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Preservative-free DURAMORPH (morphine sulfate injection, USP) is a sterile, nonpyrogenic, isobaric solution of morphine sulfate, free of antioxidants, preservatives

or other potentially neurotoxic additives and is intended for intravenous, epidural or intrathecal administration as a narcotic analgesic. Each milliliter contains morphine sulfate 0.5 mg or 1 mg and sodium chloride 9 mg in Water for Injection. pH range is 2.5-6.5. Each 10 mL DOSETTE ampul of DURAMORPH (morphine injection) is intended for SINGLE USE ONLY. Discard any unused portion. DO NOT HEAT-STERILIZE. Avinza

Pharmacokinetics
Absorption

AVINZA consists of two components, an immediate release component and an extended-release component. The oral bioavailability of morphine is less than 40% and shows large inter-individual variability due to extensive pre-systemic metabolism. Following single-dose oral administration of a 60 mg dose of AVINZA under fasting conditions, morphine concentrations of approximately 3 to 6 ng/ml were achieved within 30 minutes after dosing and maintained for the 24-hour dosing interval. The pharmacokinetics of AVINZA were shown to be dose-proportional over a single oral dose range of 30 to 120 mg in healthy volunteers and a multiple oral dose range of at least 30 to 180 mg in patients with chronic moderate to severe pain. Food Effect: When a 60 mg dose of AVINZA was administered immediately following a high fat meal, peak morphine concentrations and AUC values were similar to those observed when the dose of AVINZA was administered in a fasting state, although achievement of initial concentrations was delayed by approximately 1 hour under fed conditions. Therefore, AVINZA can be administered without regard to food. When the contents of AVINZA were administered by sprinkling on applesauce, the rate and extent of morphine absorption were found to be bioequivalent to the same dose when administered as an intact capsule. Steady State: Steady-state plasma concentrations of morphine are achieved 2 to 3 days after initiation of once-daily administration of AVINZA. AVINZA 60mg Capsules (once daily) and 10 mg morphine oral solution (6 times daily) were equally bioavailable. Graph 1: Mean Steady-State Plasma Morphine Concentrations Following Once Daily Administration of AVINZA (morphine sulfate) Capsules or 6-Times Daily Administration of Morphine Solution

A once-daily dose of AVINZA provided similar Cmax, Cmin, and AUC values and peak-trough fluctuations (% FL, Cmax-Cmin/Cav) compared to 6-times daily administration of the same total daily dose of morphine oral solution (Table 1). Table 1 : Pharmacokinetic Data Mean SD Parameter AUC (ng/mlh) Cmax (ng/ml) Cmin (ng/ml) % FL
Distribution

AVINZA Capsules Once-Daily 273.25 81.24 18.65 7.13 6.98 2.44 106.38 78.14

Morphine Oral Solution 6-Times Daily 279.11 63.00 19.96 4.82 6.61 2.15 116.22 26.67

Once absorbed, morphine is distributed to skeletal muscle, kidneys, liver, intestinal tract, lungs, spleen and brain. Although the primary site of action is the CNS, only small quantities cross the blood-brain barrier. Morphine also crosses the placental membranes and has been found in breast milk [see Use In Specific Populations]. The volume of distribution of morphine is approximately 1 to 6 L/kg, and morphine is 20 to 35% reversibly bound to plasma proteins.
Metabolism

The major pathways of morphine metabolism include glucuronidation to produce metabolites including morphine-3-glucuronide, M3G (about 50%) and morphine-6-glucuronide, M6G (about 5 to 15%) and sulfation in the liver to produce morphine-3-etheral sulfate. A small fraction (less than 5%) of morphine is demethylated. M6G has been shown to have analgesic activity but crosses the blood-brain barrier poorly, while M3G has no significant analgesic activity.
Excretion

Approximately 10% of a morphine dose is excreted unchanged in the urine. Elimination of morphine is primarily via hepatic metabolism to glucuronide metabolites M3G and M6G which are then renally excreted. A small amount of the glucuronide metabolites is excreted in the bile and there is some minor enterohepatic recycling. Seven to 10% of administered morphine is excreted in the feces. The mean adult plasma clearance of morphine is about 20 30 mL/minute/kg. The effective terminal half life of morphine after IV administration is reported to be approximately 2 hours. The terminal elimination half-life of morphine following single dose of AVINZA administration is approximately 24 hrs. Special Populations
Geriatric Patients

The pharmacokinetics of AVINZA have not been studied in elderly patients.


Pediatric Patients

The pharmacokinetics of AVINZA have not been studied in pediatric patients below the age of 18. The range of dose strengths available may not be appropriate for treatment of very young pediatric patients. Sprinkling on applesauce is NOT a suitable alternative for these patients.
Gender

A gender analysis of pharmacokinetic data from healthy subjects taking AVINZA indicated that morphine concentrations were similar in males and females.
Race

Chinese subjects given intravenous morphine had a higher clearance when compared to Caucasian subjects (1852 +/-116 ml/min compared to 1495 +/- 80 ml/min).
Hepatic Impairment

Morphine pharmacokinetics are altered in individuals with cirrhosis. Clearance was found to decrease with a corresponding increase in half-life. The M3G and M6G to morphine plasma AUC ratios also decreased in these subjects, indicating diminished metabolic activity. Adequate studies of the pharmacokinetics of morphine in patients with severe hepatic impairment have not been conducted.
Renal Impairment

Morphine pharmacokinetics are altered in patients with renal failure. The AUC is increased and clearance is decreased and the metabolites, M3G and M6G, may accumulate to much higher plasma levels in patients with renal failure as compared to patients with normal renal function. Adequate studies of the pharmacokinetics of morphine in patients with severe renal impairment have not been conducted. Drug Interaction/Alcohol Interaction In in vitro studies of the dissolution of AVINZA 30 mg mixed with 900 mL of buffer solutions containing ethanol (20% and 40%), the amount of morphine released increased in an alcohol concentration-dependent manner. While the relevance of in vitro lab tests regarding AVINZA to the clinical setting remains to be determined, this acceleration of release may correlate with in vivo rapid release of the total morphine dose, which could result in the absorption of a potentially fatal dose of morphine. Clinical Studies AVINZA was studied in a double-blind, placebo-controlled, fixed-dose, parallel group trial in 295 patients with moderate to severe pain due to osteoarthritis. These patients had either a prior sub-optimal response to acetaminophen, NSAID therapy, or previously received intermittent opioid analgesic therapy. Thirty-milligrams AVINZA capsules administered once-daily, either in the morning or the evening, were more effective than placebo in reducing pain.

Table 2 : Change from Baseline in WOMAC OA Index Pain VAS Subscale Score Overall Placebo AVINZA QAM AVINZA QPM LS Mean -36.23 -75.26a -75.39a Std. Error 11.482 11.305 11.747 a P < 0.05; REPEATED MEASURES ANALYSIS This study was not designed to assess the effects of AVINZA on the course of the osteoarthritis. Last reviewed on RxList: 7/25/2012 This monograph has been modified to include the generic and brand name in many instances.
PATIENT INFORMATION

Medication Guide AVINZA (ah-ven-zah) (morphine sulfate extended-release) Capsules AVINZA is:

A strong prescription pain medicine that contains an opioid (narcotic) that is used to treat moderate to severe around-the-clock pain.

Important information about AVINZA:


Get emergency help right away if you take too much AVINZA (overdose). AVINZA overdose can cause life threatening breathing problems that can lead to death. Never give anyone else your AVINZA. They could die from taking it. Store AVINZA away from children and in a safe place to prevent stealing or abuse. Selling or giving away AVINZA is against the law.

Do not take AVINZA if you have:


severe asthma, trouble breathing, or other lung problems. a bowel blockage or have narrowing of the stomach or intestines.

Before taking AVINZA, tell your healthcare provider if you have a history of:

head injury, seizures liver, kidney, thyroid problems problems urinating pancreas or gallbladder problems abuse of street or prescription drugs, alcohol addiction, or mental health problems.

Tell your healthcare provider if you are:


pregnant or planning to become pregnant. AVINZA may harm your unborn baby. breastfeeding. AVINZA passes into breast milk and may harm your baby. taking prescription or over-the-counter medicines, vitamins, or herbal supplements.

When taking AVINZA:


Do not change your dose. Take AVINZA exactly as prescribed by your healthcare provider. Take 1 dose once a day at the same time every day. Do not take more than 1 dose in 24 hours. If you miss a dose, do not take AVINZA. Take your next dose at your usual time the next day. Swallow AVINZA whole. Do not cut, break, chew, crush, dissolve, or inject AVINZA. If you cannot swallow AVINZA capsules, see the detailed Instructions for Use. Call your healthcare provider if the dose you are taking does not control your pain. Do not stop taking AVINZA without talking to your healthcare provider. After you stop taking AVINZA, flush any unused capsules down the toilet.

While taking AVINZA Do Not:


Drive or operate heavy machinery, until you know how AVINZA affects you. AVINZA can make you sleepy, dizzy, or lightheaded. Drink alcohol or use prescription or over-the-counter medicines that contain alcohol.

The possible side effects of AVINZA are:

constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe.

Get emergency medical help if you have:

trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue or throat, extreme drowsiness, or you are feeling faint.

These are not all the possible side effects of AVINZA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov This Medication Guide has been approved by the U.S. Food and Drug Administration.Issue: July 2012 Last reviewed on RxList: 7/25/2012 This monograph has been modified to include the generic and brand name in many instances.
Avinza Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is

safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs. MORPHINE EXTENDED-RELEASE CAPSULE - ORAL (MORE-feen) COMMON BRAND NAME(S): Avinza WARNING: Morphine has a high risk for abuse and severe, possibly fatal, breathing problems. The risk for harm is higher if you take the wrong dose/strength, or if you take it along with other drugs that might also affect breathing. Be sure you know how to take morphine and what other drugs you should avoid taking with it. Get immediate medical help if you notice unusual slow/shallow breathing. Do not crush, chew, or dissolve this medication or the contents of the capsules. Also, do not drink alcohol or use any product that contains alcohol while taking this medication. Drinking alcohol with this medication or taking crushed, chewed, or dissolved forms of extended-release morphine could cause overdose. Keep this medicine in a safe place to prevent theft, misuse, or abuse. If a child accidentally swallows this drug, get emergency medical help right away. USES: See also Warning section. This medication is used to help relieve moderate to severe ongoing pain (such as due to cancer). Morphine belongs to a class of drugs known as narcotic (opiate) analgesics. It works in the brain to change how your body feels and responds to pain. The higher strengths of this drug (more than 30 milligrams per capsule) should be used only if you have been regularly taking moderate to large amounts of narcotic pain medication. These strengths may cause overdose (even death) if taken by a person who has not been regularly taking narcotic medication. Do not use the extended-release form of morphine to relieve pain that is mild or that will go away in a few days. This medication is not for occasional ("as needed") use. HOW TO USE: Take this medication on a regular schedule as directed by your doctor, not as needed for sudden (breakthrough) pain. Take this drug with or without food, usually once daily (every 24 hours). If you have nausea, it may help to take this drug with food. Ask your doctor or pharmacist about other ways to decrease nausea (such as lying down for 1 to 2 hours with as little head movement as possible). Swallow the capsules whole. Adults who have trouble swallowing the capsule may open the capsule and carefully sprinkle its contents on a spoonful of soft, cool applesauce. Swallow all of

