Sandostatin LAR Depot

Generic Name: octreotide (Injection route, Intramuscular route)

ok-TREE-oh-tide

Commonly used brand name(s)

In the U.S.

• Sandostatin


• Sandostatin LAR Depot

Available Dosage Forms:

• Powder for Suspension


• Powder for Solution


• Solution

Therapeutic Class: Endocrine-Metabolic Agent

Pharmacologic Class: Somatostatin (class)

Uses For Sandostatin LAR Depot

Octreotide is used to treat the severe diarrhea and other symptoms that occur with certain intestinal tumors. It does not cure the tumor but it helps the patient live a more normal life.

Also, this medicine is used to treat a condition called acromegaly, which is caused by too much growth hormone in the body. Too much growth hormone produced in adults causes the hands, feet, and parts of the face to become large, thick, and bulky. Other problems such as arthritis also can develop. Octreotide works by reducing the amount of growth hormone that the body produces.

Octreotide may also be used for other medical conditions as determined by your doctor.

Octreotide is available only with your doctor's prescription.

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

• Acquired immunodeficiency syndrome (AIDS)-related diarrhea.


• Chemotherapy-induced diarrhea.


• Insulin-producing tumors of the pancreas.

Before Using Sandostatin LAR Depot

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

The short-acting form of this medicine has been tested in a limited number of children as young as 1 month of age and has not been shown to cause different side effects or problems than it does in adults.

Studies on the long-acting form of this medicine have been done in children 6 to 17 years and have not demonstrated pediatrics-specific problems that would limit the usefulness of octreotide in children .

Geriatric

Although appropriate studies on the relationship of age to the effects of octreotide have not been performed in the geriatric population, geriatrics-specific problems are not expected to limit the usefulness of octreotide in the elderly. However, elderly patients are more likely to have age-related kidney or heart problems, which may require caution and dosage adjustment in patients receiving octreotide .

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 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 not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Bepridil


• Cisapride


• Dronedarone


• Levomethadyl


• Mesoridazine


• Pimozide


• Sparfloxacin


• Terfenadine


• Thioridazine


• Ziprasidone

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.

• Acecainide


• Acetophenazine


• Ajmaline


• Amiodarone


• Amisulpride


• Amitriptyline


• Amoxapine


• Apomorphine


• Aprindine


• Arsenic Trioxide


• Asenapine


• Astemizole


• Azimilide


• Azithromycin


• Bretylium


• Chloral Hydrate


• Chloroquine


• Chlorpromazine


• Ciprofloxacin


• Citalopram


• Clarithromycin


• Clomipramine


• Clozapine


• Crizotinib


• Cyclosporine


• Dasatinib


• Desipramine


• Dibenzepin


• Disopyramide


• Dofetilide


• Dolasetron


• Doxepin


• Droperidol


• Encainide


• Enflurane


• Erythromycin


• Ethopropazine


• Flecainide


• Fluconazole


• Fluoxetine


• Fluphenazine


• Foscarnet


• Gatifloxacin


• Gemifloxacin


• Granisetron


• Halofantrine


• Haloperidol


• Halothane


• Hydroquinidine


• Ibutilide


• Iloperidone


• Imipramine


• Isoflurane


• Isradipine


• Lapatinib


• Levofloxacin


• Lidoflazine


• Lopinavir


• Lorcainide


• Lumefantrine


• Mefloquine


• Methadone


• Methotrimeprazine


• Moxifloxacin


• Nilotinib


• Norfloxacin


• Nortriptyline


• Ofloxacin


• Ondansetron


• Paliperidone


• Pazopanib


• Pentamidine


• Perflutren Lipid Microsphere


• Perphenazine


• Pipotiazine


• Pirmenol


• Posaconazole


• Prajmaline


• Probucol


• Procainamide


• Prochlorperazine


• Promazine


• Promethazine


• Propafenone


• Propiomazine


• Protriptyline


• Quetiapine


• Quinidine


• Quinine


• Ranolazine


• Risperidone


• Salmeterol


• Saquinavir


• Sematilide


• Sertindole


• Sodium Phosphate


• Sodium Phosphate, Dibasic


• Sodium Phosphate, Monobasic


• Solifenacin


• Sorafenib


• Sotalol


• Spiramycin


• Sulfamethoxazole


• Sultopride


• Sunitinib


• Tedisamil


• Telavancin


• Telithromycin


• Tetrabenazine


• Thiethylperazine


• Toremifene


• Trazodone


• Trifluoperazine


• Triflupromazine


• Trimeprazine


• Trimethoprim


• Trimipramine


• Vandetanib


• Vardenafil


• Vasopressin


• Vemurafenib


• Voriconazole


• Zolmitriptan


• Zotepine

Using this medicine 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.

• Pegvisomant

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:

• Type 1 and type 2 diabetes mellitus—Octreotide may cause high or low blood sugar; your doctor may need to change the dose of your diabetes medicine.

• Heart disease or heart rhythm problem—Your doctor may need to change the dose of your heart medicines .

• Gallbladder disease or gallstones (or history of)—This medicine may increase the chance of having gallstones.

• Kidney disease (severe)—If you have this condition, octreotide may remain in the body longer than normal; your doctor may need to change the dose of your medicine.

Proper Use of octreotide

This section provides information on the proper use of a number of products that contain octreotide. It may not be specific to Sandostatin LAR Depot. Please read with care.

To control the symptoms of your medical problem, this medicine must be taken as ordered by your doctor. Make sure that you understand exactly how to take this medicine.

Octreotide is packaged in a kit containing an ampule opener, alcohol swabs, ampules of the medicine, and, in some kits, a vial of diluent to mix with the medicine. Directions on how to prepare and inject the medicine are in the package. Read the directions carefully and ask your health care professional for additional explanation, if necessary.

It is important to follow any instructions from your doctor about the careful selection and rotation of injection sites on your body. This will help to prevent skin problems, such as irritation.

Some patients may feel pain, stinging, tingling, or burning sensations at the place where they inject the medicine. These sensations usually last only a few moments and may be eased by rubbing the spot after the injection. Injecting the medicine after it has been warmed to room temperature rather than cold from the refrigerator may reduce the discomfort. The medicine should be taken from the refrigerator 20 to 60 minutes before it is to be used. However, do not use heat to warm it faster because heat can destroy the medicine.

Put used needles and syringes in a puncture-resistant disposable container or dispose of them as directed by your health care professional. Do not reuse needles and syringes.

