zolpidem Oral, Oromucosal

zole-PI-dem

Commonly used brand name(s)

In the U.S.

• Ambien


• Ambien CR


• Edluar


• Zolpimist

Available Dosage Forms:

• Tablet


• Tablet, Extended Release


• Spray

Therapeutic Class: Nonbarbiturate Hypnotic

Uses For zolpidem

Zolpidem belongs to the group of medicines called central nervous system (CNS) depressants (medicines that slow down the nervous system). Zolpidem is used to treat insomnia (trouble in sleeping). Zolpidem helps you get to sleep faster and sleep through the night. In general, when sleep medicines are used every night for a long time, they may lose their effectiveness. In most cases, sleep medicines should be used only for short periods of time, such as 1 or 2 days, and generally for no longer than 1 or 2 weeks.

zolpidem is available only with your doctor's prescription.

Before Using zolpidem

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 zolpidem, the following should be considered:

Sleep medicines may cause a special type of memory loss or "amnesia". When this occurs, a person does not remember what has happened during the several hours between use of the medicine and the time when its effects wear off. This is usually not a problem since most people fall asleep after taking the medicine. In most instances, memory problems can be avoided by taking zolpidem only when you are able to get a full night's sleep (7 to 8 hours) before you need to be active again. Be sure to talk to your doctor if you think you are having memory problems.

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to zolpidem 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 zolpidem 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 zolpidem in the elderly. However, confusion, dizziness, and falling are more likely to occur in the elderly, who are usually more sensitive than younger adults to the effects of zolpidem. Elderly patients may require a lower dose to help reduce unwanted effects.

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

Studies in women suggest that this medication poses minimal risk to the infant when used during 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 zolpidem, 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 zolpidem 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.

• Alprazolam


• Buspirone


• Butabarbital


• Chlordiazepoxide


• Chlorpromazine


• Clonazepam


• Clorazepate


• Dexmedetomidine


• Diazepam


• Diphenhydramine


• Doxylamine


• Estazolam


• Eszopiclone


• Ethchlorvynol


• Flumazenil


• Flurazepam


• Fospropofol


• Halazepam


• Hydromorphone


• Hydroxyzine


• Lorazepam


• Meprobamate


• Midazolam


• Oxazepam


• Oxycodone


• Pentobarbital


• Phenobarbital


• Prazepam


• Promethazine


• Propofol


• Quazepam


• Ramelteon


• Secobarbital


• Tapentadol


• Temazepam


• Thioridazine


• Triazolam


• Zaleplon

Using zolpidem 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.

• Bupropion


• Carbamazepine


• Ciprofloxacin


• Desipramine


• Ketoconazole


• Rifampin


• Sertraline


• St John's Wort


• Telaprevir


• Venlafaxine

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.

Using zolpidem with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use zolpidem, or give you special instructions about the use of food, alcohol, or tobacco.

• Ethanol


• food

Other Medical Problems

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

• Alcohol abuse, history of or


• Drug abuse or dependence, history of—Dependence on zolpidem may develop.

• Diseases affecting metabolism or disease involving blood circulation—Caution should be used in patients with these medical problems.

• Emphysema, asthma, bronchitis, or other chronic lung disease or


• Mental depression, history of or


• Mental illness, history of or


• Myasthenia gravis (severe muscle weakness) or


• Sleep apnea (temporary stopping of breathing during sleep)—Use with caution. Zolpidem may make these conditions worse.

• Kidney disease or


• Liver disease—Use with caution. Higher blood levels of zolpidem may result, increasing the chance of side effects.

Proper Use of zolpidem

Take zolpidem only as directed by your doctor. 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. If too much is taken, it may become habit-forming (causing mental or physical dependence).

zolpidem should come with a Medication Guide. Read and follow these instructions carefully. Ask your doctor if you have any questions.

Take zolpidem just before going to bed, when you are ready to go to sleep. zolpidem works very quickly to put you to sleep.

You should swallow the extended-release tablets whole. Do not divide, crush, or chew them.

Do not take zolpidem when your schedule does not permit you to get a full night's sleep (7 to 8 hours). If you must wake up before this, you may continue to feel drowsy and may experience memory problems, because the effects of the medicine have not had time to wear off.

Zolpidem should not be taken with food or right after a meal. It will work faster if you take it on an empty stomach. However, if your doctor tells you to take the medicine a certain way, take it exactly as directed.

If you are using the oral spray for the first time, it must be primed by spraying it for 5 times in a safe direction away from your face and other people. If the oral spray has not been used for 14 days, it must be primed again with 1 spray.

To use the oral spray:

• Pull the child-resistant cap to separate it from the base.


• Remove the clear protective cap from the pump.


• Hold the container upright with the black spray opening pointed directly into your mouth.


• Fully press down on the pump to make sure that a full dose (5 mg) of is sprayed directly into the mouth over the tongue. If a 10 mg dose is prescribed by your doctor, a second spray should be given.


• Put the clear protective cap back over the pump after each use.

To use the sublingual tablets:

• Do not open the blister pack that contains the tablet until you are ready to take it. Do not use the tablet if the seal of the blister pack is broken.


• Remove the tablet from the blister pack by peeling back the top layer of paper, then push the tablet through the foil.


• Place the tablet under your tongue. It should melt quickly. Do not crush, chew, or swallow the tablet. Do not eat or drink anything after using zolpidem.


• If you are taking Intermezzo®, check the time before you take zolpidem. Intermezzo® should be taken only if at least 4 hours of sleep remain before the planned time of awakening.

Use only the brand of zolpidem that your doctor prescribed. Different brands may not work the same way.

Dosing

The dose of zolpidem 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 zolpidem. 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 the treatment of insomnia (trouble in sleeping):
  
  • For oral dosage form (extended-release tablets):
    
    • Adults—12.5 milligrams (mg) once a day at bedtime.
    
    
    • Older adults—6.25 mg once a day at bedtime.
    
    
    • Children—Use and dose must be determined by the doctor.
    
    
  
  
  • For oral dosage form (oral spray):
    
    • Adults—10 milligrams (mg) or 2 sprays into the mouth at bedtime.
    
    
    • Older adults—5 mg or 1 spray into the mouth at bedtime.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  
  • For oral dosage form (sublingual tablets):
    
    • Adults—
      
      • Edluar™: 10 milligrams (mg) placed under the tongue at bedtime.
      
      
      • Intermezzo®: 1.75 mg (for women) and 3.5 mg (for men) placed under the tongue at bedtime.
      
      
    
    
    • Older adults—Intermezzo®: 1.75 mg (for both men and women) placed under the tongue at bedtime.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  
  • For oral dosage form (tablets):
    
    • Adults—10 milligrams (mg) once a day at bedtime.
    
    
    • Older adults—5 mg once a day at bedtime.
    
    
    • Children—Use and dose must be determined by the doctor.
    
    
  
  

Missed Dose

If you miss a dose of zolpidem, 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.

Throw the child-resistant container of the oral spray when the 60 sprays have already been used.

Precautions While Using zolpidem

It is very important that your doctor check your progress at regular visits to make sure zolpidem is working properly and to check for unwanted effects.

If you think you need to take zolpidem for more than 7 to 10 days, be sure to discuss it with your doctor. Insomnia that lasts longer than this may be a sign of another medical problem.

zolpidem will add to the effects of alcohol and other CNS depressants (medicines that 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; medicine for seizures or barbiturates; muscle relaxants; or anesthetics, including some dental anesthetics. Check with your doctor before taking any of the above while you are using zolpidem.

zolpidem may cause some people, especially older persons, to become drowsy, dizzy, lightheaded, clumsy or unsteady, or less alert than they are normally. Even though zolpidem is taken at bedtime, it may cause some people to feel drowsy or less alert on arising. Also, zolpidem may cause double vision or other vision problems. Make sure you know how you react to zolpidem before you drive, use machines, or do anything else that could be dangerous if you are dizzy, or are not alert or able to see well.