the drug/food mixture immediately without chewing. Then rinse your mouth and swallow the rinse liquid to make sure that you have swallowed all of the dose. Do not chew the mixture or prepare a supply in advance. Do not give this medication to a child this way, since they might chew the mixture and overdose. For children who have trouble swallowing the capsule, ask the doctor about using a different form of morphine instead. The dosage is based on your medical condition and response to treatment. Do not increase your dose, take the medication more frequently, or take it for a longer time than prescribed. Properly stop the medication when so directed. The maximum recommended dose of this medication is 1600 milligrams per 24-hour period. Taking more than the maximum dose might increase the risk of damage to your kidneys from an ingredient in this medication (fumaric acid). Before you start taking this medication, ask your doctor or pharmacist if you should stop or change the dose of your other narcotic medication(s). For added pain relief, your doctor may direct you to also take quick-acting narcotic or non-narcotic pain medications (such as acetaminophen, ibuprofen). Ask your doctor or pharmacist if you have any questions about using morphine safely with other drugs. This medication may cause withdrawal reactions, especially if it has been used regularly for a long time or in high doses. In such cases, withdrawal symptoms (such as restlessness, watering eyes, runny nose, nausea, sweating, muscle aches) may occur if you suddenly stop using this medication. To prevent withdrawal reactions, your doctor may reduce your dose gradually. Ask your doctor or pharmacist for more details, and report any withdrawal reactions immediately. When this medication is used for a long time, it may not work as well. Talk with your doctor if this medication stops working well. Along with its benefits, this medication may rarely cause abnormal drug-seeking behavior (addiction). This risk may be increased if you have abused alcohol or drugs in the past. Take this medication exactly as prescribed to lessen the risk of addiction. Tell your doctor if your pain persists or worsens.
Avinza Consumer (continued) SIDE EFFECTS: Nausea, vomiting, constipation, lightheadedness, dizziness, or drowsiness may occur. Some of these side effects may decrease after you have been using this medication for a while. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

To prevent constipation, eat a diet adequate in fiber, drink plenty of water, and exercise. Ask your pharmacist for help in selecting a laxative (such as a stimulant type with stool softener). To reduce the risk of dizziness and lightheadedness, get up slowly when rising from a sitting or lying position.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects. Tell your doctor immediately if any of these unlikely but serious side effects occur: mental/mood changes (such as agitation, confusion, hallucinations), severe stomach/abdominal pain, difficulty urinating. Seek immediate medical attention if any of these rare but serious side effects occur: fainting, seizure, slow/shallow breathing, unusual drowsiness/difficulty waking up. A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing. This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist. PRECAUTIONS: Before taking morphine, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details. Before using this medication, tell your doctor or pharmacist your medical history, especially of: brain disorders (such as head injury, tumor, seizures), breathing problems (such as asthma, sleep apnea, chronic obstructive pulmonary disease-COPD), kidney disease, liver disease, mental/mood disorders (such as confusion, depression), personal or family history of regular use/abuse of drugs/alcohol, stomach/intestinal problems (such as blockage, constipation, diarrhea due to infection, paralytic ileus), difficulty urinating (such as due to enlarged prostate). This drug may make you dizzy or drowsy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely. Avoid alcoholic beverages. Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products). Older adults may be more sensitive to the effects of this drug, especially dizziness, drowsiness, or urinary problems. Before using this medication, women of childbearing age should talk with their doctor(s) about the risks and benefits. Tell your doctor if you are pregnant or if you plan to become pregnant. During pregnancy, this medication should be used only when clearly needed. It may slightly increase the risk of birth defects if used during the first two months of pregnancy. Also, using it for a long time or in high doses near the expected delivery date may harm the unborn baby. To lessen the risk, take the smallest effective dose for the shortest possible time. Tell the doctor right

away if you notice any symptoms in your newborn baby such as slow/shallow breathing, irritability, abnormal/persistent crying, vomiting, or diarrhea. This drug passes into breast milk and may rarely have undesirable effects on a nursing infant. Tell the doctor immediately if your baby develops unusual sleepiness, difficulty feeding, or trouble breathing. Consult your doctor before breast-feeding DRUG INTERACTIONS: The effects of some drugs can change if you take other drugs or herbal products at the same time. This can increase your risk for serious side effects or may cause your medications not to work correctly. These drug interactions are possible, but do not always occur. Your doctor or pharmacist can often prevent or manage interactions by changing how you use your medications or by close monitoring. To help your doctor and pharmacist give you the best care, be sure to tell your doctor and pharmacist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products) before starting treatment with this product. While using this product, do not start, stop, or change the dosage of any other medicines you are using without your doctor's approval. Some products that may interact with this drug include: products that contain alcohol (such as cough-and-cold syrups), certain pain medications (mixed narcotic agonist-antagonists such as pentazocine, nalbuphine, butorphanol), narcotic antagonists (such as naltrexone). Other medications can affect how morphine works and your risk for side effects. Examples include cimetidine, quinidine, rifampin, among others. The risk of serious side effects (such as slow/shallow breathing, severe drowsiness/dizziness) may be increased if this medication is taken with other products that may also affect breathing or cause drowsiness. Therefore, tell your doctor or pharmacist if you are taking other products such as allergy or cough-and-cold products, anti-seizure drugs (such as phenobarbital), medicine for sleep or anxiety (such as alprazolam, diazepam, zolpidem), muscle relaxants, other narcotic pain relievers (such as codeine), and psychiatric medicines (such as risperidone, amitriptyline, trazodone). Your medications or doses of your medications may need to be changed. This medication may interfere with certain laboratory tests, possibly causing false test results. Make sure laboratory personnel and all your doctors know you use this drug. This document does not contain all possible drug interactions. Keep a list of all the products you use. Share this list with your doctor and pharmacist to lessen your risk for serious medication problems. OVERDOSE: If overdose is suspected, contact a poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: slow breathing, slow heartbeat, loss of consciousness.

NOTES: Do not share this medication with others. It is against the law. This medication has been prescribed for your current condition only. Do not use it later for another condition unless told to do so by your doctor. A different medication may be necessary in that case. MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up. STORAGE: Store at room temperature between 59-86 degrees F (15-30 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medications away from children and pets. Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product. Information last revised September 2011. Copyright(c) 2011 First Databank, Inc. MS Contin (morphine sulfate) belongs to the group of drugs called narcotic pain relievers. MS Contin (morphine sulfate) is the generic form of Morphine and is prescribed to treat moderate to severe pain. The most common side effects of MS Contin (morphine sulfate) are constipation, lightheadedness, dizziness, sedation, nausea, vomiting, sweating, dysphoria, and euphoria. Drug interactions and warnings include: avoiding concomitant use of other central nervous system depressants including sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers, and alcohol as these may produce additive depressant effects. MS Contin (morphine sulfate)should be used in pregnant women only if the need MS Contin (morphine sulfate) clearly outweighs the potential risk to the fetus. Ordinarily, nursing should not be undertaken while a patient is receiving MS Contin (morphine sulfate) since morphine may be excreted in the milk. This medication may cause withdrawal reactions. Our MS Contin (morphine sulfate) Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication. 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.
MS-Contin in Detail - Patient Information: 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. Call your doctor at once if you have any of these serious side effects:

shallow breathing, slow heartbeat; seizure (convulsions); cold, clammy skin; confusion; severe weakness or dizziness; or feeling light-headed, fainting.

Less serious side effects are more likely to occur, such as:

constipation; warmth, tingling, or redness under your skin; nausea, vomiting, stomach pain, diarrhea, loss of appetite; dizziness, headache, anxiety; memory problems; or sleep problems (insomnia).

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088. Read the entire detailed patient monograph for MS-Contin (Morphine Sulfate ControlledRelease)
MS-Contin Overview - Patient Information: Side Effects SIDE EFFECTS: Nausea, vomiting, constipation, lightheadedness, dizziness, or drowsiness may occur. Some of these side effects may decrease after you have been using this medication for a while. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

To prevent constipation, eat a diet adequate in fiber, drink plenty of water, and exercise. Ask your pharmacist for help in selecting a laxative (such as a stimulant type with stool softener). To reduce the risk of dizziness and lightheadedness, get up slowly when rising from a sitting or lying position. Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects. Tell your doctor immediately if any of these unlikely but serious side effects occur: mental/mood changes (such as agitation, confusion, hallucinations), severe stomach/abdominal pain, difficulty urinating. Seek immediate medical attention if any of these rare but serious side effects occur: fainting, seizure, slow/shallow breathing, unusual drowsiness/difficulty waking up.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing. This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist. In the US Call your doctor for medical advice about side effects. You may report side effects to FDA at 1800-FDA-1088. In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345. Read the entire patient information overview for MS-Contin (Morphine Sulfate ControlledRelease)
MS-Contin FDA Prescribing Information: Side Effects (Adverse Reactions) SIDE EFFECTS

The following adverse reactions described elsewhere in the labeling include:


Respiratory Depression [see WARNINGS AND PRECAUTIONS] Chronic Pulmonary Disease [see WARNINGS AND PRECAUTIONS] Head Injuries and Increased Intracranial Pressure [see WARNINGS AND PRECAUTIONS] Interactions with Other CNS Depressants [see WARNINGS AND PRECAUTIONS] Hypotensive Effect [see WARNINGS AND PRECAUTIONS] Gastrointestinal Effects [see WARNINGS AND PRECAUTIONS] Seizures [see WARNINGS AND PRECAUTIONS]

Clinical Trial Experience 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. MS CONTIN may increase the risk of serious adverse reactions such as those observed with other opioid analgesics, including respiratory depression, apnea, respiratory arrest, circulatory depression, hypotension, or shock [see OVERDOSAGE].
Most Frequently Observed Reactions

In clinical trials, the most common adverse reactions with MS Contin were constipation, dizziness, sedation, nausea, vomiting, sweating, dysphoria, and euphoric mood.

Some of these effects seem to be more prominent in ambulatory patients and in those not experiencing severe pain.
Less Frequently Observed Reactions

Cardiovascular disorders: tachycardia, bradycardia, palpitations Eye disorders: visual impairment, vision blurred, diplopia, miosis Gastrointestinal disorders: dry mouth, diarrhea, abdominal pain, constipation, dyspepsia General disorders and administration site conditions: chills, feeling abnormal, edema, edema peripheral, weakness Hepatobiliary disorders: biliary colic Metabolism and nutrition disorders: anorexia Musculoskeletal and connective tissue disorders: muscle rigidity, muscle twitching Nervous system disorders: presyncope, syncope, headache, tremor, uncoordinated muscle movements, convulsion, intracranial pressure increased, taste alteration, paresthesia, nystagmus Psychiatric disorders: agitation, mood altered, anxiety, depression, abnormal dreams, hallucination, disorientation, insomnia Renal and urinary disorders: urinary retention, urinary hesitation, antidiuretic effects Reproductive system and breast disorders: reduced libido and/or potency Respiratory, thoracic and mediastinal disorders: laryngospasm Skin and subcutaneous tissue disorders: pruritus, urticaria, rash Vascular disorders: flushing, hypotension, hypertension Post-Marketing Experience The following adverse reactions have been identified during postapproval use of MS CONTIN: amenorrhea, asthenia, bronchospasm, confusional state, drug hypersensitivity, fatigue, hyperalgesia, hypertonia, ileus, increased hepatic enzymes, intestinal obstruction, lethargy, malaise, pulmonary edema, thinking disturbances, somnolence, and vertigo. Anaphylaxis has been reported with ingredients contained in MS CONTIN. Advise patients how to recognize such a reaction and when to seek medical attention.