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 long-acting injection dosage form:
  
  • For treating the severe diarrhea that occurs with certain types of intestinal tumors:
    
    • Adults and teenagers—At first, 20 milligrams (mg) injected into the gluteal muscle once every four weeks for two months. Then, the dose will be adjusted by your doctor, based on your response to the medicine.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  
  • For treating acromegaly:
    
    • Adults—At first, 20 mg injected into the gluteal muscle once every four weeks for three months. Then, the dose will be adjusted by your doctor, based on your response to the medicine.
    
    
  
  


• For short-acting injection dosage form:
  
  • For treating the severe diarrhea that occurs with certain types of intestinal tumors:
    
    • Adults and teenagers—At first, 50 micrograms (mcg) injected under the skin two or three times a day. Then, the dose is slowly increased. Some people may need doses as high as 600 mcg a day for the first two weeks. Thereafter, the dose is usually between 50 and 1500 mcg per day.
    
    
    • Children—The dose is based on body weight and must be determined by your doctor. The usual dose is 1 to 10 mcg per kilogram (kg) (0.45 to 4.5 mcg per pound) of body weight a day, injected under the skin.
    
    
  
  
  • For treating acromegaly:
    
    • Adults—At first, 50 mcg injected under the skin or into a vein three times a day. Then, the dose is slowly increased to 100 to 200 mcg three times a day. Higher doses may be needed, as determined by your doctor.
    
    
  
  

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.

If you miss a dose of the long-acting form of this medicine, contact your doctor.

Storage

Store in the refrigerator. Do not freeze.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ampules of the short-acting form of octreotide may be kept at room temperature for 14 days when they are protected from light. If the ampuls are not protected from light, problems with the solution can develop much sooner.

Precautions While Using Sandostatin LAR Depot

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

Sandostatin LAR Depot 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 or rare

• Changes in menstrual periods


• convulsions (seizures)


• decreased sexual ability in males


• depressed mood


• dry skin and hair


• dry, puffy skin


• feeling cold


• hoarseness or husky voice


• muscle cramps and stiffness


• slowed heartbeat


• swelling of front part of neck


• unconsciousness


• unusual tiredness or weakness


• weight gain

Check with your doctor as soon as possible if any of the following side effects occur:

More common

• Irregular heartbeat


• slow heartbeat

Less common or rare

• Hyperglycemia (high blood sugar), including blurred vision, drowsiness, dry mouth, flushed dry skin, fruit-like breath odor, increased urination (frequency and volume), ketones in urine, loss of appetite, nausea, stomachache, tiredness, troubled breathing (rapid and deep), unusual thirst, or vomiting


• hypoglycemia (low blood sugar), including anxious feeling, behavior change similar to drunkenness, blurred vision, cold sweats, confusion, cool pale skin, difficulty in concentrating, drowsiness, excessive hunger, fast heartbeat, headache, nausea, nervousness, nightmares, restless sleep, shakiness, slurred speech, or unusual tiredness or weakness


• inflammation of the pancreas gland, including abdominal or stomach pain or bloating, nausea, or vomiting

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

• Constipation


• diarrhea


• headache


• pain, stinging, tingling, or burning sensation at place of injection, with redness and swelling


• passing of gas

Less common or rare

• Backache


• bladder pain


• bloody or cloudy urine


• blurred or loss of vision


• chills


• cough


• difficult, burning, or painful urination


• discouragement


• disturbed color perception


• dizziness or light-headedness


• double vision


• feeling sad or empty


• fever


• frequent urge to urinate


• frequent urination usually with very small amounts of urine


• general feeling of discomfort or illness


• hair loss


• halos around lights


• irritability


• itching skin


• joint pain


• lack or loss of appetite


• loss of interest or pleasure


• lower back or side pain


• muscle aches and pains


• nausea


• night blindness


• overbright appearance of lights


• redness or flushing of face


• runny nose


• shivering


• sore throat


• stools that float, are foul smelling, and fatty in appearance


• sweating


• swelling of feet or lower legs


• tiredness


• trouble concentrating


• trouble sleeping


• tunnel vision


• 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: Sandostatin LAR Depot side effects (in more detail)

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More Sandostatin LAR Depot resources

• Sandostatin LAR Depot Side Effects (in more detail)
• Sandostatin LAR Depot Use in Pregnancy & Breastfeeding
• Sandostatin LAR Depot Drug Interactions
• Sandostatin LAR Depot Support Group
• 1 Review for Sandostatin LAR Depot - Add your own review/rating

• Sandostatin LAR Depot Kit MedFacts Consumer Leaflet (Wolters Kluwer)


• Octreotide Prescribing Information (FDA)


• Octreotide MedFacts Consumer Leaflet (Wolters Kluwer)


• Octreotide Acetate Monograph (AHFS DI)


• Sandostatin Prescribing Information (FDA)


• Sandostatin Consumer Overview

Compare Sandostatin LAR Depot with other medications

• Acromegaly
• Carcinoid Tumor
• Diabetes, Type 1
• Diarrhea
• Gastrinoma
• Glucagonoma
• Insulinoma
• Pituitary Adenoma
• Small Bowel or Pancreatic Fistula
• Vasoactive Intestinal Peptide Tumor

Theo-24

Generic Name: theophylline (thee OFF i lin)

Brand Names: Elixophyllin, Theo-24, Theo-Time, TheoCap, Theochron, Uniphyl

What is Theo-24 (theophylline)?

Theophylline is a bronchodilator. It works by relaxing muscles in the lungs and chest, and makes the lungs less sensitive to allergens and other causes of bronchospasm.

Theophylline is used to treat the symptoms of asthma, bronchitis and emphysema.

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

What is the most important information I should know about Theo-24 (theophylline)?

If there are any changes in the brand, strength, or type of theophylline you use, your dosage needs may change. Always check your medicine when it is refilled to make sure you have received the correct brand and type as prescribed by your doctor. Ask the pharmacist if you have any questions about the medicine you receive at the pharmacy.

Do not start or stop smoking without first talking to your doctor. Smoking changes the way your body uses theophylline, and you may need to use a different dose. Avoid drinks or foods that contain caffeine, such as coffee, tea, cola, and chocolate. Caffeine may increase some of the side effects of theophylline.

There are many other medicines that can interact with theophylline. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor. Keep a list with you of all the medicines you use and show this list to any doctor or other healthcare provider who treats you.

What should I discuss with my healthcare provider before taking Theo-24 (theophylline)?