If you develop any unusual and strange thoughts or behavior while you are taking zolpidem, be sure to discuss it with your doctor. Some changes that have occurred in people taking zolpidem are like those seen in people who drink alcohol and then act in a manner that is not normal. Other changes may be more unusual and extreme, such as confusion, worsening of depression, hallucinations (seeing, hearing, or feeling things that are not there), suicidal thoughts, and unusual excitement, nervousness, or irritability.

zolpidem may cause sleep-related behaviors such as driving a car (sleep-driving), walking (sleep-walking), having sex, making phone calls, or preparing and eating food while asleep or not fully awake. If these reactions occur, tell your doctor right away.

If you will be taking zolpidem for a long time, do not stop taking it without first checking with your doctor. Your doctor may want you to gradually reduce the amount you are taking before stopping completely. Stopping zolpidem suddenly may cause withdrawal side effects.

After taking zolpidem for insomnia, you may have difficulty sleeping (rebound insomnia) for the first few nights after you stop taking it.

If you think you or someone else may have taken an overdose of zolpidem, get emergency help at once. Taking an overdose of zolpidem or taking alcohol or other CNS depressants with zolpidem may lead to breathing problems and unconsciousness. Some signs of an overdose are severe drowsiness, severe nausea or vomiting, staggering, and troubled breathing.

Zolpidem may cause a serious type of allergic reaction called anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Stop taking zolpidem and call your doctor right away if you have itching; hives; hoarseness; trouble breathing or swallowing; or any swelling of your hands, face, mouth, or throat while you are using zolpidem.

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.

zolpidem 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:

Less common

• Clumsiness or unsteadiness


• confusion


• mental depression

Rare

• Dizziness, lightheadedness, or fainting


• falling


• fast heartbeat


• hallucinations (seeing, hearing, or feeling things that are not there)


• skin rash


• swelling of the face


• trouble with sleeping


• unusual excitement, nervousness, or irritability


• wheezing or difficulty with breathing

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

Symptoms of overdose

• Clumsiness or unsteadiness (severe)


• dizziness (severe)


• double vision or other vision problems


• drowsiness (severe)


• nausea (severe)


• slow heartbeat


• troubled breathing


• vomiting (severe)

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

• Sleepiness or unusual drowsiness

Less common

• Abdominal or stomach pain


• abnormal or decreased touch sensation


• abnormal sensation of movement


• appetite disorder


• balance disorder


• binge eating


• bladder pain


• bloated


• bloody or cloudy urine


• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings


• change in hearing


• chest discomfort


• chills


• confusion about identity, place, and time


• constipation


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


• daytime drowsiness


• diarrhea


• difficult, burning, or painful urination


• difficulty with moving


• difficulty with swallowing


• discouragement


• double vision or other vision problems


• drugged feelings


• dryness of mouth


• ear drainage


• earache


• excess air or gas in the stomach or intestines


• eye redness


• false or unusual sense of well-being


• fear


• feeling of unreality


• feeling sad or empty


• fever


• frequent bowel movements


• frequent urge to urinate


• full feeling


• general feeling of discomfort or illness


• generalized slowing of mental and physical activity


• headache


• hearing loss


• heartburn


• hives or welts


• itching ears


• joint pain


• lack of appetite


• lack of feeling or emotion


• lack or loss of self-control


• lack or loss of strength


• longer or heavier menstrual periods


• loss of balance


• loss of interest or pleasure


• memory problems


• mood swings


• muscle aches, cramping, pain, or stiffness


• nausea


• nervousness


• nightmares or unusual dreams


• pain in the joints


• passing gas


• redness of the skin


• redness or soreness of the throat


• sense of detachment from self or body


• shortness of breath or troubled breathing


• skin rash


• skin wrinkling


• sneezing


• sore throat


• stress symptoms


• stuffy or runny nose


• swollen joints


• tiredness


• trouble concentrating


• trouble with sleeping


• vision blurred


• visual depth perception altered


• vomiting

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: zolpidem Oral, Oromucosal side effects (in more detail)

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• Insomnia

Micro-K

potassium chloride

Dosage Form: capsule, extended release
Micro-K® Extencaps®

Micro-K® 10 Extencaps®

(Potassium Chloride Extended-Release Capsules, USP)

U.S. Patent No. 4,259,315

Rx Only

P3511-4 06/05

DESCRIPTION

Micro-K® Extencaps® Capsules and Micro-K® 10 Extencaps® Capsules are oral dosage forms of microencapsulated potassium chloride containing 600 and 750 mg, respectively, of potassium chloride, USP, equivalent to 8 and 10 mEq of potassium, respectively.

Dispersibility of potassium chloride (KCI) is accomplished by microencapsulation and a dispersing agent. The resultant flow characteristics of the KCI microcapsules and the controlled release of K+ ions by the microcapsular membrane are intended to avoid the possibility that excessive amounts of KCI can be localized at any point on the mucosa of the gastrointestinal tract.

Each crystal of KCI is microencapsulated by a patented process with an insoluble polymeric coating which functions as a semi-permeable membrane; it allows for the controlled release of potassium and chloride ions over an eight-to ten-hour period. Fluids pass through the membrane and gradually dissolve the potassium chloride within the microcapsules. The resulting potassium chloride solution slowly diffuses outward through the membrane. Micro-K® and Micro-K® 10 are electrolyte replenishers. The chemical name of the active ingredient is potassium chloride and the structural formula is KCI. Potassium chloride, USP, occurs as a white, granular powder or as colorless crystals. It is odorless and has a saline taste. Its solutions are neutral to litmus. It is freely soluble in water and insoluble in alcohol.

The inactive ingredients are edible ink, ethylcellulose, FD&C Blue No. 2 aluminum lake, FD&C Yellow No. 6, gelatin, magnesium stearate, sodium lauryl sulfate, titanium dioxide. May contain FD&C Red No. 40 and Yellow No. 6 aluminum lakes.

CLINICAL PHARMACOLOGY

Potassium ion is the principal intracellular cation of most body tissues. Potassium ions participate in a number of essential physiological processes, including the maintenance of intracellular tonicity, the transmission of nerve impulses, the contraction of cardiac, skeletal, and smooth muscle, and the maintenance of normal renal function.

The intracellular concentration of potassium is approximately 150 to 160 mEq per liter. The normal adult plasma concentration is 3.5 to 5 mEq per liter. An active ion transport system maintains this gradient across the plasma membrane.

Potassium is a normal dietary constituent and under steady-state conditions the amount of potassium absorbed from the gastrointestinal tract is equal to the amount excreted in the urine. The usual dietary intake of potassium is 50 to 100 mEq per day.

Potassium depletion will occur whenever the rate of potassium loss through renal excretion and/or loss from the gastrointestinal tract exceeds the rate of potassium intake. Such depletion usually develops slowly as a consequence of therapy with diuretics, primary or secondary hyperaldosteronisms, diabetic ketoacidosis, or inadequate replacement of potassium in patients on prolonged parenteral nutrition. Depletion can develop rapidly with severe diarrhea, especially if associated with vomiting. Potassium depletion due to these causes is usually accompanied by a concomitant loss of chloride and is manifested by hypokalemia and metabolic alkalosis. Potassium depletion may produce weakness, fatigue, disturbances of cardiac rhythm (primarily ectopic beats), prominent U-waves in the electrocardiogram, and in advanced cases, flaccid paralysis and/or impaired ability to concentrate urine.

If potassium depletion associated with metabolic alkalosis cannot be managed by correcting the fundamental cause of the deficiency, e.g., where the patient requires long-term diuretic therapy, supplemental potassium in the form of high potassium food or potassium chloride may be able to restore normal potassium levels.

In rare circumstances (e.g., patients with renal tubular acidosis) potassium depletion may be associated with metabolic acidosis and hyperchloremia. In such patients potassium replacement should be accomplished with potassium salts other than the chloride, such as potassium bicarbonate, potassium citrate, potassium acetate, or potassium gluconate.