Read the entire FDA prescribing information for MS-Contin (Morphine Sulfate ControlledRelease) MS CONTIN tablets are for oral use and contain morphine sulfate, an agonist at the mu-opioid receptor. Each tablet contains the following inactive ingredients common to all strengths: cetostearyl alcohol, hydroxyethyl cellulose, hypromellose, magnesium stearate, polyethylene glycol, talc and titanium dioxide. The tablet strengths describe the amount of morphine per tablet as the pentahydrated sulfate salt (morphine sulfate). The 15 mg tablets also contain: FD&C Blue No. 2, lactose, polysorbate 80 The 30 mg tablets also contain: D&C Red No. 7, FD&C Blue No. 1, lactose, polysorbate 80 The 60 mg tablets also contain: D&C Red No. 30, D&C Yellow No. 10, hydroxypropyl cellulose, lactose The 100 mg tablets also contain: black iron oxide The 200 mg tablets also contain: D&C Yellow No. 10, FD&C Blue No. 1, hydroxypropyl cellulose Morphine sulfate is an odorless, white, crystalline powder with a bitter taste. It has a solubility of 1 in 21 parts of water and 1 in 1000 parts of alcohol, but is practically insoluble in chloroform or ether. The octanol: water partition coefficient of morphine is 1.42 at physiologic pH and the pKb is 7.9 for the tertiary nitrogen (mostly ionized at pH 7.4). Its structural formula is:

What are the possible side effects of morphine?

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. Call your doctor at once if you have any of these serious side effects:

shallow breathing, slow heartbeat; seizure (convulsions); cold, clammy skin; confusion; severe weakness or dizziness; or feeling light-headed, fainting.

Less serious side effects are more likely to occur, such as:

constipation; warmth, tingling, or redness under your...

Read All Potential Side Effects and See Pictures of MS-Contin


What are the precautions when taking morphine sulfate controlled-release (MS-Contin)?

Before taking morphine, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details. Before using this medication, tell your doctor or pharmacist your medical history, especially of: brain disorders (such as head injury, tumor, seizures), breathing problems (such as asthma, sleep apnea, chronic obstructive pulmonary disease-COPD), kidney disease, liver disease, mental/mood disorders (such as confusion, depression), personal or family history of regular use/abuse of drugs/alcohol, stomach/intestinal problems (such as blockage, constipation, diarrhea due to infection, paralytic ileus), difficulty urinating... Read All Potential Precautions of MS-Contin Last reviewed on RxList: 7/23/2012 This monograph has been modified to include the generic and brand name in many instances.
INDICATIONS

MS CONTIN is indicated for the management of moderate to severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time. Limitations of Use

MS CONTIN is not for use:


As an as-needed (prn) analgesic. For pain that is mild or not expected to persist for an extended period of time For acute pain In the immediate postoperative period (the first 24 hours following surgery) for patients not previously taking the drug, because its safety in this setting has not been established. For postoperative pain unless the patient is already receiving chronic opioid therapy prior to surgery or if the postoperative pain is expected to be moderate to severe and persist for an extended period of time.

MS CONTIN 100 mg and 200 mg tablets are only for patients in whom tolerance to an opioid of comparable potency is established. Patients considered opioid-tolerant are those taking at least 60 mg of morphine daily, at least 30 mg of oral oxycodone daily, at least 8 mg of oral hydromorphone daily, or an equianalgesic dose of another opioid for a week or longer.
DOSAGE AND ADMINISTRATION

Initial Dosing Initiate the dosing regimen for each patient individually, taking into account the patient's prior analgesic treatment experience. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with MS CONTIN [see WARNINGS AND PRECAUTIONS]. Consider the following factors when selecting an initial dose of MS CONTIN:

Total daily dose, potency, and any prior opioid the patient has been taking previously; Reliability of the relative potency estimate used to calculate the equivalent dose of morphine needed (Note: potency estimates may vary with the route of administration); Patient's degree of opioid experience and opioid tolerance; General condition and medical status of the patient; Concurrent medication; Type and severity of the patient's pain.

MS Contin is administered at a frequency of twice daily (every 12 hours) or three times daily (every 8 hours).
Use of MS Contin as the First Opioid Analgesic

There has been no systematic evaluation of MS CONTIN as an initial opioid analgesic in the management of pain. Because it may be more difficult to titrate a patient using controlled-release morphine, it is ordinarily advisable to begin treatment using an immediate-release formulation.
Conversion from Other Oral Morphine to MS CONTIN

Patients receiving other oral morphine formulations may be converted to MS CONTIN by administering one-half of the patient's 24hour requirement as MS CONTIN on an every-12-hour schedule or by administering one-third of the patient's daily requirement as MS CONTIN on an every-8-hour schedule.
Conversion from Parenteral Morphine or Other Opioids (Parenteral or Oral) to MS CONTIN

While there are useful tables of oral and parenteral equivalents, there is substantial inter-patient variability in the relative potency of different opioid drugs and formulations. As such, it is safer to underestimate a patient's 24-hour oral morphine dose and provide rescue medication (e.g., immediate-release morphine) than to overestimate the 24-hour oral morphine dose and manage an adverse reaction. Consider the following general points: Parenteral to oral morphine ratio: Between 2 to 6 mg of oral morphine may be required to provide analgesia equivalent to 1 mg of parenteral morphine. Typically, a dose of morphine that is approximately three times the previous daily parenteral morphine requirement is sufficient. Other parenteral or oral non-morphine opioids to oral morphine sulfate: Specific recommendations are not available because of a lack of systematic evidence for these types of analgesic substitutions. Published relative potency data are available, but such ratios are approximations. In general, begin with half of the estimated daily morphine requirement as the initial dose, managing inadequate analgesia by supplementation with immediate-release morphine. The first dose of MS CONTIN may be taken with the last dose of any immediate-release opioid medication due to the extended-release characteristics of the MS CONTIN formulation. Titration and Maintenance of Therapy Individually titrate MS CONTIN to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving MS CONTIN to assess the maintenance of pain control and the relative incidence of adverse reactions. During chronic therapy, especially for non-cancer-related pain (or pain associated with other terminal illnesses), periodically reassess the continued need for the use of opioid analgesics. If the level of pain increases, attempt to identify the source of increased pain, while adjusting the MS CONTIN dose to decrease the level of pain. Because steady-state plasma concentrations are approximated in 1 day, MS CONTIN dosage adjustments may be done every 1 to 2 days. Patients who experience breakthrough pain may require dosage adjustment or rescue medication with an appropriate dose of an immediate-release opioid and non-opioid medication. If signs of excessive opioid-related adverse reactions are observed, the next dose may be reduced. Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

During chronic, around-the-clock opioid therapy, especially for non-cancer pain syndromes, the continued need for around-the-clock opioid therapy should be reassessed periodically (e.g., every 6 to 12 months) as appropriate. Discontinuation of MS CONTIN When the patient no longer requires therapy with MS CONTIN tablets, use a gradual downward titration of the dose to prevent signs and symptoms of withdrawal in the physically-dependent patient. Do not abruptly discontinue MS CONTIN. Administration of MS CONTIN Instruct patients to swallow MS CONTIN tablets intact. The tablets are not to be crushed, dissolved, or chewed due to the risk of rapid release and absorption of a potentially fatal dose of morphine [see WARNINGS AND PRECAUTIONS].
HOW SUPPLIED

Dosage Forms And Strengths


MS CONTIN(morphine sulfate controlled-release) Tablets 15 mg Round, blue-colored, filmcoated tablets bearing the symbol PF on one side and M 15 on the other MS CONTIN(morphine sulfate controlled-release) Tablets 30 mg Round, lavender-colored, filmcoated tablets bearing the symbol PF on one side and M 30 on the other MS CONTIN(morphine sulfate controlled-release) Tablets 60 mg Round, orange-colored, filmcoated tablets bearing the symbol PF on one side and M 60 on the other MS CONTIN(morphine sulfate controlled-release) Tablets 100 mg* Round, gray-colored, filmcoated tablets bearing the symbol PF on one side and 100 on the other MS CONTIN(morphine sulfate controlled-release) Tablets 200 mg* Capsule-shaped, greencolored, film-coated tablets bearing the symbol PF on one side and M 200 on the other

*100 mg and 200 mg tablets are for use in opioid-tolerant patients only Storage And Handling MS CONTIN (morphine sulfate controlled-release) Tablets 15 mg are round, blue-colored, film-coated tablets bearing the symbol PF on one side and M 15 on the other. They are supplied as follows: NDC 59011-260-10: opaque plastic bottles containing 100 tablets MS CONTIN (morphine sulfate controlled-release) Tablets 30 mg are round, lavendercolored, film-coated tablets bearing the symbol PF on one side and M 30 on the other. They are supplied as follows:

NDC 59011-261-25: opaque plastic bottles containing 100 tablets NDC 59011-261-05: opaque plastic bottles containing 500 tablets MS CONTIN (morphine sulfate controlled-release) Tablets 60 mg are round, orangecolored, film-coated tablets bearing the symbol PF on one side and M 60 on the other. They are supplied as follows: NDC 59011-262-10: opaque plastic bottles containing 100 tablets NDC 59011-262-05: opaque plastic bottles containing 500 tablets MS CONTIN (morphine sulfate controlled-release) Tablets 100 mg are round, graycolored, film-coated tablets bearing the symbol PF on one side and 100 on the other. They are supplied as follows: NDC 59011-263-10: opaque plastic bottles containing 100 tablets NDC 59011-263-05: opaque plastic bottles containing 500 tablets MS CONTIN (morphine sulfate controlled-release) Tablets 200 mg are capsule-shaped, green-colored, film-coated tablets bearing the symbol PF on one side and M 200 on the other. They are supplied as follows: NDC 59011-264-10: opaque plastic bottles containing 100 tablets Store at 25C (77F); excursions permitted between 15-30C (59-86F). Dispense in a tight, light-resistant container. CAUTION DEA FORM REQUIRED Purdue Pharma L.P. Stamford, CT 06901-3431 Last reviewed on RxList: 7/23/2012 This monograph has been modified to include the generic and brand name in many instances.
SIDE EFFECTS

The following adverse reactions described elsewhere in the labeling include:


Respiratory Depression [see WARNINGS AND PRECAUTIONS] Chronic Pulmonary Disease [see WARNINGS AND PRECAUTIONS] Head Injuries and Increased Intracranial Pressure [see WARNINGS AND PRECAUTIONS] Interactions with Other CNS Depressants [see WARNINGS AND PRECAUTIONS] Hypotensive Effect [see WARNINGS AND PRECAUTIONS] Gastrointestinal Effects [see WARNINGS AND PRECAUTIONS]

Seizures [see WARNINGS AND PRECAUTIONS]

Clinical Trial Experience 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. MS CONTIN may increase the risk of serious adverse reactions such as those observed with other opioid analgesics, including respiratory depression, apnea, respiratory arrest, circulatory depression, hypotension, or shock [see OVERDOSAGE].
Most Frequently Observed Reactions

In clinical trials, the most common adverse reactions with MS Contin were constipation, dizziness, sedation, nausea, vomiting, sweating, dysphoria, and euphoric mood. Some of these effects seem to be more prominent in ambulatory patients and in those not experiencing severe pain.
Less Frequently Observed Reactions

Cardiovascular disorders: tachycardia, bradycardia, palpitations Eye disorders: visual impairment, vision blurred, diplopia, miosis Gastrointestinal disorders: dry mouth, diarrhea, abdominal pain, constipation, dyspepsia General disorders and administration site conditions: chills, feeling abnormal, edema, edema peripheral, weakness Hepatobiliary disorders: biliary colic Metabolism and nutrition disorders: anorexia Musculoskeletal and connective tissue disorders: muscle rigidity, muscle twitching Nervous system disorders: presyncope, syncope, headache, tremor, uncoordinated muscle movements, convulsion, intracranial pressure increased, taste alteration, paresthesia, nystagmus Psychiatric disorders: agitation, mood altered, anxiety, depression, abnormal dreams, hallucination, disorientation, insomnia Renal and urinary disorders: urinary retention, urinary hesitation, antidiuretic effects Reproductive system and breast disorders: reduced libido and/or potency

Respiratory, thoracic and mediastinal disorders: laryngospasm Skin and subcutaneous tissue disorders: pruritus, urticaria, rash Vascular disorders: flushing, hypotension, hypertension Post-Marketing Experience The following adverse reactions have been identified during postapproval use of MS CONTIN: amenorrhea, asthenia, bronchospasm, confusional state, drug hypersensitivity, fatigue, hyperalgesia, hypertonia, ileus, increased hepatic enzymes, intestinal obstruction, lethargy, malaise, pulmonary edema, thinking disturbances, somnolence, and vertigo. Anaphylaxis has been reported with ingredients contained in MS CONTIN. Advise patients how to recognize such a reaction and when to seek medical attention. Read the MS-Contin (morphine sulfate controlled-release) Side Effects Center for a complete guide to possible side effects
DRUG INTERACTIONS

CNS Depressants Concurrent use of MS CONTIN and other central nervous system (CNS) depressants including sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers, and alcohol can increase the risk of respiratory depression, hypotension, profound sedation or coma. Monitor patients receiving CNS depressants and MS CONTIN for signs of respiratory depression and hypotension. When such combined therapy is contemplated, reduce the initial dose of one or both agents. Mixed Agonists/Antagonist Opioid Analgesics Mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol) may reduce the analgesic effect of MS CONTIN or may precipitate withdrawal symptoms in these patients. Avoid the use of agonist/antagonist analgesics in patients receiving MS CONTIN. Muscle Relaxants Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Monitor patients receiving muscle relaxants and MS CONTIN for signs of respiratory depression that may be greater than otherwise expected. Monoamine Oxidase Inhibitors (MAOIs)

The effects of morphine may be potentiated by MAOIs. Monitor patients on concurrent therapy with an MAOI and MS CONTIN for increased respiratory and central nervous system depression. MAOIs have been reported to potentiate the effects of morphine anxiety, confusion, and significant depression of respiration or coma. MS CONTIN should not be used in patients taking MAOIs or within 14 days of stopping such treatment. Cimetidine Cimetidine can potentiate morphine-induced respiratory depression. There is a report of confusion and severe respiratory depression when a patient undergoing hemodialysis was concurrently administered morphine and cimetidine. Monitor patients for respiratory depression when MS CONTIN and cimetidine are used concurrently. Diuretics Morphine can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Morphine may also lead to acute retention of urine by causing spasm of the sphincter of the bladder, particularly in men with enlarged prostates. Anticholinergics Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of urinary retention or reduced gastric motility when MS CONTIN is used concurrently with anticholinergic drugs. P-Glycoprotein (PGP) Inhibitors PGP-inhibitors (e.g., quinidine) may increase the absorption/exposure of morphine sulfate by about two-fold. Therefore, monitor patients for signs of respiratory and central nervous system depression when MS CONTIN is used concurrently with PGP inhibitors. Drug Abuse And Dependence
Controlled Substance

MS CONTIN contains morphine, a Schedule II controlled substance with a high potential for abuse similar to other opioids including fentanyl, hydromorphone, methadone, oxycodone, and oxymorphone. MS CONTIN can be abused and is subject to misuse, addiction, and criminal diversion [see WARNINGS AND PRECAUTIONS]. The high drug content in extended-release formulations adds to the risk of adverse outcomes from abuse and misuse.
Abuse

All patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Drug abuse is the intentional non-therapeutic use of an over-thecounter or prescription drug, even once, for its rewarding psychological or physiological effects. Drug abuse includes, but is not limited to the following examples: the use of a prescription or over-thecounter drug to get high, or the use of steroids for performance enhancement and muscle build up. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and include: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance , and sometimes a physical withdrawal. Drug seeking behavior is very common to addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated claims of loss of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). Doctor shopping (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction. MS CONTIN, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests as required by state law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to reduce abuse of opioid drugs.
Risks Specific to Abuse of MS CONTIN

MS CONTIN is for oral use only. Abuse of MS CONTIN poses a risk of overdose and death. This risk is increased with concurrent abuse of MS CONTIN with alcohol and other substances. Taking cut, broken, chewed, crushed, or dissolved MS CONTIN enhances drug release and increases the risk of over dose and death. Due to the presence of talc as one of the excipients in MS CONTIN, parenteral abuse can be expected to result in local tissue necrosis, infection, pulmonary granulomas, and increased risk of

endocarditis and valvular heart injury. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.
Dependence

Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, e.g., naloxone, nalmefene, or mixed agonist/antagonist analgesics (pentazocine, butorphanol, , nalbuphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage. MS CONTIN should not be abruptly discontinued [see DOSAGE AND ADMINISTRATION]. If MS CONTIN is abruptly discontinued in a physically-dependent patient, an abstinence syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use In Specific Populations]. Last reviewed on RxList: 7/23/2012 This monograph has been modified to include the generic and brand name in many instances.
WARNINGS

Included as part of the PRECAUTIONS section.


PRECAUTIONS

Abuse Potential MS CONTIN contains morphine, an opioid agonist and a Schedule II controlled substance. Morphine can be abused in a manner similar to other opioid agonists, legal or illicit. Opioid agonists are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing MS CONTIN in situations where there is concern about increased risks of misuse, abuse, or diversion. Concerns about abuse, addiction, and diversion should not, however, prevent the proper management of pain.

Assess each patient's risk for opioid abuse or addiction prior to prescribing MS CONTIN. The risk for opioid abuse is increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Patients at increased risk may still be appropriately treated with modified-release opioid formulations; however these patients will require intensive monitoring for signs of misuse, abuse, or addiction. Routinely monitor all patients receiving opioids for signs of misuse, abuse, and addiction because these drugs carry a risk for addiction even under appropriate medical use. Misuse or abuse of MS CONTIN by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of the opioid and pose a significant risk that could result in overdose and death [see OVERDOSAGE]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. Life-Threatening Respiratory Depression Respiratory depression is the chief hazard of opioid agonists, including MS CONTIN. Respiratory depression if not immediately recognized and treated, may lead to respiratory arrest and death. Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with a sighing pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status [see OVERDOSAGE]. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of MS CONTIN, the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with MS CONTIN and following dose increases. Instruct patients against use by individuals other than the patient for whom MS CONTIN was prescribed and to keep MS CONTIN out of the reach of children, as such inappropriate use may result in fatal respiratory depression. To reduce the risk of respiratory depression, proper dosing and titration of MS CONTIN are essential [see DOSAGE AND ADMINISTRATION]. Overestimating the MS CONTIN dose when converting patients from another opioid product can result in fatal overdose with the first dose. Respiratory depression has also been reported with use of modified-release opioids when used as recommended and not misused or abused. To further reduce the risk of respiratory depression, consider the following:

Proper dosing and titration are essential and MS CONTIN should only be prescribed by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain. MS CONTIN 100 mg and 200 mg tablets are for use in opioidtolerant patients only. Ingestion of these strengths of MS CONTIN tablets may cause fatal respiratory depression when administered to patients not already tolerant to high doses of opioids.

Instruct patients to swallow MS CONTIN tablets intact. The tablets are not to be crushed, dissolved, or chewed. The resulting morphine dose may be fatal, particularly in opioid-nave individuals. MS CONTIN is contraindicated in patients with respiratory depression and in patients with conditions that increase the risk of life-threatening respiratory depression [see CONTRAINDICATIONS].

Accidental Exposure Accidental consumption of MS CONTIN, especially in children, can result in a fatal overdose of morphine. Elderly, Cachectic, and Debilitated Patients Respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Therefore, monitor such patients closely, particularly when initiating and titrating MS CONTIN and when MS CONTIN is given concomitantly with other drugs that depress respiration. Use in Patients with Chronic Pulmonary Disease Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression for respiratory depression, particularly when initiating therapy and titrating with MS CONTIN, as in these patients, even usual therapeutic doses of MS CONTIN may decrease respiratory drive to the point of apnea. Consider the use of alternative non-opioid analgesics in these patients if possible. Interactions with Alcohol, CNS Depressants, and Illicit Drugs Hypotension, and profound sedation, coma or respiratory depression may result if MS CONTIN is used concomitantly with other CNS depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, muscle relaxants, other opioids). When considering the use of MS CONTIN in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient's response, including the degree of tolerance that has developed to CNS depression. Additionally, consider the patient's use, if any, of alcohol and/or illicit drugs that can cause CNS depression. If MS CONTIN therapy is to be initiated in a patient taking a CNS depressant, start with a lower MS CONTIN dose than usual and monitor patients for signs of sedation and respiratory depression and consider using a lower dose of the concomitant CNS depressant [see DRUG INTERACTIONS]. Hypotensive Effects MS CONTIN may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration

of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see DRUG INTERACTIONS]. Monitor these patients for signs of hypotension after initiating or titrating the dose of MS CONTIN. In patients with circulatory shock, MS CONTIN may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of MS CONTIN in patients with circulatory shock. Use in Patients with Head Injury or Increased Intracranial Pressure Monitor patients taking MS CONTIN who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy with MS CONTIN. MS CONTIN may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of MS CONTIN in patients with impaired consciousness or coma. Use in Patients with Gastrointestinal Conditions MS CONTIN is contraindicated in patients with paralytic ileus. Avoid the use of MS CONTIN in patients with other GI obstruction. The morphine in MS CONTIN may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Opioids may cause increases in the serum amylase. Use in Patients with Convulsive or Seizure Disorders The morphine in MS CONTIN may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during MS CONTIN therapy. Avoidance of Withdrawal Avoid the use of mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including MS CONTIN. In these patients, mixed agonists/antagonists analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms. When discontinuing MS CONTIN, gradually taper the dose [see DOSAGE AND ADMINISTRATION]. Do not abruptly discontinue MS CONTIN. Driving and Operating Machinery MS CONTIN may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or

operate dangerous machinery unless they are tolerant to the effects of MS CONTIN and know how they will react to the medication. Patient Counseling Information See FDA-approved patient labeling (Medication Guide)
Abuse Potential