Do not use this medication if you are allergic to theophylline.

Before taking theophylline, tell your doctor if you are allergic to any drugs, or if you have:

• 
  

  a stomach ulcer;

  
  


• 
  

  epilepsy or other seizure disorder;

  
  


• 
  

  a heart rhythm problem;

  
  


• 
  

  congestive heart failure;

  
  


• 
  

  fluid in your lungs;

  
  


• 
  

  underactive thyroid;

  
  


• 
  

  a high fever;

  
  


• 
  

  liver disease (such as cirrhosis or hepatitis);

  
  


• 
  

  kidney disease; or

  
  


• 
  

  if you have recently quit smoking cigarettes or marijuana.

  
  

If you have any of these conditions, you may need a dose adjustment or special tests to safely take theophylline.

FDA pregnancy category C. This medication may be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. Theophylline can pass into breast milk and may harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Older adults may be more likely to have side effects from theophylline.

How should I take Theo-24 (theophylline)?

Take this medication exactly as it was prescribed for you. Do not take the medication in larger amounts, or take it for longer than recommended by your doctor. Follow the directions on your prescription label.

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

Take this medicine with a full glass of water.

You may take theophylline with or without food, but take it the same way every time.

Do not crush, chew, break, or open an extended-release tablet or capsule unless your doctor tells you to. Swallow the pill whole. It is specially made to release medicine slowly in the body. Breaking or opening the pill would cause too much of the drug to be released at one time.

Your doctor may tell you to break a regular theophylline tablet before you take it. Some tablets have special scored marks on them to make breaking the tablet easier. Follow your doctor's instructions.

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

If there are any changes in the brand, strength, or type of theophylline you use, your dosage needs may change. Always check your medicine when it is refilled to make sure you have received the correct brand and type as prescribed by your doctor. Ask the pharmacist if you have any questions about the medicine you receive at the pharmacy.

Do not start or stop smoking without first talking to your doctor. Smoking changes the way your body uses theophylline, and you may need to use a different dose. Store theophylline at room temperature, away from moisture, heat, and light.

What happens if I miss a dose?

Take the missed dose as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at your next regularly scheduled time. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine. Overdose symptoms may include nausea, vomiting, insomnia, tremors, restlessness, uneven heartbeats, and seizure (convulsions). Seizures caused by a theophylline overdose can cause death or permanent brain damage.

What should I avoid while taking Theo-24 (theophylline)?

Theophylline can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert. Avoid drinks or foods that contain caffeine, such as coffee, tea, cola, and chocolate. Caffeine may increase some of the side effects of theophylline.

Theo-24 (theophylline) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using theophylline and call your doctor at once if you have any of these serious side effects:

• 
  

  seizure (convulsions);

  
  


• 
  

  worsening of your condition, or symptoms of new illness;

  
  


• 
  

  severe or ongoing nausea and vomiting, headache, fast or uneven heart rate, and trouble sleeping (insomnia);

  
  


• 
  

  coughing up blood or vomit that looks like coffee grounds;

  
  


• 
  

  ongoing fever;

  
  


• 
  

  feeling restless, irritable, nervous, or jittery.

  
  


• 
  

  tremors; or

  
  


• 
  

  urinating more than usual.

  
  

Less serious side effects may include:

• 
  

  mild nausea, loss of appetite, weight loss;

  
  


• 
  

  restlessness, tremor, or insomnia; or

  
  


• 
  

  headache, lightheadedness, or dizziness.

  
  

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 Theo-24 (theophylline)?

Before taking theophylline, tell your doctor if you are using any of the following drugs:

• 
  

  carbamazepine (Carbatrol, Tegretol);

  
  


• 
  

  cimetidine (Tagamet);

  
  


• 
  

  enoxacin (Penetrex);

  
  


• 
  

  ephedrine or similar medications found in cold medicine or diet pills;

  
  


• 
  

  erythromycin (E.E.S., E-Mycin, Ery-Tab);

  
  


• 
  

  fluvoxamine (Luvox);

  
  


• 
  

  propranolol (Inderal, InnoPran);

  
  


• 
  

  rifampin (Rifadin, Rifater, Rifamate, Rimactane);

  
  


• 
  

  St. John's wort; or

  
  


• 
  

  thiabendazole (Mintezol).

  
  

This list is not complete and there are many other medicines that can interact with theophylline. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor. Keep a list with you of all the medicines you use and show this list to any doctor or other healthcare provider who treats you.

More Theo-24 resources

• Theo-24 Side Effects (in more detail)
• Theo-24 Use in Pregnancy & Breastfeeding
• Drug Images
• Theo-24 Drug Interactions
• Theo-24 Support Group
• 2 Reviews for Theo-24 - Add your own review/rating

• Theo-24 Advanced Consumer (Micromedex) - Includes Dosage Information


• Theophylline Prescribing Information (FDA)


• Theophylline Professional Patient Advice (Wolters Kluwer)


• Elixophyllin Elixir MedFacts Consumer Leaflet (Wolters Kluwer)


• Elixophyllin Prescribing Information (FDA)


• Quibron-T MedFacts Consumer Leaflet (Wolters Kluwer)


• Quibron-T Prescribing Information (FDA)


• Theo-24 Prescribing Information (FDA)


• TheoCap Sustained-Release Capsules MedFacts Consumer Leaflet (Wolters Kluwer)


• Theochron Sustained-Release Tablets MedFacts Consumer Leaflet (Wolters Kluwer)


• Theolair tablets Prescribing Information (FDA)


• Theophyllines Monograph (AHFS DI)


• Uniphyl Prescribing Information (FDA)

Compare Theo-24 with other medications

• Apnea of Prematurity
• Asthma, acute
• Asthma, Maintenance

Where can I get more information?

• Your pharmacist can provide more information about theophylline.

See also: Theo-24 side effects (in more detail)

Suboxone Film

Generic Name: buprenorphine and naloxone

Dosage Form: sublingual film, soluble
FULL PRESCRIBING INFORMATION

Indications and Usage for Suboxone Film

SUBOXONE sublingual film is indicated for maintenance treatment of opioid dependence and should be used as part of a complete treatment plan to include counseling and psychosocial support.

Under the Drug Addiction Treatment Act (DATA) codified at 21 U.S.C. 823(g), prescription use of this product in the treatment of opioid dependence is limited to physicians who meet certain qualifying requirements, and who have notified the Secretary of Health and Human Services (HHS) of their intent to prescribe this product for the treatment of opioid dependence and have been assigned a unique identification number that must be included on every prescription.