INDICATIONS AND USAGE

BECAUSE OF REPORTS OF INTESTINAL AND GASTRIC ULCERATION AND BLEEDING WITH CONTROLLED-RELEASE POTASSIUM CHLORIDE PREPARATIONS, THESE DRUGS SHOULD BE RESERVED FOR THOSE PATIENTS WHO CANNOT TOLERATE OR REFUSE TO TAKE LIQUID OR EFFERVESCENT POTASSIUM PREPARATIONS OR FOR PATIENTS IN WHOM THERE IS A PROBLEM OF COMPLIANCE WITH THESE PREPARATIONS.

1. For the treatment of patients with hypokalemia with or without metabolic alkalosis, in digitalis intoxications, and in patients with hypokalemic familial periodic paralysis. If hypokalemia is the result of diuretic therapy, consideration should be given to the use of a lower dose of diuretic, which may be sufficient without leading to hypokalemia.


2. For the prevention of hypokalemia in patients who would be at particular risk if hypokalemia were to develop e.g., digitalized patients or patients with significant cardiac arrhythmias, hepatic cirrhosis with ascites, states of aldosterone excess with normal renal function, potassium-losing nephropathy, and certain diarrheal states.

The use of potassium salts in patients receiving diuretics for uncomplicated essential hypertension is often unnecessary when such patients have a normal dietary pattern and when low doses of the diuretic are used. Serum potassium should be checked periodically, however, and if hypokalemia occurs, dietary supplementation with potassium-containing foods may be adequate to control milder cases. In more severe cases, and if dose adjustment of the diuretic is ineffective or unwarranted, supplementation with potassium salts may be indicated.

CONTRAINDICATIONS

Potassium supplements are contraindicated in patients with hyperkalemia since a further increase in serum potassium concentration in such patients can produce cardiac arrest. Hyperkalemia may complicate any of the following conditions: chronic renal failure, systemic acidosis such as diabetic acidosis, acute dehydration, extensive tissue breakdown as in severe burns, adrenal insufficiency, or the administration of a potassium-sparing diuretic (e.g., spironolactone, triamterene, amiloride) (see OVERDOSAGE).

Controlled-release formulations of potassium chloride have produced esophageal ulceration in certain cardiac patients with esophageal compression due to an enlarged left atrium. Potassium supplementation, when indicated in such patients, should be given as a liquid preparation.

All solid oral dosage forms of potassium chloride are contraindicated in any patient in whom there is structural, pathological (e.g., diabetic gastroparesis) or pharmacologic (use of anticholinergic agents or other agents with anticholineric properties at sufficient doses to exert anticholinergic effects) cause for arrest or delay in capsule passage through the gastrointestinal tract.

WARNINGS

Hyperkalemia (see OVERDOSAGE)

In patients with impaired mechanisms for excreting potassium, the administration of potassium salts can produce hyperkalemia and cardiac arrest. This occurs most commonly in patients given potassium by the intravenous route but may also occur in patients given potassium orally. Potentially fatal hyperkalemia can develop rapidly and be asymptomatic. The use of potassium salts in patients with chronic renal disease, or any other condition which impairs potassium excretion, requires particularly careful monitoring of the serum potassium concentration and appropriate dosage adjustments.

Interaction with Potassium-Sparing Diuretics

Hypokalemia should not be treated by the concomitant administration of potassium salts and a potassium-sparing diuretic (e.g., spironolactone, triamterene, or amiloride), since the simultaneous administration of these agents can produce severe hyperkalemia.

Interaction with Angiotensin Converting Enzyme Inhibitors

Angiotensin converting enzyme (ACE) inhibitors (e.g., captopril, enalapril) will produce some potassium retention by inhibiting aldosterone production. Potassium supplements should be given to patients receiving ACE inhibitors only with close monitoring.

Gastrointestinal Lesions

Solid oral dosage forms of potassium chloride can produce ulcerative and/or stenotic lesions of the gastrointestinal tract. Based on spontaneous adverse reaction reports, enteric-coated preparations of potassium chloride are associated with an increased frequency of small bowel lesions (40 - 50 per 100,000 patient years) compared to sustained-release wax matrix formulations (less than one per 100,000 patient years). Because of the lack of extensive marketing experience with microencapsulated products, a comparison between such products and wax matrix or enteric-coated products is not available. Micro-K® Extencaps® and Micro-K® 10 Extencaps® are microencapsulated capsules formulated to provide a controlled rate of release of microencapsulated potassium chloride and thus to minimize the possibility of high local concentration of potassium near the gastrointestinal wall.

Prospective trials have been conducted in normal human volunteers in which the upper gastrointestinal tract was evaluated by endoscopic inspection before and after one week of solid oral potassium chloride therapy. The ability of this model to predict events occurring in usual clinical practice is unknown. Trials which approximated usual clinical practice did not reveal any clear differences between the wax matrix and microencapsulated dosage forms. In contrast, there was a higher incidence of gastric and duodenal lesions in subjects receiving a high dose of a wax matrix controlled-release formulation under conditions which did not resemble usual or recommended clinical practice (i.e., 96 mEq per day in divided doses of potassium chloride administered to fasted patients, in the presence of an anticholinergic drug to delay gastric emptying). The upper gastrointestinal lesions observed by endoscopy were asymptomatic and were not accompanied by evidence of bleeding (hemoccult testing). The relevance of these findings to the usual conditions (i.e., non-fasting, no anticholinergic agent, smaller doses) under which controlled-release potassium chloride products are used is uncertain; epidemiologic studies have not identified an elevated risk, compared to microencapsulated products, for upper gastrointestinal lesions in patients receiving wax matrix formulations. Micro-K® Extencaps® and Micro-K® 10 Extencaps® should be discontinued immediately and the possibility of ulceration, obstruction or perforation considered if severe vomiting, abdominal pain, distention, or gastrointestinal bleeding occur.

Metabolic Acidosis

Hypokalemia in patients with metabolic acidosis should be treated with an alkalinizing potassium salt such as potassium bicarbonate, potassium citrate, potassium acetate, or potassium gluconate.

PRECAUTIONS:

General

The diagnosis of potassium depletion is ordinarily made by demonstrating hypokalemia in a patient with a clinical history suggesting some cause for potassium depletion. In interpreting the serum potassium level, the physician should bear in mind that acute alkalosis per se can produce hypokalemia in the absence of a deficit in total body potassium, while acute acidosis per se can increase the serum potassium concentration into the normal range even in the presence of a reduced total body potassium. The treatment of potassium depletion, particularly in the presence of cardiac disease, renal disease, or acidosis, requires careful attention to acid-base balance and appropriate monitoring of serum electrolytes, the electrocardiogram, and the clinical status of the patient.

Information for Patients

Physicians should consider reminding the patient of the following: To take each dose with meals and with a full glass of water or other suitable liquid. To take each dose without crushing, chewing, or sucking the capsules. To take this medicine following the frequency and amount prescribed by the physician. This is especially important if the patient is also taking diuretics and/or digitalis preparations. To check with the physician if there is trouble swallowing capsules or if the capsules seem to stick in the throat.

To check with the physician at once if tarry stools or other evidence of gastrointestinal bleeding is noticed.

Laboratory Tests

Regular serum potassium determinations are recommended, especially in patients with renal insufficiency or diabetic nephropathy. When blood is drawn for analysis of plasma potassium it is important to recognize that artifactual elevations can occur after improper venipuncture technique or as a result of in vitro hemolysis of the sample.

Drug Interactions

Potassium-sparing diuretics, angiotensin converting enzyme inhibitors (see WARNINGS).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity, mutagenicity and fertility studies in animals have not been performed. Potassium is a normal dietary constituent.

Pregnancy

Teratogenic Effects: Category C Animal reproduction studies have not been conducted with Micro-K®. It is unlikely that potassium supplementation that does not lead to hyperkalemia would have an adverse effect on the fetus or would affect reproductive capacity.