Inform patients that MS CONTIN contains morphine, a Schedule II controlled substance that is subject to abuse. Instruct patients not to share MS CONTIN with others and to take steps to protect MS CONTIN from theft or misuse.
Life-Threatening Respiratory Depression

Discuss the risk of respiratory depression with patients, explaining that the risk is greatest when starting MS CONTIN or when the dose is increased. Advise patients how to recognize respiratory depression and to seek medical attention if they are experiencing breathing difficulties.
Accidental Exposure

Instruct patients to take steps to store MS CONTIN securely. Accidental exposure, especially in children, may results in serious harm or death. Advise patients to dispose of unused MS CONTIN by flushing the tablets down the toilet.
Risks from Concomitant Use of Alcohol and other CNS Depressants

Inform patients that the concomitant use of alcohol with MS CONTIN can increase the risk of life-threatening respiratory depression. Instruct patients not to consume alcoholic beverages, as well as prescription and over-the-counter drug products that contain alcohol, during treatment with MS CONTIN. Inform patients that potentially serious additive effects may occur if MS CONTIN is used with other CNS depressants, and not to use such drugs unless supervised by a health care provider.
Important Administration Instructions

Instruct patients how to properly take MS CONTIN, including the following:


Swallowing MS CONTIN tablets whole Not crushing, chewing, or dissolving the tablets Using MS CONTIN exactly as prescribed to reduce the risk of life-threatening adverse reactions (e.g., respiratory depression) Not discontinuing MS CONTIN without first discussing the need for a tapering regimen with the prescriber

Hypotension

Inform patients that MS CONTIN may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position).
Driving or Operating Heavy Machinery

Inform patients that MS CONTIN may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication.
Constipation

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention.
Anaphylaxis

Inform patients that anaphylaxis has been reported with ingredients contained in MS CONTIN. Advise patients how to recognize such a reaction and when to seek medical attention.
Pregnancy

Advise female patients that MS CONTIN can cause fetal harm and to inform the prescriber if they are pregnant or plan to become pregnant. Healthcare professionals can telephone Purdue Pharma's Medical Services Department (1-888726-7535) for information on this product. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis

Studies in animals to evaluate the carcinogenic potential of morphine have not been conducted.
Mutagenesis

No formal studies to assess the mutagenic potential of morphine have been conducted. In the published literature, morphine was found to be mutagenic in vitro increasing DNA fragmentation in human T-cells. Morphine was reported to be mutagenic in the in vivo mouse micronucleus assay and positive for the induction of chromosomal aberrations in mouse spermatids and murine lymphocytes. Mechanistic studies suggest that the in vivo clastogenic effects reported with morphine in mice may be related to increases in glucocorticoid levels produced by morphine in

this species. In contrast to the above positive findings, in vitro studies in the literature have also shown that morphine did not induce chromosomal aberrations in human leukocytes or translocations or lethal mutations in Drosophila.
Impairment of Fertility

No formal nonclinical studies to assess the potential of morphine to impair fertility have been conducted. Several nonclinical studies from the literature have demonstrated adverse effects on male fertility in the rat from exposure to morphine. One study in which male rats were administered morphine sulfate subcutaneously prior to mating (up to 30 mg/kg twice daily) and during mating (20 mg/kg twice daily) with untreated females, a number of adverse reproductive effects including reduction in total pregnancies, higher incidence of pseudopregnancies, and reduction in implantation sites were seen. Studies from the literature have also reported changes in hormonal levels (i.e., testosterone, luteinizing hormone, serum corticosterone) following treatment with morphine. These changes may be associated with the reported effects on fertility in the rat. Use In Specific Populations Pregnancy
Teratogenic Effects (Pregnancy Category C)

No formal studies to assess the teratogenic effects of morphine in animals have been conducted. It is also not known whether morphine can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Morphine should be given to a pregnant woman only if clearly needed. In humans, the frequency of congenital anomalies has been reported to be no greater than expected among the children of 70 women who were treated with morphine during the first four months of pregnancy or in 448 women treated with morphine anytime during pregnancy. Furthermore, no malformations were observed in the infant of a woman who attempted suicide by taking an overdose of morphine and other medication during the first trimester of pregnancy. Several literature reports indicate that morphine administered subcutaneously during the early gestational period in mice and hamsters produced neurological, soft tissue and skeletal abnormalities. With one exception, the effects that have been reported were following doses that were maternally toxic and the abnormalities noted were characteristic of those observed when maternal toxicity is present. In one study, following subcutaneous infusion of doses greater than or equal to 0.15 mg/kg to mice, exencephaly, hydronephrosis, intestinal hemorrhage, split supraoccipital, malformed sternebrae, and malformed xiphoid were noted in the absence of maternal toxicity. In the hamster, morphine sulfate given subcutaneously on gestation day 8 produced exencephaly and cranioschisis. In rats treated with subcutaneous infusions of morphine during the period of organogenesis, no teratogenicity was observed. No maternal toxicity was observed in this study, however, increased mortality and growth retardation were seen in the offspring. In two studies performed in the rabbit, no evidence of teratogenicity was reported at subcutaneous doses up to 100 mg/kg.

Non-Teratogenic Effects

Infants born to mothers who have taken opioids chronically may exhibit neonatal withdrawal syndrome [see Use In Specific Populations], reversible reduction in brain volume, small size, decreased ventilatory response to CO2 and increased risk of sudden infant death syndrome. Morphine sulfate should be used by a pregnant woman only if the need for opioid analgesia clearly outweighs the potential risks to the fetus. Controlled studies of chronic in utero morphine exposure in pregnant women have not been conducted. Published literature has reported that exposure to morphine during pregnancy in animals is associated with reduction in growth and a host of behavioral abnormalities in the offspring. Morphine treatment during gestational periods of organogenesis in rats, hamsters, guinea pigs and rabbits resulted in the following treatment-related embryotoxicity and neonatal toxicity in one or more studies: decreased litter size, embryo-fetal viability, fetal and neonatal body weights, absolute brain and cerebellar weights, delayed motor and sexual maturation, and increased neonatal mortality, cyanosis and hypothermia. Decreased fertility in female offspring, and decreased plasma and testicular levels of luteinizing hormone and testosterone, decreased testes weights, seminiferous tubule shrinkage, germinal cell aplasia, and decreased spermatogenesis in male offspring were also observed. Decreased litter size and viability were observed in the offspring of male rats administered morphine (25 mg/kg, IP) for 1 day prior to mating. Behavioral abnormalities resulting from chronic morphine exposure of fetal animals included altered reflex and motor skill development, mild withdrawal, and altered responsiveness to morphine persisting into adulthood. Labor and Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. MS CONTIN is not recommended for use in women during and immediately prior to labor. Occasionally, opioid analgesics may prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilatation which tends to shorten labor. Closely observe neonates whose mothers received opioid analgesics during labor for signs of respiratory depression. An opioid antagonist, naloxone, should be available for reversal of opioid-induced respiratory depression in the neonate in such situations. Nursing Mothers Morphine is excreted in breast milk, with a milk to plasma morphine AUC ratio of approximately 2.5:1. The amount of morphine received by the infant varies depending on the maternal plasma concentration, the amount of milk ingested by the infant, and the extent of first pass metabolism. Withdrawal signs can occur in breast-feeding infants when maternal administration of morphine is stopped.

Because of the potential for adverse reactions in nursing infants from MS CONTIN, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness in pediatric patients below the age of 18 have not been established. Geriatric Use The pharmacokinetics of MS CONTIN have not been studied in elderly patients. Clinical studies of MS CONTIN did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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. Neonatal Opioid Withdrawal Syndrome Chronic maternal use of morphine during pregnancy can affect the fetus with subsequent withdrawal signs. Neonatal withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration and severity of neonatal withdrawal syndrome vary based on the drug used, duration of use, the dose of last maternal use, and rate of elimination drug by the newborn. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening and should be treated according to protocols developed by neonatology experts. Last reviewed on RxList: 7/23/2012 This monograph has been modified to include the generic and brand name in many instances.
OVERDOSE

Clinical Presentation Acute overdosage with morphine is manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, and death. Marked mydriasis rather than miosis may be seen due to severe hypoxia in overdose situations. Treatment of Overdose In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques.

The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to morphine overdose. Such agents should be administered cautiously to persons who are known, or suspected to be physically dependent on MS CONTIN. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute withdrawal syndrome. Because the duration of reversal would be expected to be less than the duration of action of morphine in MS CONTIN, carefully monitor the patient until spontaneous respiration is reliably re-established. MS CONTIN will continue to release morphine and add to the morphine load for 24 to 48 hours or longer following ingestion necessitating prolonged monitoring. If the response to opioid antagonists is suboptimal or not sustained, additional antagonist should be administered as directed in the product's prescribing information. In an individual physically dependent on opioids, administration of the usual dose of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.
CONTRAINDICATIONS

MS CONTIN is contraindicated in patients with:


Significant respiratory depression Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment Known or suspected paralytic ileus Hypersensitivity (e.g., anaphylaxis) to morphine [see ADVERSE REACTIONS]

Last reviewed on RxList: 7/23/2012 This monograph has been modified to include the generic and brand name in many instances.
CLINICAL PHARMACOLOGY

Mechanism of Action Morphine sulfate, an opioid agonist, is relatively selective for the mu receptor, although it can interact with other opioid receptors at higher doses. In addition to analgesia, the widely diverse effects of morphine sulfate include analgesia, dysphoria, euphoria, somnolence, respiratory depression, diminished gastrointestinal motility, altered circulatory dynamics, histamine release, physical dependence, and alterations of the endocrine and autonomic nervous systems. Morphine produces both its therapeutic and its adverse effects by interaction with one or more classes of specific opioid receptors located throughout the body. Morphine acts as a full agonist,

binding with and activating opioid receptors at sites in the periaqueductal and peri-ventricular grey matter, the ventro-medial medulla and the spinal cord to produce analgesia.
Effects on the Central Nervous System

The principal actions of therapeutic value of morphine are analgesia and sedation. Specific CNS opiate receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are likely to play a role in the expression of analgesic effects. Morphine produces respiratory depression by direct action on brainstem respiratory centers. The mechanism of respiratory depression involves a reduction in the responsiveness of the brainstem respiratory centers to increases in carbon dioxide tension, and to electrical stimulation. Morphine depresses the cough reflex by direct effect on the cough center in the medulla. Morphine causes miosis, even in total darkness. Pinpoint pupils are a sign of narcotic overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen with worsening hypoxia.
Effects on the Gastrointestinal Tract and Other Smooth Muscle