Suboxone Film Dosage and Administration

SUBOXONE sublingual film is administered sublingually as a single daily dose. SUBOXONE sublingual film should be used in patients who have been initially inducted using SUBUTEX® (buprenorphine) sublingual tablets.

Maintenance

• SUBOXONE sublingual film is indicated for maintenance treatment. The recommended target dosage of SUBOXONE sublingual film is 16/4 mg buprenorphine/naloxone/day, as a single daily dose.


• The dosage of SUBOXONE sublingual film should be progressively adjusted in increments/decrements of 2/0.5 mg or 4/1 mg buprenorphine/naloxone to a level that holds the patient in treatment and suppresses opioid withdrawal signs and symptoms.


• The maintenance dose of SUBOXONE sublingual film is generally in the range of 4/1 mg buprenorphine/naloxone to 24/6 mg buprenorphine/naloxone per day depending on the individual patient. Dosages higher than this have not been demonstrated to provide any clinical advantage.

Method of Administration

Place the SUBOXONE sublingual film under the tongue. If an additional SUBOXONE sublingual film is necessary to achieve the prescribed dose, place the additional sublingual film sublingually on the opposite side from the first film. Place the sublingual film in a manner to minimize overlapping as much as possible. The sublingual film must be kept under the tongue until the film is completely dissolved. SUBOXONE sublingual film should NOT be chewed, swallowed, or moved after placement.

Proper administration technique should be demonstrated to the patient.

Clinical Supervision

Treatment should be initiated with supervised administration, progressing to unsupervised administration as the patient's clinical stability permits.  SUBOXONE sublingual film is subject to diversion and abuse.  When determining the prescription quantity for unsupervised administration, consider the patient's level of stability, the security of his or her home situation, and other factors likely to affect the ability to manage supplies of take-home medication.

Ideally patients should be seen at reasonable intervals (e.g., at least weekly during the first month of treatment) based upon the individual circumstances of the patient. Medication should be prescribed in consideration of the frequency of visits.  Provision of multiple refills is not advised early in treatment or without appropriate patient follow-up visits.  Periodic assessment is necessary to determine compliance with the dosing regimen, effectiveness of the treatment plan, and overall patient progress.

Once a stable dosage has been achieved and patient assessment (e.g., urine drug screening) does not indicate illicit drug use, less frequent follow-up visits may be appropriate. A once-monthly visit schedule may be reasonable for patients on a stable dosage of medication who are making progress toward their treatment objectives. Continuation or modification of pharmacotherapy should be based on the physician's evaluation of treatment outcomes and objectives such as:

1. Absence of medication toxicity.


2. Absence of medical or behavioral adverse effects.


3. Responsible handling of medications by the patient.


4. Patient's compliance with all elements of the treatment plan (including recovery-oriented activities, psychotherapy, and/or other psychosocial modalities).


5. Abstinence from illicit drug use (including problematic alcohol and/or benzodiazepine use).

If treatment goals are not being achieved, the physician should re-evaluate the appropriateness of continuing the current treatment.

Unstable Patients

Physicians will need to decide when they cannot appropriately provide further management for particular patients. For example, some patients may be abusing or dependent on various drugs, or unresponsive to psychosocial intervention such that the physician does not feel that he/she has the expertise to manage the patient. In such cases, the physician may want to assess whether to refer the patient to a specialist or more intensive behavioral treatment environment. Decisions should be based on a treatment plan established and agreed upon with the patient at the beginning of treatment.

Patients who continue to misuse, abuse, or divert buprenorphine products or other opioids should be provided with, or referred to, more intensive and structured treatment.

Stopping Treatment

The decision to discontinue therapy with SUBOXONE sublingual film after a period of maintenance should be made as part of a comprehensive treatment plan. Both gradual and abrupt discontinuation of buprenorphine has been used, but the data are insufficient to determine the best method of dose taper at the end of treatment.

Switching between SUBOXONE (buprenorphine and naloxone) Sublingual Tablets and SUBOXONE Sublingual film

Patients being switched between SUBOXONE (buprenorphine and naloxone) sublingual tablets and SUBOXONE sublingual film should be started on the same dosage as the previously administered product. However, dosage adjustments may be necessary when switching between products. Because of the potentially greater relative bioavailability of SUBOXONE sublingual film compared to SUBOXONE (buprenorphine and naloxone) sublingual tablets, patients switching from SUBOXONE (buprenorphine and naloxone) sublingual tablets to SUBOXONE sublingual film should be monitored for over-medication. Those switching from SUBOXONE sublingual film to SUBOXONE (buprenorphine and naloxone) sublingual tablets should be monitored for withdrawal or other indications of under-dosing. In clinical studies, pharmacokinetics of SUBOXONE sublingual film was similar to the respective dosage strengths of SUBOXONE (buprenorphine and naloxone) sublingual tablets, although not all doses and dose combinations met bioequivalence criteria.

Dosage Forms and Strengths

SUBOXONE sublingual film is supplied as an orange rectangular sublingual film with a white printed logo in two dosage strengths:

• buprenorphine/naloxone 2 mg/0.5 mg, and


• buprenorphine/naloxone 8 mg/2 mg.

Contraindications

SUBOXONE sublingual film should not be administered to patients who have been shown to be hypersensitive to buprenorphine or naloxone as serious adverse reactions, including anaphylactic shock, have been reported [see Warnings and Precautions (5.7)].

Warnings and Precautions

Abuse Potential

Buprenorphine can be abused in a manner similar to other opioids, legal or illicit. Prescribe and dispense buprenorphine with appropriate precautions to minimize risk of misuse, abuse, or diversion, and ensure appropriate protection from theft, including in the home. Clinical monitoring appropriate to the patient's level of stability is essential. Multiple refills should not be prescribed early in treatment or without appropriate patient follow-up visits. [see Drug Abuse and Dependence (9.2)].

Respiratory Depression

Buprenorphine, particularly when taken by the IV route, in combination with benzodiazepines or other CNS depressants (including alcohol), has been associated with significant respiratory depression and death. Many, but not all post-marketing reports regarding coma and death associated with the concomitant use of buprenorphine and benzodiazepines, involved misuse by self-injection. Deaths have also been reported in association with concomitant administration of buprenorphine with other depressants such as alcohol or other CNS depressant drugs. Patients should be warned of the potential danger of self-administration of benzodiazepines or other depressants while under treatment with SUBOXONE sublingual film. [see Drug Interactions (7.3)]

In the case of overdose, the primary management should be the re-establishment of adequate ventilation with mechanical assistance of respiration, if required. Naloxone may be of value for the management of buprenorphine overdose. Higher than normal doses and repeated administration may be necessary.