Nursing Mothers

The normal potassium ion content of human milk is about 13 mEq per liter. Since oral potassium becomes part of the body potassium pool, so long as body potassium is not excessive, the contribution of potassium chloride supplementation should have little or no effect on the level in human milk.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of potassium chloride extended-release capsules did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Adverse Reactions

One of the most severe adverse effects is hyperkalemia (see CONTRAINDICATIONS, WARNINGS, and OVERDOSAGE). Gastrointestinal bleeding and ulceration have been reported in patients treated with Micro-K® Extencaps® (see CONTRAINDICATIONS and WARNINGS). In addition to gastrointestinal bleeding and ulceration, perforation and obstruction have been reported in patients treated with other solid KCI dosage forms, and may occur with Micro-K® Extencaps®.

The most common adverse reactions to the oral potassium salts are nausea, vomiting, flatulence, abdominal discomfort, and diarrhea. These symptoms are due to irritation of the gastrointestinal tract and are best managed by taking the dose with meals, or reducing the amount taken at one time. Skin rash has been reported rarely with potassium preparations.

OVERDOSAGE

The administration of oral potassium salts to persons with normal excretory mechanisms for potassium rarely causes serious hyperkalemia. However, if excretory mechanisms are impaired or if potassium is administered too rapidly intravenously, potentially fatal hyperkalemia can result (see CONTRAINDICATIONS and WARNINGS). It is important to recognize that hyperkalemia is usually asymptomatic and may be manifested only by an increased serum potassium concentration (6.5 - 8.0 mEq/L) and characteristic electrocardiographic changes (peaking of T-waves, loss of P-waves, depression of ST segment, and prolongation of the QT interval). Late manifestations include muscle paralysis and cardiovascular collapse from cardiac arrest (9 - 12 mEq/L).

Treatment measures for hyperkalemia include the following: (1) elimination of foods and medications containing potassium and of any agents with potassium-sparing properties; (2) intravenous administration of 300 to 500 mL/hr of 10% dextrose solution containing 10 to 20 units of crystalline insulin per 1,000 mL; (3) correction of acidosis, if present, with intravenous sodium bicarbonate; (4) use of exchange resins, hemodialysis, or peritoneal dialysis. In treating hyperkalemia, it should be recalled that in patients who have been stabilized on digitalis, too rapid a lowering of the serum potassium concentration can produce digitalis toxicity.

The extended release feature means that absorption and toxic effects may be delayed for hours. Consider standard measures to remove any unabsorbed drug.

DOSAGE AND ADMINISTRATION

The usual dietary intake of potassium by the average adult is 50 to 100 mEq per day. Potassium depletion sufficient to cause hypokalemia usually requires the loss of 200 mEq or more of potassium from the total body store.

Dosage must be adjusted to the individual needs of each patient. The dose for the prevention of hypokalemia is typically in the range of 20 mEq per day. Doses of 40 to 100 mEq per day or more are used for the treatment of potassium depletion. Dosage should be divided if more than 20 mEq per day is given such that no more than 20 mEq is given in a single dose. Because of the potential for gastric irritation (see WARNINGS), Micro-K® Extencaps® should be taken with meals and with a full glass of water or other liquid.

Patients who have difficulty swallowing capsules may sprinkle the contents of the capsule onto a spoonful of soft food. The soft food, such as applesauce or pudding, should be swallowed immediately without chewing and followed with a glass of cool water or juice to ensure complete swallowing of the microcapsules. The food used should not be hot and should be soft enough to be swallowed without chewing. Any microcapsule/food mixture should be used immediately and not stored for future use.

HOW SUPPLIED

Micro-K® Extencaps containing 600 mg of microencapsulated potassium chloride (equivalent to 8 mEq K), are pale orange capsules, imprinted "Micro-K" on the cap and "Ther-Rx 010" on the body, packaged as follows:

NDC 64011-010-04 bottle of 100 capsules

NDC 64011-010-08 bottle of 500 capsules

NDC 64011-010-11 Dis-Co® unit dose packages of 100 capsules

Micro-K® 10 Extencaps® containing 750 mg of microencapsulated potassium chloride (equivalent to 10 mEq K), are pale orange and opaque white capsules, imprinted "Micro-K 10" on the cap and "Ther-Rx 009" on the body, packaged as follows:

NDC 64011-009-04 bottle of 100 capsules

NDC 64011-009-08 bottle of 500 capsules

NDC 64011-009-11 Dis-Co® unit dose packages of 100 capsules

Store at controlled room temperature 20°-25°C (68°-77°F).

Dispense in tight container.

Mktd. by Ther-Rx Corp. St. Louis, MO 63044

06/05

P3511-4

NDC 64011-010-04 100 Capsules

Micro-K

Extencaps

(potassium chloride)

(600 mg)

8 mEq K

Rx Only Ther-Rx Corporation

NDC 64011-010-08 500 Capsules

Micro-K

Extencaps

(potassium chloride)

(600 mg)

8 mEq K

Rx Only Ther-Rx Corporation

Dis-Co

NDC 64011-010-11

Micro-K

Extencaps

(potassium chloride)

(600 mg)

8 mEq K

Rx Only

100 Capsules (Unit Dose Pack)

Ther-Rx Corporation

NDC 64011-009-04 100 Capsules

Micro-K 10

Extencaps

(potassium chloride)

(750 mg)

10 mEq K

Rx Only Ther-Rx Corporation

NDC 64011-009-08 500 Capsules

Micro-K 10

Extencaps

(potassium chloride)

(750 mg)

10 mEq K

Rx Only Ther-Rx Corporation

Dis-Co

NDC 64011-009-11

Micro-K

Extencaps

(potassium chloride)

(750 mg)

10 mEq K

Rx Only

100 Capsules (Unit Dose Pack)

Ther-Rx Corporation

Micro-K EXTENCAPS  potassium chloride  capsule, extended release

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 64011-010 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength POTASSIUM CHLORIDE (POTASSIUM CATION) POTASSIUM CHLORIDE 600 mg

Inactive Ingredients Ingredient Name Strength ETHYLCELLULOSE (100 CPS)   FD&C BLUE NO. 2   FD&C YELLOW NO. 6   GELATIN   MAGNESIUM STEARATE   SODIUM LAURYL SULFATE   TITANIUM DIOXIDE   FD&C RED NO. 40

Product Characteristics Color ORANGE (orange) Score no score Shape CAPSULE (CAPSULE) Size 23mm Flavor Imprint Code Micro;k;Ther;Rx;010 Contains

Packaging # NDC Package Description Multilevel Packaging 1 64011-010-04 100 CAPSULE In 1 BOTTLE None 2 64011-010-08 500 CAPSULE In 1 BOTTLE None 3 64011-010-11 100 CAPSULE In 1 BLISTER PACK None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA018238	08/01/2009

Micro-K 10 EXTENCAPS  potassium chloride  capsule, extended release

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 64011-009 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength POTASSIUM CHLORIDE (POTASSIUM CATION) POTASSIUM CHLORIDE 750 mg

Inactive Ingredients Ingredient Name Strength ETHYLCELLULOSE (100 CPS)   FD&C BLUE NO. 2   FD&C YELLOW NO. 6   GELATIN   MAGNESIUM STEARATE   SODIUM LAURYL SULFATE   TITANIUM DIOXIDE   FD&C RED NO. 40

Product Characteristics Color ORANGE (orange) , WHITE (white) Score no score Shape CAPSULE (CAPSULE) Size 23mm Flavor Imprint Code Micro;K;Ther;Rx;009 Contains

Packaging # NDC Package Description Multilevel Packaging 1 64011-009-04 100 CAPSULE In 1 BOTTLE None 2 64011-009-08 500 CAPSULE In 1 BOTTLE None 3 64011-009-11 100 CAPSULE In 1 BLISTER PACK None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA018238	08/01/2009

Labeler - Ther-Rx Corporation (055041706)

Registrant - KV Pharmaceutical (006291405)

Establishment
Name	Address	ID/FEI	Operations
KV Pharmaceutical		161097225	manufacture