Morphine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and in the duodenum. Digestion of food is delayed in the small intestine and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm. The end result is constipation. Morphine can cause a marked reduction in gastric, biliary and pancreatic secretions, spasm of the sphincter of Oddi, and transient elevations in serum amylase.
Effects on the Cardiovascular System

Morphine produces peripheral vasodilation which may result in orthostatic hypotension. Release of histamine can occur and may contribute to opioid-induced hypotension. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, and sweating.
Effects on the Endocrine System

Opioids inhibit the secretion of ACTH, cortisol, testosterone, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.
Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

Pharmacodynamics
Plasma Level-Analgesia Relationships

While plasma morphine-efficacy relationships can be demonstrated in non-tolerant individuals, they are influenced by a wide variety of factors and are not generally useful as a guide to the clinical use of morphine. Dosages of morphine should be chosen and must be titrated on the basis of clinical evaluation of the patient and the balance between therapeutic and adverse effects.
CNS Depressant/Alcohol Interaction

Additive pharmacodynamic effects may be expected when MS CONTIN is used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression. Pharmacokinetics MS CONTIN is a controlled-release tablet containing morphine sulfate. Morphine is released from MS CONTIN somewhat more slowly than from immediate-release oral preparations. Following oral administration of a given dose of morphine, the amount ultimately absorbed is essentially the same whether the source is MS CONTIN or an immediate-release formulation. Because of pre-systemic elimination (i.e., metabolism in the gut wall and liver) only about 40% of the administered dose reaches the central compartment.
Absorption

The oral bioavailability of morphine is approximately 20 to 40%. When MS CONTIN is given on a fixed dosing regimen, steady-state is achieved in about a day.
Food Effect

The effect of food upon the systemic bioavailability of MS CONTIN has not been systematically evaluated for all strengths. One study, conducted with the 30 mg MS CONTIN tablets, showed no significant differences in Cmax and AUC (0-24h) values, whether the tablet was taken while fasting or with a high-fat breakfast.
Distribution

Once absorbed, morphine is distributed to skeletal muscle, kidneys, liver, intestinal tract, lungs, spleen, and brain. Morphine also crosses placental membranes and has been found in breast milk. The volume of distribution (Vd) for morphine is approximately 3 to 4 liters per kilogram and morphine is 30 to 35% reversibly bound to plasma proteins.
Metabolism

The major pathways of morphine metabolism include glucuronidation to produce metabolites including morphine-3-glucuronide, M3G (about 50%) and morphine-6-glucuronide, M6G (about

5 to 15%) and sulfation in the liver to produce morphine-3-etheral sulfate. A small fraction (less than 5%) of morphine is demethylated. M6G has been shown to have analgesic activity but crosses the blood-brain barrier poorly, while M3G has no significant analgesic activity.
Excretion

The elimination of morphine occurs primarily as renal excretion of M3G and its effective halflife after intravenous administration is normally 2 to 4 hours. Approximately 10% of the dose is excreted unchanged in urine. In some studies involving longer periods of plasma sampling, a longer terminal half-life of about 15 hours was reported. A small amount of the glucuronide conjugate is excreted in the bile, and there is some minor enterohepatic recycling. Special Populations
Geriatric Patients

The Pharmacokinetics of MS CONTIN have not been studied in elderly patients.


Pediatric Patients

The pharmacokinetics of MS CONTIN have not been studied in pediatric patients below the age of 18.
Gender

A gender analysis of pharmacokinetic data from healthy subjects taking MS CONTIN indicated that morphine concentrations were similar in males and females.
Race

Chinese subjects given intravenous morphine had a higher clearance when compared to Caucasian subjects (1852 +/-116 ml/min compared to 1495 +/- 80 ml/min).
Hepatic Impairment

Morphine pharmacokinetics are altered in individuals with cirrhosis. Clearance was found to decrease with a corresponding increase in half-life. The M3G and M6G to morphine plasma AUC ratios also decreased in these subjects, indicating diminished metabolic activity. Adequate studies of the pharmacokinetics of morphine in patients with severe hepatic impairment have not been conducted.
Renal Impairment

Morphine pharmacokinetics are altered in patients with renal failure. The AUC is increased and clearance is decreased and the metabolites, M3G and M6G, may accumulate to much higher plasma levels in patients with renal failure as compared to patients with normal renal function.

Adequate studies of the pharmacokinetics of morphine in patients with severe renal impairment have not been conducted. Last reviewed on RxList: 7/23/2012 This monograph has been modified to include the generic and brand name in many instances.
PATIENT INFORMATION

Medication Guide MS CONTIN (MS-KON-tin) (morphine sulfate controlled-release) Tablets. MS CONTIN is:

A strong prescription pain medicine that contains an opioid (narcotic) that is used to treat moderate to severe around-the-clock pain.

Important information about MS CONTIN:


Get emergency help right away if you take too much MS CONTIN (overdose). MS CONTIN overdose can cause life-threatening breathing problems that can lead to death. Never give anyone else your MS CONTIN. They could die from taking it. Store MS CONTIN away from children and in a safe place to prevent stealing or abuse. Selling or giving away MS CONTIN is against the law.

Do not take MS CONTIN if you have:


severe asthma, trouble breathing, or other lung problems. a bowel blockage or have narrowing of the stomach or intestines.

Before taking MS CONTIN, tell your healthcare provider if you have a history of:

head injury, seizures liver, kidney, thyroid problems problems urinating pancreas or gallbladder problems abuse of street or prescription drugs, alcohol addiction, or mental health problems.

Tell your healthcare provider if you are:


pregnant or planning to become pregnant. MS CONTIN may harm your unborn baby. breastfeeding. MS CONTIN passes into breast milk and may harm your baby. taking prescription or over the counter medicines, vitamins, or herbal supplements.

When taking MS CONTIN:

Do not change your dose. Take MS CONTIN exactly as prescribed by your healthcare provider. Take each dose at the same time every day. If you miss a dose, take MS CONTIN as soon as possible and then take your next dose 8 or 12 hours later as directed by your healthcare provider. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take more than 1 dose in 8 hours. Swallow MS CONTIN whole. Do not cut, break, chew, crush, dissolve, or inject MS CONTIN. Call your healthcare provider if the dose you are taking does not control your pain. Do not stop taking MS CONTIN without talking to your healthcare provider. After you stop taking MS CONTIN, flush any unused tablets down the toilet.

While taking MS CONTIN Do Not:


Drive or operate heavy machinery, until you know how MS CONTIN affects you. MS CONTIN can make you sleepy, dizzy, or lightheaded. Drink alcohol or use prescription or over-the-counter medicines that contain alcohol.

The possible side effects of MS CONTIN are:

constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe.

Get emergency medical help if you have:

trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue or throat, extreme drowsiness, or you are feeling faint.

These are not all the possible side effects of MS CONTIN. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov Last reviewed on RxList: 7/23/2012 This monograph has been modified to include the generic and brand name in many instances.
MS-Contin Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs. MORPHINE SUSTAINED-ACTION - ORAL (MOR-feen SUL-fate) COMMON BRAND NAME(S): MS Contin, Oramorph

WARNING: Morphine has a high risk for abuse and severe, possibly fatal, breathing problems. The risk for harm is higher if you take the wrong dose/strength, or if you take it along with other drugs that might also affect breathing. Be sure you know how to take morphine and what other drugs you should avoid taking with it. Get immediate medical help if you notice unusual slow/shallow breathing. The higher strengths of this drug (100 or 200 milligrams per tablet/capsule) should be used only if you have been regularly taking moderate to large amounts of narcotic pain medication. These strengths may cause overdose (even death) if taken by a person who has not been regularly taking narcotic medication. Do not break, crush, chew, or dissolve this medication. Taking broken, crushed, chewed, or dissolved forms of sustained-action morphine could cause overdose. Keep this medicine in a safe place to prevent theft, misuse, or abuse. If a child accidentally swallows this drug, get emergency medical help right away. USES: See also Warning section. This medication is used to help relieve moderate to severe ongoing pain (such as due to cancer). Morphine belongs to a class of drugs known as narcotic (opiate) analgesics. It works in the brain to change how your body feels and responds to pain. Do not use the sustained-action form of morphine to relieve pain that is mild or that will go away in a few days. This medication is not for occasional ("as needed") use. HOW TO USE: Take this medication on a regular schedule as directed by your doctor, not as needed for sudden (breakthrough) pain. Take this drug with or without food, usually 2 or 3 times daily (every 8 or 12 hours). If you have nausea, it may help to take this drug with food. Ask your doctor or pharmacist about other ways to decrease nausea (such as lying down for 1 to 2 hours with as little head movement as possible). Swallow the tablets/capsules whole. Do not break, crush, chew, or dissolve the tablet/capsule. Doing so can release all of the drug at once, increasing the risk of morphine overdose. Adults who have trouble swallowing the capsule may open the capsule and mix the contents in liquid or sprinkle on a spoonful of soft food (such as applesauce). Swallow all of the drug/food mixture immediately without chewing. Then rinse your mouth and swallow the rinse liquid to make sure that you have swallowed all of the dose. Do not chew the mixture or prepare a supply in advance. Do not give this medication to a child this way, since they might chew the mixture and overdose. For children who have trouble swallowing the capsule, ask the doctor about using a different form of morphine instead. The dosage is based on your medical condition and response to treatment. Do not increase your dose, take the medication more frequently, or take it for a longer time than prescribed. Properly stop the medication when so directed.