SUBOXONE sublingual film should be used with caution in patients with compromised respiratory function (e.g., chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression).

CNS Depression

Patients receiving buprenorphine in the presence of opioid analgesics, general anesthetics, benzodiazepines, phenothiazines, other tranquilizers, sedative/hypnotics or other CNS depressants (including alcohol) may exhibit increased CNS depression. Consider dose reduction of CNS depressants, SUBOXONE sublingual film, or both in situations of concomitant prescription. [see Drug Interactions (7.3)].

Unintentional Pediatric Exposure

Buprenorphine can cause severe, possibly fatal, respiratory depression in children who are accidentally exposed to it. Store buprenorphine-containing medications safely out of the sight and reach of children and destroy any unused medication appropriately [see Disposal of Unused SUBOXONE Sublingual Film (17.2)].

Dependence

Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces physical dependence of the opioid type, characterized by withdrawal signs and symptoms upon abrupt discontinuation or rapid taper. The withdrawal syndrome is typically milder than seen with full agonists and may be delayed in onset. Buprenorphine can be abused in a manner similar to other opioids. This should be considered when prescribing or dispensing buprenorphine in situations when the clinician is concerned about an increased risk of misuse, abuse, or diversion. [see Drug Abuse and Dependence (9.3)]

Hepatitis, Hepatic Events

Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving buprenorphine in clinical trials and through post-marketing adverse event reports. The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of death, hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy. In many cases, the presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant usage of other potentially hepatotoxic drugs, and ongoing injecting drug use may have played a causative or contributory role. In other cases, insufficient data were available to determine the etiology of the abnormality. Withdrawal of buprenorphine has resulted in amelioration of acute hepatitis in some cases; however, in other cases no dose reduction was necessary. The possibility exists that buprenorphine had a causative or contributory role in the development of the hepatic abnormality in some cases. Liver function tests, prior to initiation of treatment is recommended to establish a baseline. Periodic monitoring of liver function during treatment is also recommended. A biological and etiological evaluation is recommended when a hepatic event is suspected. Depending on the case, SUBOXONE sublingual film may need to be carefully discontinued to prevent withdrawal signs and symptoms and a return by the patient to illicit drug use, and strict monitoring of the patient should be initiated.

Allergic Reactions

Cases of hypersensitivity to buprenorphine and naloxone containing products have been reported both in clinical trials and in the post-marketing experience. Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported. The most common signs and symptoms include rashes, hives, and pruritus. A history of hypersensitivity to buprenorphine or naloxone is a contraindication to the use of SUBOXONE sublingual film.

Precipitation of Opioid Withdrawal Signs and Symptoms

Because it contains naloxone, SUBOXONE sublingual film is highly likely to produce marked and intense withdrawal signs and symptoms if misused parenterally by individuals dependent on full opioid agonists such as heroin, morphine, or methadone. Because of the partial agonist properties of buprenorphine, SUBOXONE sublingual film may precipitate opioid withdrawal signs and symptoms in such persons if administered sublingually before the agonist effects of the opioid have subsided.

Neonatal Withdrawal

Neonatal withdrawal has been reported in the infants of women treated with buprenorphine during pregnancy. From post-marketing reports, the time to onset of neonatal withdrawal signs ranged from Day 1 to Day 8 of life with most cases occurring on Day 1. Adverse events associated with the neonatal withdrawal syndrome included hypertonia, neonatal tremor, neonatal agitation, and myoclonus, and there have been reports of convulsions, apnea, respiratory depression, and bradycardia.

Use in Opioid Naïve Patients

There have been reported deaths of opioid naive individuals who received a 2 mg dose of buprenorphine as a sublingual tablet for analgesia. SUBOXONE sublingual film is not appropriate as an analgesic.

Impairment of Ability to Drive or Operate Machinery

SUBOXONE sublingual film may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery, especially during treatment induction and dose adjustment. Patients should be cautioned about driving or operating hazardous machinery until they are reasonably certain that SUBOXONE sublingual film therapy does not adversely affect his or her ability to engage in such activities.

Orthostatic Hypotension

Like other opioids, SUBOXONE sublingual film may produce orthostatic hypotension in ambulatory patients.

Elevation of Cerebrospinal Fluid Pressure

Buprenorphine, like other opioids, may elevate cerebrospinal fluid pressure and should be used with caution in patients with head injury, intracranial lesions and other circumstances when cerebrospinal pressure may be increased. Buprenorphine can produce miosis and changes in the level of consciousness that may interfere with patient evaluation.

Elevation of Intracholedochal Pressure

Buprenorphine has been shown to increase intracholedochal pressure, as do other opioids, and thus should be administered with caution to patients with dysfunction of the biliary tract.

Effects in Acute Abdominal Conditions

As with other opioids, buprenorphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions.

General Precautions

SUBOXONE sublingual film should be administered with caution in debilitated patients and those with myxedema or hypothyroidism, adrenal cortical insufficiency (e.g., Addison's disease); CNS depression or coma; toxic psychoses; prostatic hypertrophy or urethral stricture; acute alcoholism; delirium tremens; or kyphoscoliosis.

Adverse Reactions

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse Events in Clinical Trials - SUBOXONE Sublingual film

The safety of SUBOXONE sublingual film is supported by clinical trials using SUBUTEX (buprenorphine) sublingual tablets and SUBOXONE (buprenorphine and naloxone) sublingual tablets, and other trials using buprenorphine sublingual solutions, as well as an open-label study in 194 patients treated with SUBOXONE sublingual film. In total, safety data from clinical studies are available from over 3000 opioid-dependent subjects exposed to buprenorphine at doses in the range used in the treatment of opioid dependence. Few differences in the adverse event profile were noted among SUBOXONE sublingual film, SUBOXONE (buprenorphine and naloxone) sublingual tablets, SUBUTEX (buprenorphine) sublingual tablets and a buprenorphine ethanolic sublingual solution.

The most common adverse event (>1%) associated with the sublingual administration of the SUBOXONE sublingual film was oral hypoesthesia. Other adverse events were constipation, glossodynia, oral mucosal erythema, vomiting, intoxication, disturbance in attention, palpitations, insomnia, withdrawal syndrome, hyperhidrosis, and blurred vision.