Establishment
Name	Address	ID/FEI	Operations
KV Pharmaceutical		034060843	analysis

Establishment
Name	Address	ID/FEI	Operations
KV Pharmaceutical		152053658	manufacture

Revised: 12/2009Ther-Rx Corporation

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

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• Hypokalemia
• Prevention of Hypokalemia

QVAR

Generic Name: beclomethasone dipropionate

Dosage Form: aerosol, metered
PRODUCT INFORMATION

 

QVAR® 40mcg

(beclomethasone dipropionate HFA, 40 mcg)

INHALATION AEROSOL

For Oral Inhalation Only


 QVAR® 80mcg

(beclomethasone dipropionate HFA, 80 mcg)

INHALATION AEROSOL

For Oral Inhalation Only

QVAR Description

The active component of QVAR 40 mcg Inhalation Aerosol and QVAR 80 mcg Inhalation Aerosol is beclomethasone dipropionate, USP, an anti-inflammatory corticosteroid having the chemical name 9-chloro-11β,17,21-trihydroxy-16β-methylpregna-1,4-diene-3,20-dione 17,21-dipropionate. Beclomethasone dipropionate (BDP) is a diester of beclomethasone, a synthetic corticosteroid chemically related to dexamethasone. Beclomethasone differs from dexamethasone in having a chlorine at the 9-alpha carbon in place of a fluorine, and in having a 16 beta-methyl group instead of a 16 alpha-methyl group. Beclomethasone dipropionate is a white to creamy white, odorless powder with a molecular formula of C28H37ClO7 and a molecular weight of 521.1. Its chemical structure is:

QVAR is a pressurized, metered-dose aerosol intended for oral inhalation only. Each unit contains a solution of beclomethasone dipropionate in propellant HFA-134a (1,1,1,2 tetrafluoroethane) and ethanol. QVAR 40 mcg delivers 40 mcg of beclomethasone dipropionate from the actuator and 50 mcg from the valve. QVAR 80 mcg delivers 80 mcg of beclomethasone dipropionate from the actuator and 100 mcg from the valve. Both products deliver 50 microliters (59 milligrams) of solution formulation from the valve with each actuation. The 40 mcg and the 80 mcg canisters provide either 100 inhalations or 120 inhalations. QVAR should be "primed" or actuated twice prior to taking the first dose from a new canister, or when the inhaler has not been used for more than ten days. Avoid spraying in the eyes or face while priming QVAR. This product does not contain chlorofluorocarbons (CFCs).

QVAR - Clinical Pharmacology

Airway inflammation is known to be an important component in the pathogenesis of asthma. Inflammation occurs in both large and small airways. Corticosteroids have multiple anti-inflammatory effects, inhibiting both inflammatory cells (e.g., mast cells, eosinophils, basophils, lymphocytes, macrophages, and neutrophils) and release of inflammatory mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines). These anti-inflammatory actions of corticosteroids such as beclomethasone dipropionate contribute to their efficacy in asthma.

Beclomethasone dipropionate is a prodrug that is rapidly activated by hydrolysis to the active monoester, 17 monopropionate (17-BMP). Beclomethasone 17 monopropionate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor which is approximately 13 times that of dexamethasone, 6 times that of triamcinolone acetonide, 1.5 times that of budesonide and 25 times that of beclomethasone dipropionate. The clinical significance of these findings is unknown.

Studies in patients with asthma have shown a favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects with recommended doses of QVAR.

Pharmacokinetics

Beclomethasone dipropionate (BDP) undergoes rapid and extensive conversion to beclomethasone-17-monopropionate (17-BMP) during absorption. The pharmacokinetics of 17-BMP has been studied in asthmatics given single doses.

Absorption

The mean peak plasma concentration (Cmax) of BDP was 88 pg/ml at 0.5 hour after inhalation of 320 mcg using QVAR (four actuations of the 80 mcg/actuation strength). The mean peak plasma concentration of the major and most active metabolite, 17-BMP, was 1419 pg/ml at 0.7 hour after inhalation of 320 mcg of QVAR. When the same nominal dose is provided by the two QVAR strengths (40 and 80 mcg/actuation), equivalent systemic pharmacokinetics can be expected. The Cmax of 17-BMP increased dose proportionally in the dose range of 80 and 320 mcg.

Metabolism

Three major metabolites are formed via cytochrome P450 3A catalyzed biotransformation - beclomethasone-17-monopropionate (17-BMP), beclomethasone-21-monopropionate (21-BMP) and beclomethasone (BOH). Lung slices metabolize BDP rapidly to 17-BMP and more slowly to BOH. 17-BMP is the most active metabolite.

Distribution

The in vitro protein binding for 17-BMP was reported to be 94-96% over the concentration range of 1000 to 5000 pg/mL. Protein binding was constant over the concentration range evaluated. There is no evidence of tissue storage of BDP or its metabolites.

Elimination

The major route of elimination of inhaled BDP appears to be via hydrolysis. More than 90% of inhaled BDP is found as 17-BMP in the systemic circulation. The mean elimination half-life of 17-BMP is 2.8 hours. Irrespective of the route of administration (injection, oral or inhalation), BDP and its metabolites are mainly excreted in the feces. Less than 10% of the drug and its metabolites are excreted in the urine.

Special Populations

Formal pharmacokinetic studies using QVAR were not conducted in any special populations.

Pediatrics

The pharmacokinetics of 17-BMP, including dose and strength proportionalities, is similar in children and adults, although the exposure is highly variable. In 17 children (mean age 10 years), the Cmax of 17-BMP was 787 pg/ml at 0.6 hour after inhalation of 160 mcg (four actuations of the 40 mcg/actuation strength of HFA beclomethasone dipropionate). The systemic exposure to 17-BMP from 160 mcg of HFA-BDP administered without a spacer was comparable to the systemic exposure to 17-BMP from 336 mcg CFC-BDP administered with a large volume spacer in 14 children (mean age 12 years). This implies that approximately twice the systemic exposure to 17-BMP would be expected for comparable mg doses of HFA-BDP without a spacer and CFC-BDP with a large volume spacer.

Pharmacodynamics

Improvement in asthma control following inhalation can occur within 24 hours of beginning treatment in some patients, although maximum benefit may not be achieved for 1 to 2 weeks, or longer. The effects of QVAR on the hypothalamic-pituitary-adrenal (HPA) axis were studied in 40 corticosteroid naive patients. QVAR, at doses of 80, 160 or 320 mcg twice daily was compared with placebo and 336 mcg twice daily of beclomethasone dipropionate in a CFC propellant based formulation (CFC-BDP). Active treatment groups showed an expected dose-related reduction in 24-hour urinary free cortisol (a sensitive marker of adrenal production of cortisol). Patients treated with the highest recommended dose of QVAR (320 mcg twice daily) had a 37.3% reduction in 24-hour urinary free cortisol compared to a reduction of 47.3% produced by treatment with 336 mcg twice daily of CFC-BDP. There was a 12.2% reduction in 24 hour urinary free cortisol seen in the group of patients that received 80 mcg twice daily of QVAR and a 24.6% reduction in the group of patients that received 160 mcg twice daily. An open label study of 354 asthma patients given QVAR at recommended doses for one year assessed the effect of QVAR treatment on the HPA axis (as measured by both morning and stimulated plasma cortisol). Less than 1% of patients treated for one year with QVAR had an abnormal response (peak less than 18 mcg/dL) to short-cosyntropin test.

Clinical Trials

Blinded, randomized, parallel, placebo-controlled and active-controlled clinical studies were conducted in 940 adult asthma patients to assess the efficacy and safety of QVAR in the treatment of asthma. Fixed doses ranging from 40 mcg to 160 mcg twice daily were compared to placebo, and doses ranging from 40 mcg to 320 mcg twice daily were compared with doses of 42 mcg to 336 mcg twice daily of an active CFC-BDP comparator. These studies provided information about appropriate dosing through a range of asthma severity. A blinded, randomized, parallel, placebo-controlled study was conducted in 353 pediatric patients (age 5-12 years) to assess the efficacy and safety of HFA beclomethasone dipropionate in the treatment of asthma. Fixed doses of 40 mcg and 80 mcg twice daily were compared with placebo in this study. In these adult and pediatric efficacy trials, at the doses studied, measures of pulmonary function [forced expiratory volume in 1 second (FEV1) and morning peak expiratory flow (AM PEF)] and asthma symptoms were significantly improved with QVAR treatment when compared to placebo.

