-8 M.

Hydration (3 L/d) and urinary alkalinization with sodium bicarbonate solution should be employed concomitantly.  The bicarbonate dose should be adjusted to maintain the urine pH at 7.0 or greater.

Megaloblastic Anemia Due to Folic Acid Deficiency

Up to 1 mg daily.  There is no evidence that doses greater than 1 mg/day have greater efficacy than those of 1 mg; additionally, loss of folate in urine becomes roughly logarithmic as the amount administered exceeds 1 mg.

Each 200 mg vial of Leucovorin Calcium for Injection when reconstituted with 20 mL, of sterile diluent yields a leucovorin concentration of 10 mg per mL.  Each 500 mg vial of Leucovorin Calcium for Injection when reconstituted with 50 mL of sterile diluent yields a leucovorin concentration of 10 mg per mL.  Leucovorin Calcium for Injection contains no preservative.  Reconstitute the lyophilized vial products with Bacteriostatic Water for Injection, USP (benzyl alcohol preserved), or Sterile Water for Injection, USP.  When reconstituted with Bacteriostatic Water for Injection, USP, the resulting solution must be used within 7 days.  If the product is reconstituted with Sterile Water for Injection, USP, use immediately and discard any unused portion.

Because of the benzyl alcohol contained in Bacteriostatic Water for Injection, USP, when doses greater than 10 mg/m2 are administered, Leucovorin Calcium for Injection should be reconstituted with Sterile Water for Injection, USP, and used immediately (see WARNINGS).

Because of the calcium content of the leucovorin solution, no more than 160 mg of leucovorin should be injected intravenously per minute (16 mL of a 10 mg/mL, or 8 mL of a 20 mg/mL solution per minute).

Parenteral products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Leucovorin should not be mixed in the same infusion as 5-fluorouracil, since this may lead to the formation of a precipitate.

How is Leucovorin Injection Supplied

Leucovorin Calcium for Injection is supplied as follows:

Product  No.	NDC No.	Strength
701050	63323-710-50	200 mg/vial	Packaged individually.
701100	63323-711-00	500 mg/vial	Packaged individually.

Store at 20°C to 25°C (68° to 77°F) [see USP Controlled Room Temperature].  Protect from light.  Retain in carton until time of use.

REFERENCES

1. Poon, MA, et al. Biochemical Modulation of Fluorouracil: Evidence of Significant Improvement of Survival and Quality of Life in patients with Advanced Colorectal Carcinoma, J Clin Oncol 1989;7:1407-1418.


2. Poon, MA, et al. Biochemical Modulation of Fluorouracil with Leucovorin: Confirmatory Evidence of Improved Therapeutic Efficacy in Advanced Colorectal Cancer, J Clin Oncol 1991;9,11:1967-1972.


3. Grem, J.L., Shoemaker, D.D., Petrelli, N.J., Douglas, H.O. "Severe and Fatal Toxic Effects Observed in Treatment with High- and Low-Dose Leucovorin Plus 5-Fluorouracil for Colorectal Carcinoma", Cancer Treat Rep 71:1122,1987.


4. Link, MP, Goorin, AH, Miser, AW, et al. “The Effect of Adjuvant Chemotherapy on Relapse-Free Survival in Patients with Osteosarcoma of the Extremity.” N Engl J Med 1986;314:1600-1606.


5. Meropol NJ, Creaven PJ, White RM, et al. "Seizures Associated With Leucovorin Administration in Cancer Patients." JNCL 1995;87(1):56-58.

451214

Issued: December 2009

PACKAGE LABEL - PRINCIPAL DISPLAY - Leucovorin 200 mg Vial Label

NDC 63323-710-50

701050

LEUCOVORIN CALCIUM FOR INJECTION

200 mg/vial

FOR IV OR IM USE

LYOPHILIZED

Rx only

PACKAGE LABEL - PRINCIPAL DISPLAY - Leucovorin 200 mg Vial Carton Label

NDC 63323-710-50

701050

LEUCOVORIN CALCIUM FOR INJECTION

200 mg/vial

FOR IV OR IM USE

LYOPHILIZED

Rx only

PACKAGE LABEL - PRINCIPAL DISPLAY - Leucovorin 500 mg Vial Label

NDC 63323-711-00

701100

LEUCOVORIN CALCIUM FOR INJECTION

500 mg/vial*

FOR IV OR IM USE

LYOPHILIZED

Rx only

PACKAGE LABEL - PRINCIPAL DISPLAY - Leucovorin 500 mg Vial Carton Label

NDC 63323-711-00

701100

LEUCOVORIN CALCIUM FOR INJECTION

500 mg/vial*

FOR IV OR IM USE

LYOPHILIZED

Rx only

LEUCOVORIN CALCIUM  leucovorin calcium  injection, powder, lyophilized, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 63323-710 Route of Administration INTRAMUSCULAR, INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength LEUCOVORIN CALCIUM (LEUCOVORIN CALCIUM) LEUCOVORIN CALCIUM 200 mg  in 20 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE 180 mg  in 20 mL SODIUM HYDROXIDE   HYDROCHLORIC ACID