Other adverse event data were derived from larger, controlled studies of SUBOXONE (buprenorphine and naloxone) and SUBUTEX (buprenorphine) tablets and of buprenorphine sublingual solution. In a comparative study of SUBOXONE (buprenorphine and naloxone) and SUBUTEX (buprenorphine) sublingual tablets, adverse event profiles were similar for subjects treated with 16/4 mg SUBOXONE (buprenorphine and naloxone) sublingual tablets or 16 mg SUBUTEX (buprenorphine) sublingual tablets. The following adverse events were reported to occur by at least 5% of patients in a 4-week study of SUBOXONE (buprenorphine and naloxone) sublingual tablets and SUBUTEX (buprenorphine) sublingual tablets.

Table 1. Adverse Events (≥5%) by Body System and Treatment Group in a 4-week Study

Abbreviations: COSTART = Coding Symbols for Thesaurus of Adverse Reaction Terms.
Body System/ Adverse Event (COSTART Terminology)	SUBOXONE (buprenorphine and naloxone) sublingual tablets 16/4 mg/day N=107 n (%)	SUBUTEX (buprenorphine) sublingual tablets 16 mg/day N=103 n (%)	Placebo N=107 n (%)
Body as a Whole
Asthenia	7 (6.5%)	5 (4.9%)	7 (6.5%)
Chills	8 (7.5%)	8 (7.8%)	8 (7.5%)
Headache	39 (36.4%)	30 (29.1%)	24 (22.4%)
Infection	6 (5.6%)	12 (11.7%)	7 (6.5%)
Pain	24 (22.4%)	19 (18.4%)	20 (18.7%)
Pain abdomen	12 (11.2%)	12 (11.7%)	7 (6.5%)
Pain back	4 (3.7%)	8 (7.8%)	12 (11.2%)
Withdrawal syndrome	27 (25.2%)	19 (18.4%)	40 (37.4%)
Cardiovascular System
Vasodilation	10 (9.3%)	4 (3.9%)	7 (6.5%)
Digestive System
Constipation	13 (12.1%)	8 (7.8%)	3 (2.8%)
Diarrhea	4 (3.7%)	5 (4.9%)	16 (15.0%)
Nausea	16 (15.0%)	14 (13.6%)	12 (11.2%)
Vomiting	8 (7.5%)	8 (7.8%)	5 (4.7%)
Nervous System
Insomnia	15 (14.0%)	22 (21.4%)	17 (15.9%)
Respiratory System
Rhinitis	5 (4.7%)	10 (9.7%)	14 (13.1%)
Skin And Appendages
Sweating	15 (14.0%)	13 (12.6%)	11 (10.3%)

The adverse event profile of buprenorphine was also characterized in the dose-controlled study of a buprenorphine ethanolic solution, over a range of doses in four months of treatment. Table 2 shows adverse events reported by at least 5% of subjects in any dose group in the dose-controlled trial.

Table 2. Adverse Events (≥5%) by Body System and Treatment Group in a 16-week Study

*Sublingual solution. Doses in this table cannot necessarily be delivered in tablet form, but for comparison purposes:
1 mg solution would be less than a tablet dose of 2 mg
4 mg solution approximates a 6 mg tablet dose
8 mg solution approximates a 12 mg tablet dose
16 mg solution approximates a 24 mg tablet dose
Body System/ Adverse Event (COSTART Terminology)	Buphrenorphine Dose
	Very Low* N=184 n (%)	Low* N=180 n (%)	Moderate* N=186 n (%)	High* N=181 n (%)	Total* N=731 n (%)
Body as a Whole
Abscess	9 (5%)	2 (1%)	3 (2%)	2 (1%)	16 (2%)
Asthenia	26 (14%)	28 (16%)	26 (14%)	24 (13%)	104 (14%)
Chills	11 (6%)	12 (7%)	9 (5%)	10 (6%)	42 (6%)
Fever	7 (4%)	2 (1%)	2 (1%)	10 (6%)	21 (3%)
Flu syndrome	4 (2%)	13 (7%)	19 (10%)	8 (4%)	44 (6%)
Headache	51 (28%)	62 (34%)	54 (29%)	53 (29%)	220 (30%)
Infection	32 (17%)	39 (22%)	38 (20%)	40 (22%)	149 (20%)
Injury accidental	5 (3%)	10 (6%)	5 (3%)	5 (3%)	25 (3%)
Pain	47 (26%)	37 (21%)	49 (26%)	44 (24%)	177 (24%)
Pain back	18 (10%)	29 (16%)	28 (15%)	27 (15%)	102 (14%)
Withdrawal syndrome	45 (24%)	40 (22%)	41 (22%)	36 (20%)	162 (22%)
Digestive System
Constipation	10 (5%)	23 (13%)	23 (12%)	26 (14%)	82 (11%)
Diarrhea	19 (10%)	8 (4%)	9 (5%)	4 (2%)	40 (5%)
Dyspepsia	6 (3%)	10 (6%)	4 (2%)	4 (2%)	24 (3%)
Nausea	12 (7%)	22 (12%)	23 (12%)	18 (10%)	75 (10%)
Vomiting	8 (4%)	6 (3%)	10 (5%)	14 (8%)	38 (5%)
Nervous System
Anxiety	22 (12%)	24 (13%)	20 (11%)	25 (14%)	91 (12%)
Depression	24 (13%)	16 (9%)	25 (13%)	18 (10%)	83 (11%)
Dizziness	4 (2%)	9 (5%)	7 (4%)	11 (6%)	31 (4%)
Insomnia	42 (23%)	50 (28%)	43 (23%)	51 (28%)	186 (25%)
Nervousness	12 (7%)	11 (6%)	10 (5%)	13 (7%)	46 (6%)
Somnolence	5 (3%)	13 (7%)	9 (5%)	11 (6%)	38 (5%)
Respiratory System
Cough increase	5 (3%)	11 (6%)	6 (3%)	4 (2%)	26 (4%)
Pharyngitis	6 (3%)	7 (4%)	6 (3%)	9 (5%)	28 (4%)
Rhinitis	27 (15%)	16 (9%)	15 (8%)	21 (12%)	79 (11%)
Skin and Appendages
Sweat	23 (13%)	21 (12%)	20 (11%)	23 (13%)	87 (12%)
Special Senses
Runny eyes	13 (7%)	9 (5%)	6 (3%)	6 (3%)	34 (5%)

Adverse Events – Post-marketing Experience with SUBOXONE Sublingual Tablets

The most frequently reported post-marketing adverse event not observed in clinical trials was peripheral edema.