In controlled clinical trials with adult patients not adequately controlled with beta-agonist alone, QVAR was effective at improving asthma control at doses as low as 40 mcg twice daily (80 mcg/day). Comparable asthma control was achieved at lower daily doses of QVAR than with CFC-BDP. Treatment with increasing doses of both QVAR and CFC-BDP generally resulted in increased improvement in FEV1. In this trial the improvement in FEV1 across doses was greater for QVAR than for CFC-BDP, indicating a shift in the dose response curve for QVAR.

Patients Not Previously Receiving Corticosteroid Therapy

In a 6 week clinical trial, 270 steroid naive patients with symptomatic asthma being treated with as-needed beta-agonist bronchodilators, were randomized to receive either 40 mcg twice daily of QVAR, 80 mcg twice daily of QVAR, or placebo. Both doses of QVAR were effective in improving asthma control with significantly greater improvements in FEV1, AM PEF, and asthma symptoms than with placebo. Shown below is the change from baseline in AM PEF during this trial.

A 6-Week Clinical Trial in Patients with Mild to Moderate Asthma Not on Corticosteroid Therapy Prior to Study Entry: Mean Change in AM PEF

In a 6-week clinical trial, 256 patients with symptomatic asthma being treated with as-needed beta-agonist bronchodilators, were randomized to receive either 160 mcg twice daily of QVAR (delivered as either 40 mcg/actuation or 80 mcg/actuation) or placebo. Treatment with QVAR significantly improved asthma control, as assessed by FEV1, AM PEF, and asthma symptoms, when compared to treatment with placebo. Comparable improvement in AM PEF was seen for patients receiving 160 mcg twice daily QVAR from the 40 mcg and 80 mcg strength products.

Patients Responsive to a Short Course of Oral Corticosteroids

In another clinical trial, 347 patients with symptomatic asthma, being treated with as-needed inhaled beta-agonist bronchodilators and, in some cases, inhaled corticosteroids, were given a 7-12 day course of oral corticosteroids and then randomized to receive either 320 mcg daily of QVAR, 672 mcg of CFC-BDP, or placebo. Patients treated with either QVAR or CFC-BDP had significantly better asthma control, as assessed by AM PEF, FEV1 and asthma symptoms, and fewer study withdrawals due to asthma symptoms, than those treated with placebo over 12 weeks of treatment. A daily dose of 320 mcg QVAR administered in divided doses provided comparable control of AM PEF and FEV1 as 672 mcg of CFC-BDP. Shown below are the mean AM PEF results from this trial.

A 12-Week Clinical Trial in Moderate Symptomatic Patients with Asthma Responding to Oral Corticosteroid Therapy: Mean AM PEF by Study Week

Patients Previously on Inhaled Corticosteroids

In a 6-week clinical trial, 323 patients, who exhibited a deterioration in asthma control during an inhaled corticosteroid washout period, were randomized to daily treatment with either 40, 160, or 320 mcg twice daily QVAR or 42, 168, or 336 mcg twice daily CFC-BDP. Treatment with increasing doses of both QVAR and CFC-BDP resulted in increased improvement in FEV1, FEF25-75% (forced expiratory flow over 25-75% of the vital capacity), and asthma symptoms. Shown below is the change from baseline in FEV1 as percent predicted after 6 weeks of treatment.

A 6-Week Dose Response Clinical Trial in Patients with Inhaled Corticosteroid Dependent Asthma: Mean Change in FEV1 as Percent of Predicted

Patients Previously Maintained on Oral Corticosteroids

Clinical experience has shown that some patients with asthma who require oral corticosteroid therapy for control of symptoms can be partially or completely withdrawn from oral corticosteroids if therapy with beclomethasone dipropionate aerosol is substituted. Inhaled corticosteroids may not be effective for all patients with asthma or at all stages of the disease in a given patient.

Pediatric Experience

In one 12-week clinical trial, pediatric patients (age 5-12 years) with symptomatic asthma (N=353) being treated with as-needed beta-agonist bronchodilators were randomized to receive either 40 mcg or 80 mcg twice daily of HFA beclomethasone dipropionate or placebo. Both doses were effective in improving asthma control with significantly greater improvements in FEV1 (9% and 10% predicted change from baseline at week 12 in FEV1 percent predicted, respectively) than with placebo (4% predicted change).

Indications and Usage for QVAR

QVAR is indicated in the maintenance treatment of asthma as prophylactic therapy in patients 5 years of age and older. QVAR is also indicated for asthma patients who require systemic corticosteroid administration, where adding QVAR may reduce or eliminate the need for the systemic corticosteroids.

Beclomethasone dipropionate is NOT indicated for the relief of acute bronchospasm.

Contraindications

QVAR is contraindicated in the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required. Hypersensitivity to any of the ingredients of this preparation contraindicates its use.

Warnings

Particular care is needed in patients who are transferred from systemically active corticosteroids to QVAR because deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function.

Patients who have been previously maintained on 20 mg or more per day of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infections (particularly gastroenteritis) or other conditions with severe electrolyte loss. Although QVAR may provide control of asthmatic symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid that is necessary for coping with these emergencies.

During periods of stress or a severe asthmatic attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physician for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic steroids during periods of stress or a severe asthma attack.

Transfer of patients from systemic steroid therapy to QVAR may unmask allergic conditions previously suppressed by the systemic steroid therapy, e.g., rhinitis, conjunctivitis, and eczema.

Persons who are on drugs which suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in non-immune children or adults on corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. It is not known how the dose, route and duration of corticosteroid administration affects the risk of developing a disseminated infection. Nor is the contribution of the underlying disease and/or prior corticosteroid treatment known. If exposed to chickenpox, prophylaxis with varicella-zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.

QVAR is not a bronchodilator and is not indicated for rapid relief of bronchospasm.

As with other inhaled asthma medications, bronchospasm, with an immediate increase in wheezing, may occur after dosing. If bronchospasm occurs following dosing with QVAR, it should be treated immediately with a short acting inhaled bronchodilator. Treatment with QVAR should be discontinued and alternate therapy instituted. Patients should be instructed to contact their physician immediately when episodes of asthma, which are not responsive to bronchodilators, occur during the course of treatment with QVAR. During such episodes, patients may require therapy with oral corticosteroids.

Precautions

General

During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal, e.g., joint and/or muscular pain, lassitude and depression, despite maintenance or even improvement of respiratory function. Although suppression of HPA function below the clinical normal range did not occur with doses of QVAR up to and including 640 mcg/day, a dose dependent reduction of adrenal cortisol production was observed. Since inhaled beclomethasone dipropionate is absorbed into the circulation and can be systemically active, HPA axis suppression by QVAR could occur when recommended doses are exceeded or in particularly sensitive individuals. Since individual sensitivity to effects on cortisol production exist, physicians should consider this information when prescribing QVAR. Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with these drugs should be observed carefully for any evidence of systemic corticosteroid effect. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.

It is possible that systemic corticosteroid effects, such as hypercorticism and adrenal suppression, may appear in a small number of patients, particularly at higher doses. If such changes occur, QVAR should be reduced slowly, consistent with accepted procedures for management of asthma symptoms and for tapering of systemic steroids.

A 12 month randomized controlled clinical trial evaluated the effects of HFA beclomethasone dipropionate without spacer versus CFC beclomethasone dipropionate with large volume spacer on growth in children age 5-11. A total of 520 patients were enrolled, of whom 394 received HFA-BDP (100 – 400 mcg/day ex-valve) and 126 received CFC-BDP (200 – 800 mcg/day ex-valve). Similar control of asthma was noted in each treatment arm. When comparing results at month 12 to baseline, the mean growth velocity in children treated with HFA-BDP was approximately 0.5 cm/year less than that noted with children treated with CFC-BDP via large volume spacer.