Before you start taking this medication, ask your doctor or pharmacist if you should stop or change the dose of your other narcotic medication(s). For added pain relief, your doctor may direct you to also take quick-acting narcotic or non-narcotic pain medications (such as acetaminophen, ibuprofen). Ask your doctor or pharmacist if you have any questions about using morphine safely with other drugs. This medication may cause withdrawal reactions, especially if it has been used regularly for a long time or in high doses. In such cases, withdrawal symptoms (such as restlessness, watering eyes, runny nose, nausea, sweating, muscle aches) may occur if you suddenly stop using this medication. To prevent withdrawal reactions, your doctor may reduce your dose gradually. Ask your doctor or pharmacist for more details, and report any withdrawal reactions immediately. When this medication is used for a long time, it may not work as well. Talk with your doctor if this medication stops working well. Along with its benefits, this medication may rarely cause abnormal drug-seeking behavior (addiction). This risk may be increased if you have abused alcohol or drugs in the past. Take this medication exactly as prescribed to lessen the risk of addiction. Tell your doctor if your pain persists or worsens.
MS-Contin Consumer (continued) SIDE EFFECTS: Nausea, vomiting, constipation, lightheadedness, dizziness, or drowsiness may occur. Some of these side effects may decrease after you have been using this medication for a while. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

To prevent constipation, eat a diet adequate in fiber, drink plenty of water, and exercise. Ask your pharmacist for help in selecting a laxative (such as a stimulant type with stool softener). To reduce the risk of dizziness and lightheadedness, get up slowly when rising from a sitting or lying position. Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects. Tell your doctor immediately if any of these unlikely but serious side effects occur: mental/mood changes (such as agitation, confusion, hallucinations), severe stomach/abdominal pain, difficulty urinating. Seek immediate medical attention if any of these rare but serious side effects occur: fainting, seizure, slow/shallow breathing, unusual drowsiness/difficulty waking up. A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist. In the US Call your doctor for medical advice about side effects. You may report side effects to FDA at 1800-FDA-1088. In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345. Read the MS-Contin (morphine sulfate controlled-release) Side Effects Center for a complete guide to possible side effects PRECAUTIONS: Before taking morphine, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details. Before using this medication, tell your doctor or pharmacist your medical history, especially of: brain disorders (such as head injury, tumor, seizures), breathing problems (such as asthma, sleep apnea, chronic obstructive pulmonary disease-COPD), kidney disease, liver disease, mental/mood disorders (such as confusion, depression), personal or family history of regular use/abuse of drugs/alcohol, stomach/intestinal problems (such as blockage, constipation, diarrhea due to infection, paralytic ileus), difficulty urinating (such as due to enlarged prostate). This drug may make you dizzy or drowsy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely. Avoid alcoholic beverages. Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products). Older adults may be more sensitive to the effects of this drug, especially dizziness, drowsiness, or urinary problems. Before using this medication, women of childbearing age should talk with their doctor(s) about the risks and benefits. Tell your doctor if you are pregnant or if you plan to become pregnant. During pregnancy, this medication should be used only when clearly needed. It may slightly increase the risk of birth defects if used during the first two months of pregnancy. Also, using it for a long time or in high doses near the expected delivery date may harm the unborn baby. To lessen the risk, take the smallest effective dose for the shortest possible time. Tell the doctor right away if you notice any symptoms in your newborn baby such as slow/shallow breathing, irritability, abnormal/persistent crying, vomiting, or diarrhea.

This drug passes into breast milk and may rarely have undesirable effects on a nursing infant. Tell the doctor immediately if your baby develops unusual sleepiness, difficulty feeding, or trouble breathing. Consult your doctor before breast-feeding. DRUG INTERACTIONS: The effects of some drugs can change if you take other drugs or herbal products at the same time. This can increase your risk for serious side effects or may cause your medications not to work correctly. These drug interactions are possible, but do not always occur. Your doctor or pharmacist can often prevent or manage interactions by changing how you use your medications or by close monitoring. To help your doctor and pharmacist give you the best care, be sure to tell your doctor and pharmacist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products) before starting treatment with this product. While using this product, do not start, stop, or change the dosage of any other medicines you are using without your doctor's approval. Some products that may interact with this drug include: certain pain medications (mixed narcotic agonist/antagonists such as pentazocine, nalbuphine, butorphanol), narcotic antagonists (such as naltrexone). Other medications can affect how morphine works and your risk for side effects. Examples include cimetidine, quinidine, rifampin, among others. The risk of serious side effects (such as slow/shallow breathing, severe drowsiness/dizziness) may be increased if this medication is taken with other products that may also affect breathing or cause drowsiness. Therefore, tell your doctor or pharmacist if you are taking other products such as alcohol, allergy or cough-and-cold products, anti-seizure drugs (such as phenobarbital), medicine for sleep or anxiety (such as alprazolam, diazepam, zolpidem), muscle relaxants, other narcotic pain relievers (such as codeine), and psychiatric medicines (such as risperidone, amitriptyline, trazodone). Your medications or doses of your medications may need to be changed. This medication may interfere with certain laboratory tests, possibly causing false test results. Make sure laboratory personnel and all your doctors know you use this drug. This document does not contain all possible drug interactions. Keep a list of all the products you use. Share this list with your doctor and pharmacist to lessen your risk for serious medication problems. OVERDOSE: If overdose is suspected, contact a poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: slow breathing, slow heartbeat, loss of consciousness. NOTES: Do not share this medication with others. It is against the law.

This medication has been prescribed for your current condition only. Do not use it later for another condition unless told to do so by your doctor. A different medication may be necessary in that case. MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up. STORAGE: Store at room temperature between 59-86 degrees F (15-30 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets. Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product. Information last revised September 2011. Copyright(c) 2011 First Databank, Inc.

NDICATIONS

DURAMORPH (morphine injection) is a systemic narcotic analgesic for administration by the intravenous, epidural or intrathecal routes. It is used for the management of pain not responsive to non-narcotic analgesics. DURAMORPH (morphine injection) administered epidurally or intrathecally, provides pain relief for extended periods without attendant loss of motor, sensory or sympathetic function. Not For Use in Continuous Microinfusion Devices
DOSAGE AND ADMINISTRATION

DURAMORPH (morphine injection) is intended for intravenous, epidural or intrathecal administration. Not For Use in Continuous Microinfusion Devices Intravenous Administration
Dosage

The initial dose of morphine should be 2 mg to 10 mg/70 kg of body weight. No information is available regarding the use of DURAMORPH (morphine injection) in patients under the age of 18.
Geriatric Use

Administer with extreme caution. (See PRECAUTIONS.) Epidural Administration DURAMORPH (morphine injection) SHOULD BE ADMINISTERED EPIDURALLY BY OR UNDER THE DIRECTION OF A PHYSICIAN EXPERIENCED IN THE TECHNIQUE OF EPIDURAL ADMINISTRATION AND WHO IS THOROUGHLY FAMILIAR WITH THE LABELING. IT SHOULD BE ADMINISTERED ONLY IN SETTINGS WHERE ADEQUATE PATIENT MONITORING IS POSSIBLE. RESUSCITATIVE EQUIPMENT AND A SPECIFIC ANTAGONIST (NALOXONE INJECTION) SHOULD BE IMMEDIATELY AVAILABLE FOR THE MANAGEMENT OF RESPIRATORY DEPRESSION AS WELL AS COMPLICATIONS WHICH MIGHT RESULT FROM INADVERTENT INTRATHECAL OR INTRAVASCULAR INJECTION. (NOTE: INTRATHECAL DOSAGE IS USUALLY 1/10 THAT OF EPIDURAL DOSAGE.) PATIENT MONITORING SHOULD BE CONTINUED FOR AT LEAST 24 HOURS AFTER EACH DOSE, SINCE DELAYED RESPIRATORY DEPRESSION MAY OCCUR. Proper placement of a needle or catheter in the epidural space should be verified before DURAMORPH (morphine injection) is injected. Acceptable techniques for verifying proper placement include: a) aspiration to check for absence of blood or cerebrospinal fluid, or b) administration of 5 mL (3 mL in obstetric patients) of 1.5% PRESERVATIVE-FREE Lidocaine and Epinephrine (1:200,000) Injection and then observe the patient for lack of tachycardia (this indicates that vascular injection has not been made) and lack of sudden onset of segmental anesthesia (this indicates that intrathecal injection has not been made).
Epidural Adult Dosage

Initial injection of 5 mg in the lumbar region may provide satisfactory pain relief for up to 24 hours. If adequate pain relief is not achieved within one hour, careful administration of incremental doses of 1 to 2 mg at intervals sufficient to assess effectiveness may be given. No more than 10 mg/24 hr should be administered. Thoracic administration has been shown to dramatically increase the incidence of early and late respiratory depression even at doses of 1 to 2 mg.
Geriatric Use

Administer with extreme caution. (See PRECAUTIONS.)


Epidural Pediatric Use

No information on use in pediatric patients is available. (See PRECAUTIONS.) Intrathecal Administration

NOTE: INTRATHECAL DOSAGE IS USUALLY 1/10 THAT OF EPIDURAL DOSAGE. DURAMORPH (morphine injection) SHOULD BE ADMINISTERED INTRATHECALLY BY OR UNDER THE DIRECTION OF A PHYSICIAN EXPERIENCED IN THE TECHNIQUE OF INTRATHECAL ADMINISTRATION AND WHO IS THOROUGHLY FAMILIAR WITH THE LABELING. IT SHOULD BE ADMINISTERED ONLY IN SETTINGS WHERE ADEQUATE PATIENT MONITORING IS POSSIBLE. RESUSCITATIVE EQUIPMENT AND A SPECIFIC ANTAGONIST (NALOXONE INJECTION) SHOULD BE IMMEDIATELY AVAILABLE FOR THE MANAGEMENT OF RESPIRATORY DEPRESSION AS WELL AS COMPLICATIONS WHICH MIGHT RESULT FROM INADVERTENT INTRAVASCULAR INJECTION. PATIENT MONITORING SHOULD BE CONTINUED FOR AT LEAST 24 HOURS AFTER EACH DOSE, SINCE DELAYED RESPIRATORY DEPRESSION MAY OCCUR. RESPIRATORY DEPRESSION (BOTH EARLY AND LATE ONSET) HAS OCCURRED MORE FREQUENTLY FOLLOWING INTRATHECAL ADMINISTRATION THAN EPIDURAL ADMINISTRATION.
Intrathecal Adult Dosage

A single injection of 0.2 to 1 mg may provide satisfactory pain relief for up to 24 hours. (CAUTION: THIS IS ONLY 0.4 TO 2 ML OF THE 5 MG/10 ML AMPUL OR 0.2 TO 1 ML OF THE 10 MG/10 ML AMPUL OF DURAMORPH (morphine injection) ). DO NOT INJECT INTRATHECALLY MORE THAN 2 ML OF THE 5 MG/10 ML AMPUL OR 1 ML OF THE 10 MG/10 ML AMPUL. USE IN THE LUMBAR AREA ONLY IS RECOMMENDED. Repeated intrathecal injections of DURAMORPH (morphine injection) are not recommended. A constant intravenous infusion of naloxone, 0.6 mg/hr, for 24 hours after intrathecal injection may be used to reduce the incidence of potential side effects.
Geriatric Use

Administer with extreme caution. (See PRECAUTIONS.)


Repeat Dosage

If pain recurs, alternative routes of administration should be considered, since experience with repeated doses of morphine by the intrathecal route is limited.
Intrathecal Pediatric Use

No information on use in pediatric patients is available. (See PRECAUTIONS.) Safety And Handling Instructions DURAMORPH (morphine injection) is supplied in sealed ampuls. Accidental dermal exposure should be treated by the removal of any contaminated clothing and rinsing the affected area with water.