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 63323-710-50 1 VIAL In 1 BOX contains a VIAL 1 20 mL In 1 VIAL This package is contained within the BOX (63323-710-50)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA040258	09/18/2010

LEUCOVORIN CALCIUM  leucovorin calcium  injection, powder, lyophilized, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 63323-711 Route of Administration INTRAMUSCULAR, INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength LEUCOVORIN CALCIUM (LEUCOVORIN CALCIUM) LEUCOVORIN CALCIUM 500 mg  in 50 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE 450 mg  in 50 mL SODIUM HYDROXIDE   HYDROCHLORIC ACID

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 63323-711-00 1 VIAL In 1 BOX contains a VIAL 1 50 mL In 1 VIAL This package is contained within the BOX (63323-711-00)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA040286	09/18/2010

Labeler - APP Pharmaceuticals, LLC (608775388)

Establishment
Name	Address	ID/FEI	Operations
APP Pharmaceuticals, LLC		023648251	MANUFACTURE

Revised: 05/2011APP Pharmaceuticals, LLC

More Leucovorin Injection resources

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

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Tylenol Cold Multi-Symptom Daytime

Generic Name: acetaminophen, dextromethorphan, and phenylephrine (a SEET a MIN of fen, DEX troe me THOR fan, and FEN il EFF rin)

Brand Names: Comtrex Cold & Cough, Daytime, Flu & Severe Cold & Cough Daytime Powder, Mapap Cold Formula, Theraflu Daytime Severe Cold & Cough, Theraflu Multi-Symptom Severe Cold, Theraflu Nighttime Severe Cold & Cough, Theraflu Warming Relief Daytime Multi-Symptom Cold, Theraflu Warming Severe Cold Daytime, Tylenol Children's Plus Cold & Cough, Tylenol Cold Multi-Symptom Daytime

What is Tylenol Cold Multi-Symptom Daytime (acetaminophen, dextromethorphan, and phenylephrine)?

Acetaminophen is a pain reliever and fever reducer.

Dextromethorphan is a cough suppressant. It affects the signals in the brain that trigger cough reflex.

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

The combination of acetaminophen, dextromethorphan, and phenylephrine is used to treat headache, fever, body aches, cough, stuffy nose, and sinus congestion caused by allergies, the common cold, or the flu.

This medicine will not treat a cough that is caused by smoking, asthma, or emphysema.

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

What is the most important information I should know about this medicine?

Do not take more of this medication than is recommended. An overdose of acetaminophen can damage your liver or cause death. Do not take this medication without a doctor's advice if you have ever had alcoholic liver disease (cirrhosis) or if you drink more than 3 alcoholic beverages per day. Do not use this medicine if you have untreated or uncontrolled diseases such as glaucoma, asthma or COPD, high blood pressure, heart disease, coronary artery disease, or overactive thyroid. Avoid drinking alcohol. It may increase your risk of liver damage while you are taking acetaminophen. Do not use this medicine if you have used an MAO inhibitor such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam, Zelapar), or tranylcypromine (Parnate) in the last 14 days. A dangerous drug interaction could occur, leading to serious side effects. Ask a doctor or pharmacist before using any other cold, allergy, pain, or sleep medication. Acetaminophen (sometimes abbreviated as APAP) is contained in many combination medicines. Taking certain products together can cause you to get too much acetaminophen which can lead to a fatal overdose. Check the label to see if a medicine contains acetaminophen or APAP.

What should I discuss with my healthcare provider before taking this medicine?

Do not take this medication without a doctor's advice if you have ever had alcoholic liver disease (cirrhosis) or if you drink more than 3 alcoholic beverages per day. You may not be able to take medicine that contains acetaminophen. Do not use this medicine if you have untreated or uncontrolled diseases such as glaucoma, asthma or COPD, high blood pressure, heart disease, coronary artery disease, or overactive thyroid. Do not use this medicine if you have used an MAO inhibitor such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam, Zelapar), or tranylcypromine (Parnate) in the last 14 days. A dangerous drug interaction could occur, leading to serious side effects.