A reduction in growth velocity in growing children may occur as a result of inadequate control of chronic diseases such as asthma or from use of corticosteroids for treatment. Physicians should closely follow the growth of all pediatric patients taking corticosteroids by any route and weigh the benefits of corticosteroid therapy and asthma control against the possibility of growth suppression.

The long-term and systemic effects of QVAR in humans are still not fully known. In particular, the effects resulting from chronic use of the agent on developmental or immunologic processes in the mouth, pharynx, trachea, and lung are unknown.

Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection of the respiratory tract; untreated systemic fungal, bacterial, parasitic or viral infections; or ocular herpes simplex.

Rare instances of glaucoma, increased intraocular pressure, and cataracts have been reported following the inhaled administration of corticosteroids.

Information for Patients

Patients being treated with QVAR should receive the following information and instructions. This information is intended to aid them in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.

Persons who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles. Patients should also be advised that if they are exposed to these diseases, medical advice should be sought without delay.

Patients should use QVAR at regular intervals as directed. Results of clinical trials indicated significant improvements may occur within the first 24 hours of treatment in some patients; however, the full benefit may not be achieved until treatment has been administered for 1 to 2 weeks, or longer. The patient should not increase the prescribed dosage but should contact their physician if symptoms do not improve or if the condition worsens.

Patients should be advised that QVAR is not intended for use in the treatment of acute asthma. The patient should be instructed to contact their physician immediately if there is any deterioration of their asthma.

Patients should be instructed on the proper use of their inhaler. Patients may wish to rinse their mouth after QVAR use. The patient should also be advised that QVAR may have a different taste and inhalation sensation than that of an inhaler containing CFC propellant.

QVAR use should not be stopped abruptly. The patient should contact their physician immediately if use of QVAR is discontinued.

For the proper use of QVAR, the patient should read and carefully follow the accompanying Patient's Instructions.

Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenicity of beclomethasone dipropionate was evaluated in rats which were exposed for a total of 95 weeks, 13 weeks at inhalation doses up to 0.4 mg/kg/day and the remaining 82 weeks at combined oral and inhalation doses up to 2.4 mg/kg/day. There was no evidence of carcinogenicity in this study at the highest dose, which is approximately 30 and 55 times the maximum recommended daily inhalation dose in adults and children, respectively, on a mg/m2 basis.

Beclomethasone dipropionate did not induce gene mutation in the bacterial cells or mammalian Chinese Hamster ovary (CHO) cells in vitro. No significant clastogenic effect was seen in cultured CHO cells in vitro or in the mouse micronucleus test in vivo.

In rats, beclomethasone dipropionate caused decreased conception rates at an oral dose of 16 mg/kg/day (approximately 200 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis). Impairment of fertility, as evidence by inhibition of the estrous cycle in dogs, was observed following treatment by the oral route at a dose of 0.5 mg/kg/day (approximately 20 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis). No inhibition of the estrous cycle in dogs was seen following 12 months of exposure to beclomethasone dipropionate by the Inhalation route at an estimated daily dose of 0.33 mg/kg (approximately 15 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis).

Pregnancy

Teratogenic Effects

Pregnancy Category C

Like other corticosteroids, parenteral (subcutaneous) beclomethasone dipropionate was teratogenic and embryocidal in the mouse and rabbit when given at a dose of 0.1 mg/kg/day in mice or at a dose of 0.025 mg/kg/day in rabbits. These doses in mice and rabbits were approximately one-half the maximum recommended daily inhalation dose in adults on a mg/m2 basis. No teratogenicity or embryocidal effects were seen in rats when exposed to an inhalation dose of 15 mg/kg/day (approximately 190 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis). There are no adequate and well controlled studies in pregnant women. Beclomethasone dipropionate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Non-teratogenic Effects

Findings of drug-related adrenal toxicity in fetuses following administration of beclomethasone dipropionate to rats suggest that infants born of mothers receiving substantial doses of QVAR during pregnancy should be observed for adrenal suppression.

Nursing Mothers

Corticosteroids are secreted in human milk. Because of the potential for serious adverse reactions in nursing infants from QVAR, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Eight-hundred and thirty-four children between the ages of 5 and 12 were treated with HFA beclomethasone dipropionate (HFA BDP) in clinical trials. The safety and effectiveness of QVAR in children below 5 years of age have not been established.

Use of QVAR with a spacer device in children less than 5 years of age is not recommended. In vitro dose characterization studies were performed with QVAR 40 mcg/actuation with the Optichamber and AeroChamber Plus® spacer utilizing inspiratory flows representative of children under 5 years old. These studies indicated that the amount of medication delivered through the spacing device decreased rapidly with increasing wait times of 5 to 10 seconds as shown in Table 1. If QVAR is used with a spacer device, it is important to inhale immediately.

Based on the average inspiratory flow rates generated by children 6 months to 5 years old, the projected daily dose derived from QVAR 40 mcg at one puff per day at various wait times is depicted in the table below:

TABLE 1

	Wait time, seconds	Mean medication delivery through AeroChamber, mcg/actuation *	Body Weight 50th percentile, kg †	Medication delivered per dose, mcg/kg ‡,§
* Summary Report; Pediatric Dose Characterization of QVAR with Spacer; 3M Pharmaceutical Development, July 21, 2004. † CDC Growth charts, developed by the National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion (2000). ‡ Includes an estimated 20% loss in the masks § QVAR 40mcg in an average adult without using a spacer delivers approximately 0.4 mcg/kg, or bid, 0.8 mcg/kg/day.
Age 6 months, Flow rate 4.8 L/min	0	11.5	7.6	1.2
Age 2 years, Flow rate 8.2 L/min	0	14.1	13.5	0.83
Age 2 years, Flow rate 8.2 L/min	5	5.4	13.5	0.32
Age 2 years, Flow rate 8.2 L/min	10	3.9	13.5	0.23
Age 5 years, Flow rate 11.0 L/min	0	17.5	18	0.78

Oral inhaled corticosteroids have been shown to cause a reduction in growth velocity in children and teenagers with extended use. If a child or teenager on any corticosteroid appears to have growth suppression, the possibility that they are particularly sensitive to this effect of corticosteroids should be considered (see PRECAUTIONS, General).

Geriatric Use

Clinical studies of QVAR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Adverse Reactions

The following reporting rates of common adverse experiences are based upon four clinical trials in which 1196 Patients (671 female and 525 male adults previously treated with as-needed bronchodilators and/or inhaled corticosteroids) were treated with QVAR (doses of 40, 80, 160, or 320 mcg twice daily) or CFC-BDP (doses of 42, 168, or 336 mcg twice daily) or placebo. The table below includes all events reported by patients taking QVAR (whether considered drug related or not) that occurred at a rate over 3% for either QVAR or CFC-BDP. In considering these data, difference in average duration of exposure and clinical trial design should be taken into account.

Adverse Events Reported by at Least 3% of the Patients for Either QVAR or CFC-BDP by Treatment and Daily Dose

Adverse Events		QVAR				CFC-BDP
	Placebo (N=289) %	Total (N=624) %	80-160 mcg (N=233) %	320 mcg (N=335) %	640 mcg (N=56) %	Total (N=283) %	84 mcg (N=59) %	336 mcg (N=55) %	672 mcg (N=169) %
HEADACHE	9	12	15	8	25	15	14	11	17
PHARYNGITIS	4	8	6	5	27	10	12	9	10
UPPER RESP TRACT INFECTION	11	9	7	11	5	12	3	9	17
RHINITIS	9	6	8	3	7	11	15	9	10
INCREASED ASTHMA SYMPTOMS	18	3	2	4	0	8	14	5	7
ORAL SYMPTOMS INHALATION ROUTE	2	3	3	3	2	6	7	5	5
SINUSITIS	2	3	3	3	0	4	7	2	4
PAIN	<1	2	1	2	5	3	3	5	2
BACK PAIN	1	1	2	<1	4	4	2	4	4
NAUSEA	0	1	<1	1	2	3	5	5	1
DYSPHONIA	2	<1	1	0	4	4	0	0	6

Other adverse events that occurred in these clinical trials using QVAR with an incidence of 1% to 3% and which occurred at a greater incidence than placebo were: dysphonia, dysmenorrhea and coughing.