Drug Interactions

Cytochrome P-450 3A4 (CYP3A4) Inhibitors and Inducers

Buprenorphine is metabolized to norbuprenorphine primarily by cytochrome CYP3A4; therefore, potential interactions may occur when SUBOXONE sublingual film is given concurrently with agents that affect CYP3A4 activity. The concomitant use of SUBOXONE sublingual film with CYP3A4 inhibitors (e.g., azole antifungals such as ketoconazole, macrolide antibiotics such as erythromycin, and HIV protease inhibitors) should be monitored and may require dose-reduction of one or both agents.

The interaction of buprenorphine with CYP3A4 inducers has not been studied; therefore, it is recommended that patients receiving SUBOXONE sublingual film be monitored for signs and symptoms of opioid withdrawal if inducers of CYP3A4 (e.g., efavirenz, phenobarbital, carbamazepine, phenytoin, rifampicin) are co-administered [see Clinical Pharmacology (12.3)].

Antiretrovirals

Three classes of antiretroviral agents have been evaluated for CYP3A4 interactions with buprenorphine. Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine and etravirine are known CYP3A inducers whereas delaviridine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects. It is recommended that patients who are on chronic buprenorphine treatment have their dose monitored if NNRTIs are added to their treatment regimen. Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine and patients in one study reported increased sedation. Symptoms of opioid excess have been found in post-marketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly. Monitoring of patients taking buprenorphine and atazanavir with and without ritonavir is recommended, and dose reduction of buprenorphine may be warranted.

Benzodiazepines

There have been a number of post-marketing reports regarding coma and death associated with the concomitant use of buprenorphine and benzodiazepines. In many, but not all, of these cases, buprenorphine was misused by self-injection. Preclinical studies have shown that the combination of benzodiazepines and buprenorphine altered the usual ceiling effect on buprenorphine-induced respiratory depression, making the respiratory effects of buprenorphine appear similar to those of full opioid agonists. SUBOXONE sublingual film should be prescribed with caution to patients taking benzodiazepines or other drugs that act on the CNS, regardless of whether these drugs are taken on the advice of a physician or are being abused/misused. Patients should be warned that it is extremely dangerous to self-administer non-prescribed benzodiazepines while taking SUBOXONE sublingual film, and should also be cautioned to use benzodiazepines concurrently with SUBOXONE sublingual film only as directed by their physician.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C.

There are no adequate and well-controlled studies of SUBOXONE sublingual film or buprenorphine/naloxone in pregnant women. SUBOXONE sublingual film should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Teratogenic Effects:

Effects on embryo-fetal development were studied in Sprague-Dawley rats and Russian white rabbits following oral (1:1) and intramuscular (IM) (3:2) administration of mixtures of buprenorphine and naloxone. Following oral administration to rats and rabbits, no teratogenic effects were observed at buprenorphine doses up to 250 mg/kg/day and 40 mg/kg/day, respectively (estimated exposure approximately 150 times and 50 times, respectively, the recommended human daily sublingual dose of 16 mg on a mg/m2 basis). No definitive drug-related teratogenic effects were observed in rats and rabbits at IM doses up to 30 mg/kg/day (estimated exposure approximately 20 times and 35 times, respectively, the recommended human daily dose of 16 mg on a mg/m2 basis). Acephalus was observed in one rabbit fetus from the low-dose group and omphalocele was observed in two rabbit fetuses from the same litter in the mid-dose group; no findings were observed in fetuses from the high-dose group. Following oral administration of buprenorphine to rats, dose-related post-implantation losses, evidenced by increases in the numbers of early resorptions with consequent reductions in the numbers of fetuses, were observed at doses of 10 mg/kg/day or greater (estimated exposure approximately 6 times the recommended human daily sublingual dose of 16 mg on a mg/m2 basis). In the rabbit, increased post-implantation losses occurred at an oral dose of 40 mg/kg/day. Following IM administration in the rat and the rabbit, post-implantation losses, as evidenced by decreases in live fetuses and increases in resorptions, occurred at 30 mg/kg/day.

Buprenorphine was not teratogenic in rats or rabbits after IM or subcutaneous (SC) doses up to 5 mg/kg/day (estimated exposure was approximately 3 and 6 times, respectively, the recommended human daily sublingual dose of 16 mg on a mg/m2 basis), after IV doses up to 0.8 mg/kg/day (estimated exposure was approximately 0.5 times and equal to, respectively, the recommended human daily sublingual dose of 16 mg on a mg/m2 basis), or after oral doses up to 160 mg/kg/day in rats (estimated exposure was approximately 95 times the recommended human daily sublingual dose of 16 mg on a mg/m2 basis) and 25 mg/kg/day in rabbits (estimated exposure was approximately 30 times the recommended human daily sublingual dose of 16 mg on a mg/m2 basis). Significant increases in skeletal abnormalities (e.g., extra thoracic vertebra or thoraco-lumbar ribs) were noted in rats after SC administration of 1 mg/kg/day and up (estimated exposure was approximately 0.6 times the recommended human daily sublingual dose of 16 mg on a mg/m2 basis), but were not observed at oral doses up to 160 mg/kg/day. Increases in skeletal abnormalities in rabbits after IM administration of 5 mg/kg/day (estimated exposure was approximately 6 times the recommended human daily sublingual dose of 16 mg on a mg/m2 basis) or oral administration of 1 mg/kg/day or greater (estimated exposure was approximately equal to the recommended human daily sublingual dose of 16 mg on a mg/m2 basis) were not statistically significant.

In rabbits, buprenorphine produced statistically significant pre-implantation losses at oral doses of 1 mg/kg/day or greater and post-implantation losses that were statistically significant at IV doses of 0.2 mg/kg/day or greater (estimated exposure approximately 0.3 times the recommended human daily sublingual dose of 16 mg on a mg/m2 basis).