Ask a doctor or pharmacist if it is safe for you to take acetaminophen, dextromethorphan, and phenylephrine if you have:

• 
  

  liver disease, cirrhosis, or a history of alcoholism;

  
  


• 
  

  diabetes;

  
  


• 
  

  glaucoma;

  
  


• 
  

  diabetes;

  
  


• 
  

  epilepsy or other seizure disorder;

  
  


• 
  

  enlarged prostate or urination problems;

  
  


• 
  

  pheochromocytoma (an adrenal gland tumor); or

  
  


• 
  

  cough with mucus, or cough caused by emphysema or chronic bronchitis.

  
  

It is not known whether acetaminophen, dextromethorphan, and phenylephrine will harm an unborn baby. Do not use this medicine without a doctor's advice if you are pregnant. Acetaminophen, dextromethorphan, and phenylephrine may pass into breast milk and may harm a nursing baby. Decongestants may also slow breast milk production. Do not use this medicine without a doctor's advice if you are breast-feeding a baby.

Artificially sweetened cold medicine may contain phenylalanine. If you have phenylketonuria (PKU), check the medication label to see if the product contains phenylalanine.

How should I take this medicine?

Use exactly as directed on the label, or as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. This medicine is usually taken only for a short time until your symptoms clear up.

Do not take more of this medication than is recommended. An overdose of acetaminophen can damage your liver or cause death. Do not give this medication to a child younger than 4 years old. Always ask a doctor before giving cough or cold medicine to a child. Death can occur from the misuse of cough or cold medicine in very young children.

Measure liquid medicine with a special dose measuring spoon or medicine cup, not with a regular table spoon. If you do not have a dose measuring device, ask your pharmacist for one.

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

Do not take for longer than 7 days in a row. Stop taking the medicine and call your doctor if you still have a fever after 3 days of use, you still have pain after 7 days (or 5 days if treating a child), if your symptoms get worse, or if you have a skin rash, ongoing headache, or any redness or swelling.

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

What happens if I miss a dose?

Since this medicine is taken when needed, you may not be on a dosing schedule. If you are taking the medication regularly, take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. An overdose of acetaminophen can be fatal.

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

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

What should I avoid while taking this medicine?

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

This medicine 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. chest pain, fast, slow, or uneven heart rate; Stop using this medication and call your doctor at once if you have any of these serious side effects:

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  chest pain, fast, slow, or uneven heart rate;

  
  


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  severe dizziness, feeling like you might pass out;

  
  


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  mood changes, confusion, hallucinations;

  
  


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  tremor, seizure (convulsions);

  
  


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  fever;

  
  


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  urinating less than usual or not at all;

  
  


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

  
  


• 
  

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

  
  


• 
  

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

  
  

Less serious side effects may include:

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  dizziness, weakness;

  
  


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  mild headache;

  
  


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  mild nausea, diarrhea, upset stomach;

  
  


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  dry mouth, nose, or throat;

  
  


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  feeling nervous, restless, irritable, or anxious; or

  
  


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  sleep problems (insomnia).

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect this medicine?

Ask a doctor or pharmacist if it is safe for you to take this medicine if you are also using any of the following drugs:

• 
  

  leflunomide (Arava);

  
  


• 
  

  tapentadol (Nucynta);

  
  


• 
  

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

  
  


• 
  

  an antidepressant;

  
  


• 
  

  birth control pills or hormone replacement therapy;

  
  


• 
  

  blood pressure medication;

  
  


• 
  

  cancer medicine;

  
  


• 
  

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

  
  


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  gout or arthritis medications (including gold injections);

  
  


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  HIV/AIDS medication;

  
  


• 
  

  medicines to treat psychiatric disorders;

  
  


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  migraine headache medicine;

  
  


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

  
  


• 
  

  seizure medication.

  
  

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

More Tylenol Cold Multi-Symptom Daytime resources

• Tylenol Cold Multi-Symptom Daytime Side Effects (in more detail)
• Tylenol Cold Multi-Symptom Daytime Use in Pregnancy & Breastfeeding
• Tylenol Cold Multi-Symptom Daytime Drug Interactions
• 0 Reviews for Tylenol Cold Multi-Symptom Daytime - Add your own review/rating

• Tylenol Cold Multi-Symptom Daytime Liquid MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Tylenol Cold Multi-Symptom Daytime with other medications

• Cold Symptoms
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• Nasal Congestion
• Pain/Fever
• Sinus Symptoms
• Tonsillitis/Pharyngitis

Where can I get more information?

• Your pharmacist can provide more information about acetaminophen, dextromethorphan, and phenylephrine.

See also: Tylenol Cold Multi-Symptom Daytime side effects (in more detail)