No patients treated with QVAR in the clinical development program developed symptomatic oropharyngeal candidiasis.

If such an infection develops, treatment with appropriate antifungal therapy or discontinuance of treatment with QVAR may be required.

Pediatric Studies

In two 12-week placebo controlled studies in steroid naive pediatric patients 5 to 12 years of age, no clinically relevant differences were found in the pattern, severity, or frequency of adverse events compared with those reported in adults, with the exception of conditions which are more prevalent in a pediatric population generally.

Adverse Event Reports from Other Sources

Rare cases of immediate and delayed hypersensitivity reactions, including urticaria, angioedema, rash, and bronchospasm, have been reported following the oral and intranasal inhalation of beclomethasone dipropionate.

Overdosage

There were no deaths over 15 days following the oral administration of a single dose of 3000 mg/kg in mice, 2000 mg/kg in rats, and 1000 mg/kg in rabbits. The doses in mice, rats, and rabbits were 19,000, 25,000, and 25,000 times, respectively, the maximum recommended daily inhalation in adults or 36,000, 48,000, and 48,000 times, respectively the maximum recommended daily inhalation dose in children on a mg/m2 basis.

QVAR Dosage and Administration

Patients should prime QVAR by actuating into the air twice before using for the first time or if QVAR has not been used for over ten days. Avoid spraying in the eyes or face when priming QVAR. QVAR is a solution aerosol, which does not require shaking. Consistent dose delivery is achieved, whether using the 40 or 80 mcg strengths, due to proportionality of the two products (i.e., two actuations of 40 mcg strength should provide a dose comparable to one actuation of the 80 mcg strength).

QVAR should be administered by the oral inhaled route in patients 5 years of age and older. Use of QVAR with a spacer device in children less than 5 years of age is not recommended (see PRECAUTIONS, Pediatric Use). The onset and degree of symptom relief will vary in individual patients. Improvement in asthma symptoms should be expected within the first or second week of starting treatment, but maximum benefit should not be expected until 3-4 weeks of therapy. For patients who do not respond adequately to the starting dose after 3-4 weeks of therapy, higher doses may provide additional asthma control. The safety and efficacy of QVAR when administered in excess of recommended doses has not been established.

Table 2: Recommended Dosing for Adults and Adolescents

Patient's Previous Therapy	Recommended Starting Dose	Highest Recommended Dose
Bronchodilators Alone	40 to 80 mcg twice daily	320 mcg twice daily
Inhaled Corticosteroids	40 to 160 mcg twice daily	320 mcg twice daily

Table 3: Recommended Dosing for Children 5 to 11 Years

Patient's Previous Therapy	Recommended Starting Dose	Highest Recommended Dose
Bronchodilators Alone	40 mcg twice daily	80 mcg twice daily
Inhaled Corticosteroids	40 mcg twice daily	80 mcg twice daily

As with any inhaled corticosteroid, physicians are advised to titrate the dose of QVAR downward over time to the lowest level that maintains proper asthma control. This is particularly important in children since a controlled study has shown that QVAR has the potential to affect growth in children. Patients should be instructed on the proper use of their inhaler.

Patients Not Receiving Systemic Corticosteroids

Patients who require maintenance therapy of their asthma may benefit from treatment with QVAR at the doses recommended above. In patients who respond to QVAR, improvement in pulmonary function is usually apparent within 1 to 4 weeks after the start of therapy. Once the desired effect is achieved, consideration should be given to tapering to the lowest effective dose.

Patients Maintained on Systemic Corticosteroids

QVAR may be effective in the management of asthmatics maintained on systemic corticosteroids and may permit replacement or significant reduction in the dosage of systemic corticosteroids.

The patient's asthma should be reasonably stable before treatment with QVAR is started. Initially, QVAR should be used concurrently with the patient's usual maintenance dose of systemic corticosteroids. After approximately one week, gradual withdrawal of the systemic corticosteroids is started by reducing the daily or alternate daily dose. Reductions may be made after an interval of one or two weeks, depending on the response of the patient. A slow rate of withdrawal is strongly recommended. Generally these decrements should not exceed 2.5 mg of prednisone or its equivalent. During withdrawal, some patients may experience symptoms of systemic corticosteroid withdrawal, e.g. joint and/or muscular pain, lassitude and depression, despite maintenance or even improvement in pulmonary function. Such patients should be encouraged to continue with the inhaler but should be monitored for objective signs of adrenal insufficiency. If evidence of adrenal insufficiency occurs, the systemic corticosteroid doses should be increased temporarily and thereafter withdrawal should continue more slowly.

During periods of stress or a severe asthma attack, transfer patients may require supplementary treatment with systemic corticosteroids.

DIRECTIONS FOR USE

Illustrated Patient's Instructions for proper use accompany each package of QVAR.

How is QVAR Supplied

QVAR is supplied in two strengths:

 

QVAR 40 mcg is supplied either in a 7.3 g canister containing 100 actuations with a beige plastic actuator and gray dust cap, and Patient's Instructions; box of one; 100 Actuations – NDC 59310-175-40 or in an 8.7 g canister containing 120 actuations with a beige plastic actuator and gray dust cap, and Patient's Instructions; box of one; 120 Actuations – NDC 59310-202-40

 

QVAR 80 mcg is supplied either in a 7.3 g canister containing 100 actuations with a dark mauve plastic actuator and gray dust cap, and Patient's Instructions; box of one; 100 Actuations – NDC 59310-177-80 or in an 8.7 g canister containing 120 actuations with a dark mauve plastic actuator and gray dust cap, and Patient's Instructions; box of one; 120 Actuations – NDC 59310-204-80

The correct amount of medication in each inhalation cannot be assured after 100 actuations from the 7.3 g canister or 120 actuations from the 8.7 g canister even though the canister is not completely empty. The canister should be discarded when the labeled number of actuations have been used.

Store QVAR Inhalation Aerosol when not being used, so that the product rests on the concave end of the canister with the plastic actuator on top.

Store at 25°C (77°F).

Excursions between 15° and 30°C (59° and 86°F) are permitted (see USP). For optimal results, the canister should be at room temperature when used. QVAR Inhalation Aerosol canister should only be used with the QVAR Inhalation Aerosol actuator and the actuator should not be used with any other inhalation drug product.

CONTENTS UNDER PRESSURE

Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 49°C (120°F) may cause bursting. Never throw container into fire or incinerator.

Keep out of reach of children.

Rx only

U.S. Patent Nos. 5605674, 5683677, 5695743, 5776432

Mktd by:

Teva Respiratory, LLC– Horsham, PA 19044

Developed and Manufactured by: 3M Drug Delivery Systems Northridge, CA 91324

OR

3M Health Care, Ltd. Loughborough, UK

September, 2010

© 2010 Teva Respiratory, LLC

639300

QVAR® is a registered trademark of IVAX LLC, a member of the TEVA Group.

Rev. 09/10

OptiChamber is a registered trademark of Respironics Healthscan, Inc. and AeroChamber Plus is a registered trademark of Trudell Medical International Trudell Partnership Holdings Limited and Packard Medical Supply Centre Ltd.

PATIENT'S INSTRUCTIONS

QVAR®

(beclomethasone dipropionate HFA)

INHALATION AEROSOL

Attention Pharmacist: Detach "PATIENT'S INSTRUCTIONS for Use" from package insert and dispense with the product.

PATIENT'S INSTRUCTIONS

It is important that you read these instructions before using QVAR.

Correct and regular use of the inhaler will prevent

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