Non-teratogenic Effects:

Dystocia was noted in pregnant rats treated intramuscularly with buprenorphine 5 mg/kg/day (approximately 3 times the recommended human daily sublingual dose of 16 mg on a mg/m2 basis). Fertility, peri-, and post-natal development studies with buprenorphine in rats indicated increases in neonatal mortality after oral doses of 0.8 mg/kg/day and up (approximately 0.5 times the recommended human daily sublingual dose of 16 mg on a mg/m2 basis), after IM doses of 0.5 mg/kg/day and up (approximately 0.3 times the recommended human daily sublingual dose of 16 mg on a mg/m2 basis), and after SC doses of 0.1 mg/kg/day and up (approximately 0.06 times the recommended human daily sublingual dose of 16 mg on a mg/m2 basis). Delays in the occurrence of righting reflex and startle response were noted in rat pups at an oral dose of 80 mg/kg/day (approximately 50 times the recommended human daily sublingual dose of 16 mg on a mg/m2 basis).

Nursing Mothers

Buprenorphine passes into breast milk. Breast-feeding is not advised in mothers treated with buprenorphine products.

An apparent lack of milk production during general reproduction studies with buprenorphine in rats caused decreased viability and lactation indices.

Pediatric Use

The safety and effectiveness of SUBOXONE sublingual film have not been established in pediatric patients.

Geriatric Use

Clinical studies of SUBOXONE sublingual film, SUBOXONE (buprenorphine and naloxone) sublingual tablets, or SUBUTEX (buprenorphine) sublingual tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently than 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.

Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone is unknown. Since both drugs are extensive

Staticin

erythromycin

Dosage Form: Topical Solution 1.5%

For Dermatologic Use Only. Not for Ophthalmic Use.

Staticin Description

Staticin® (erythromycin topical solution) 1.5% contains erythromycin for topical dermatologic use. Erythromycin is a macrolide antibiotic produced from a strain of Saccaropolyspora erythraea (formerly Streptomyces erythreus). It is a base and readily forms salts with acids.

Chemically, erythromycin is C37H67NO13. It has the following structural formula:

Erythromycin has the molecular weight of 733.94. It is a white to grayish white or pale yellow crystalline powder.

Each mL of Staticin contains 15 milligrams of erythromycin in a base of 55% alcohol, fragrance, laureth-4, and propylene glycol.

Staticin - Clinical Pharmacology

The exact mechanism by which erythromycin reduces lesions of acne vulgaris is not fully known; however, the effect appears to be due in part to the antibacterial activity of the drug.

MICROBIOLOGY

Erythromycin acts by inhibition of protein synthesis in susceptible organisms by reversibly binding to 50 S ribosomal subunits, thereby inhibiting translocation of aminoacyl transfer-RNA and inhibiting polypeptide synthesis. Antagonism has been demonstrated in vitro between erythromycin, and lincomycin, chloramphenicol, and clindamycin.

Indications and Usage for Staticin

Staticin is indicated for the topical treatment of acne vulgaris.

Contraindications

Staticin is contraindicated in those individuals who have shown hypersensitivity to any of its components.

Warnings

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including erythromycin, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of “antibiotic-associated colitis.”

After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation and treatment with an antibacterial drug clinically effective against C. difficile colitis.

Precautions

General

For topical use only; not for ophthalmic use. Concomitant topical acne therapy should be used with caution because a possible cumulative irritancy effect may occur, especially with the use of peeling, desquamating, or abrasive agents.

The use of antibiotic agents may be associated with the overgrowth of antibiotic-resistant organisms. If this occurs, discontinue use and take appropriate measures.

Avoid contact with eyes and all mucous membranes.

Information for Patients

Patients using Staticin should receive the following information and instructions:

1. This medication is to be used as directed by the physician. It is for external use only. Avoid contact with the eyes, nose, mouth, and all mucous membranes.


2. This medication should not be used for any disorder other than that for which it was prescribed.


3. Patients should not use any other topical acne medication unless otherwise directed by their physician.


4. Patients should report to their physician any signs of local adverse reactions.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No animal studies have been performed to evaluate the carcinogenic and mutagenic potential or effects on fertility of topical erythromycin. However, long-term (2-year) oral studies in rats with erythromycin ethylsuccinate and erythromycin base did not provide evidence of tumorigenicity. There was no apparent effect on male or female fertility in rats fed erythromycin (base) at levels up to 0.25% of diet.

Pregnancy

Teratogenic Effects: Pregnancy Category B

There was no evidence of teratogenicity or any other adverse effect on reproduction in female rats fed erythromycin base (up to 0.25% diet) prior to and during mating, during gestation and through weaning of two successive litters.

There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used in pregnancy only if clearly needed. Erythromycin has been reported to cross the placental barrier in humans, but fetal plasma levels are generally low.

Nursing Women

It is not known whether erythromycin is excreted in human milk after topical application. However, erythromycin is excreted in human milk following oral and parenteral erythromycin administration. Therefore, caution should be exercised when erythromycin is administered to a nursing woman.

Pediatric Use

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

Geriatric Use

Clinical studies of erythromycin topical solution for the treatment of acne vulgaris did not include subjects 65 years of age and older. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Adverse Reactions

In controlled clinical trials, the total incidence of adverse reactions associated with the use of Staticin was approximately 13%. These were dryness (7%), oiliness (2%), pruritus (2%), tenderness (2%), desquamation (2%), erythema (1%) and irritation (1%).

The following additional adverse reactions have been reported occasionally: peeling, generalized urticarial reactions and itching.

Staticin Dosage and Administration

Staticin Solution should be applied over the affected area twice a day after the skin is thoroughly washed with warm water and soap and patted dry. Acne lesions on the face, neck, shoulder, chest, and back may be treated in this manner.

This medication should be applied with applicator top. If fingertips are used, wash hands after application. Drying and peeling may be controlled by reducing the frequency of applications.

How is Staticin Supplied

Staticin® (erythromycin topical solution) 1.5% is available in a 60 mL plastic bottle with optional applicator, NDC 0072-8000-60, NSN 6505-01-118-6098.

STORAGE

Store between 15°C and 25°C (59°F and 77°F).

Westwood-Squibb Pharmaceuticals, Inc.

A Bristol-Myers Squibb Company

Princeton, NJ 08543 USA

Staticin  erythromycin  solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0072-8000 Route of Administration TOPICAL DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength erythromycin (erythromycin) Active 15 MILLIGRAM  In 1 MILLILITER alcohol Inactive   fragrance Inactive   laureth-4 Inactive   propylene glycol Inactive

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0072-8000-60 60 mL (MILLILITER) In 1 BOTTLE, WITH APPLICATOR None

Revised: 07/2006Bristol-Myers Squibb Company

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