Each ampul of DURAMORPH (morphine injection) contains a potent narcotic which has been associated with abuse and dependence among health care providers. Due to the limited indications for this product, the risk of overdosage and the risk of its diversion and abuse, it is recommended that special measures be taken to control this product within the hospital or clinic. DURAMORPH (morphine injection) should be subject to rigid accounting, rigorous control of wastage and restricted access. Parenteral drug products should be inspected for participate matter and discoloration prior to administration, whenever solution and container permit. DO NOT USE IF COLOR IS DARKER THAN PALE YELLOW, IF IT IS DISCOLORED IN ANY OTHER WAY OR IF IT CONTAINS A PRECIPITATE.
HOW SUPPLIED

Preservative-Free DURAMORPH (morphine sulfate injection, USP) is available in amber DOSETTE ampuls for intravenous, epidural and intrathecal administration: 5 mg/10 mL (0.5 mg/mL) packaged in 10s (NDC 60977-016-02) 10 mg/10 mL (1 mg/mL) packaged in 10s (NDC 60977-017-01) Also available from Baxter: INFUMORPH (Preservative-free Morphine Sulfate Sterile Solution) 200 mg/20 mL (10 mg/mL) and 500 mg/20 mL (25 mg/mL) for epidural and intrathecal administration via a continuous microinfusion device. Storage PROTECT FROM LIGHT. Store in carton at 20- 25C (68- 77F), excursions permitted to 15- 30C (59- 86F) [see USP Controlled Room Temperature] until ready to use. DO NOT FREEZE. DURAMORPH (morphine injection) contains no preservative or antioxidant. DISCARD ANY UNUSED PORTION. DO NOT HEAT-STERILIZE. Manufactured by: Baxter Healthcare Corporation, Deerfield, IL 60015 USA. For Product Inquiry 1 800 ANA DRUG (1-800-262-3784). Last reviewed on RxList: 10/29/2010 This monograph has been modified to include the generic and brand name in many instances
SIDE EFFECTS

The most serious adverse experience encountered during administration of DURAMORPH (morphine injection) is respiratory depression and/or respiratory arrest. This depression and/or respiratory arrest may be severe and could require intervention. (See WARNINGS and OVERDOSAGE.) Because of delay in maximum CNS effect with intravenously administered drug (30 min), rapid administration may result in overdosing. Single-dose neuraxial

administration may result in acute or delayed respiratory depression for periods at least as long as 24 hours. Tolerance and Myoclonus See WARNINGS for discussion of these and related hazards. While low doses of intravenously administered morphine have little effect on cardiovascular stability, high doses are excitatory, resulting from sympathetic hyperactivity and increase in circulating catecholamines. Excitation of the central nervous system, resulting in convulsions, may accompany high doses of morphine given intravenously. Dysphoric reactions may occur after any size dose and toxic psychoses have been reported. Pruritus Single-dose epidural or intrathecal administration is accompanied by a high incidence of pruritus that is dose-related but not confined to the site of administration. Pruritus, following continuous infusion of epidural or intrathecal morphine, is occasionally reported in the literature; these reactions are poorly understood as to their cause. Urinary Retention Urinary retention, which may persist 10 to 20 hours following single epidural or intrathecal administration, is a frequent side effect and must be anticipated primarily in male patients, with a somewhat lower incidence in females. Also frequently reported in the literature is the occurrence of urinary retention during the first several days of hospitalization for the initiation of continuous intrathecal or epidural morphine therapy. Patients who develop urinary retention have responded to cholinomimetic treatment and/or judicious use of catheters (see PRECAUTIONS). Constipation Constipation is frequently encountered during continuous infusion of morphine; this can usually be managed by conventional therapy. Headache Lumbar puncture-type headache is encountered in a significant minority of cases for several days following intrathecal catheter implantation; this, generally, responds to bed rest and/or other conventional therapy. Other Other adverse experiences reported following morphine therapy includeDizziness, euphoria, anxiety, hypotension, confusion, reduced male potency, decreased libido in men and women, and menstrual irregularities including amenorrhea, depression of cough reflex, interference with thermal regulation and oliguria. Evidence of histamine release such as

urticaria, wheals and/or local tissue irritation may occur. Nausea and vomiting are frequently seen in patients following morphine administration. Pruritus, nausea/vomiting and urinary retention, if associated with continuous infusion therapy, may respond to intravenous administration of a low dose of naloxone (0.2 mg). The risks of using narcotic antagonists in patients chronically receiving narcotic therapy should be considered. In general, side effects are amenable to reversal by narcotic antagonists. NALOXONE INJECTION AND RESUSCITATIVE EQUIPMENT SHOULD BE IMMEDIATELY AVAILABLE FOR ADMINISTRATION IN CASE OF LIFETHREATENING OR INTOLERABLE SIDE EFFECTS AND WHENEVER DURAMORPH (morphine injection) THERAPY IS BEING INITIATED. Drug Abuse And Dependence
Controlled Substance

Morphine sulfate is a Schedule II narcotic under the United States Controlled Substance Act (21 U.S.C. 801-886). Morphine is the most commonly cited prototype for narcotic substances that possess an addiction-forming or addiction-sustaining liability. A patient may be at risk for developing a dependence to morphine if used improperly or for overly long periods of time. As with all potent opioids which are -agonists, tolerance as well as psychological and physical dependence to morphine may develop irrespective of the route of administration (intravenous, intramuscular, intrathecal, epidural or oral). Individuals with a prior history of opioid or other substance abuse or dependence, being more apt to respond to the euphorogenic and reinforcing properties of morphine, would be considered to be at greater risk. Care must be taken to avert withdrawal in patients who have been maintained on parenteral/oral narcotics when epidural or intrathecal administration is considered. Withdrawal symptoms may occur when morphine is discontinued abruptly or upon administration of a narcotic antagonist. Read the Duramorph (morphine injection) Side Effects Center for a complete guide to possible side effects
DRUG INTERACTIONS

No information provided. Last reviewed on RxList: 10/29/2010 This monograph has been modified to include the generic and brand name in many instances.

WARNINGS

Morphine sulfate may be habit forming. (See Drug Abuse And Dependence.) Overdoses may cause respiratory depression, coma and death. DURAMORPH (morphine injection) administration should be limited to use by those familiar with the management of respiratory depression. Rapid intravenous administration may result in chest wall rigidity. Prior to any epidural or intrathecal drug administration, the physician should be familiar with patient conditions (such as infection at the injection site, bleeding diathesis, anticoagulant therapy, etc.) which call for special evaluation of the benefit versus risk potential. In the case of epidural or intrathecal administration, DURAMORPH (morphine injection) should be administered by or under the direction of a physician experienced in the techniques and familiar with the patient management problems associated with epidural or intrathecal drug administration. Because epidural administration has been associated with less potential for immediate or late adverse effects than intrathecal administration, the epidural route should be used whenever possible. SEVERE RESPIRATORY DEPRESSION UP TO 24 HOURS FOLLOWING EPIDURAL OR INTRATHECAL ADMINISTRATION HAS BEEN REPORTED. BECAUSE OF THE RISK OF SEVERE ADVERSE EFFECTS WHEN THE EPIDURAL OR INTRATHECAL ROUTE OF ADMINISTRATION IS EMPLOYED, PATIENTS MUST BE OBSERVED IN A FULLY EQUIPPED AND STAFFED ENVIRONMENT FOR AT LEAST 24 HOURS AFTER THE INITIAL DOSE. THE FACILITY MUST BE EQUIPPED TO RESUSCITATE PATIENTS WITH SEVERE OPIATE OVERDOSAGE, AND THE PERSONNEL MUST BE FAMILIAR WITH THE USE AND LIMITATIONS OF SPECIFIC NARCOTIC ANTAGONISTS (NALOXONE, NALTREXONE) IN SUCH CASES. Tolerance and Myoclonic Activity PATIENTS SOMETIMES MANIFEST UNUSUAL ACCELERATION OF NEURAXIAL MORPHINE REQUIREMENTS, WHICH MAY CAUSE CONCERN REGARDING SYSTEMIC ABSORPTION AND THE HAZARDS OF LARGE DOSES; THESE PATIENTS MAY BENEFIT FROM HOSPITALIZATION AND DETOXIFICATION. TWO CASES OF MYOCLONIC-LIKE SPASM OF THE LOWER EXTREMITIES HAVE BEEN REPORTED IN PATIENTS RECEIVING MORE THAN 20 MG/DAY OF INTRATHECAL MORPHINE. AFTER DETOXIFICATION, IT MIGHT BE POSSIBLE TO RESUME TREATMENT AT LOWER DOSES, AND SOME PATIENTS HAVE BEEN SUCCESSFULLY CHANGED FROM CONTINUOUS EPIDURAL MORPHINE TO CONTINUOUS INTRATHECAL

MORPHINE. REPEAT DETOXIFICATION MAY BE INDICATED AT A LATER DATE. THE UPPER DAILY DOSAGE LIMIT FOR EACH PATIENT DURING CONTINUING TREATMENT MUST BE INDIVIDUALIZED.
PRECAUTIONS

General Control of pain by neuraxial opiate delivery is always accompanied by considerable risk to the patients and requires a high level of skill to be successfully accomplished. The task of treating these patients must be undertaken by experienced clinical teams, well-versed in patient selection, evolving technology and emerging standards of care. For safety reasons, it is recommended that administration of DURAMORPH (morphine injection) by the epidural or intrathecal routes be limited to the lumbar area. Intrathecal use has been associated with a higher incidence of respiratory depression than epidural use. Seizures may result from high doses. Patients with known seizure disorders should be carefully observed for evidence of morphine-induced seizure activity. Use in Patients with Increased Intracranial Pressure or Head Injury DURAMORPH (morphine injection) should be used with extreme caution in patients with head injury or increased intracranial pressure. Pupillary changes (miosis) from morphine may obscure the existence, extent and course of intracranial pathology. High doses of neuraxial morphine may produce myoclonic events (see WARNINGS and ADVERSE REACTIONS). Clinicians should maintain a high index of suspicion for adverse drug reactions when evaluating altered mental status or movement abnormalities in patients receiving this modality of treatment. Use in Chronic Pulmonary Disease Care is urged in using this drug in patients who have a decreased respiratory reserve (e.g., emphysema, severe obesity, kyphoscoliosis or paralysis of the phrenic nerve). DURAMORPH (morphine injection) should not be given in cases of chronic asthma, upper airway obstruction or in any other chronic pulmonary disorder without due consideration of the known risk of acute respiratory failure following morphine administration in such patients. Use in Hepatic or Renal Disease The elimination half-life of morphine may be prolonged in patients with reduced metabolic rates and with hepatic and/or renal dysfunction. Hence, care should be exercised in administering DURAMORPH (morphine injection) epidurally to patients with these conditions, since high blood morphine levels, due to reduced clearance, may take several days to develop. Use in Biliary Surgery or Disorders of the Biliary Tract

As significant morphine is released into the systemic circulation from neuraxial administration, the ensuing smooth muscle hypertonicity may result in biliary colic. Use with Disorders of the Urinary System Initiation of neuraxial opiate analgesia is frequently associated with disturbances of micturition, especially in males with prostatic enlargement. Early recognition of difficulty in urination and prompt intervention in cases of urinary retention is indicated. Use in Ambulatory Patients Patients with reduced circulating blood volume, impaired myocardial function or on sympatholytic drugs should be monitored for the possible occurrence of orthostatic hypotension, a frequent complication in single-dose neuraxial morphine analgesia. Use with Other Central Nervous System Depressants The depressant effects of morphine are potentiated by the presence of other CNS depressants such as alcohol, sedatives, antihistaminics or psychotropic drugs. Use of neuroleptics in conjunction with neuraxial morphine may increase the risk of respiratory depression. Carcinogenesis, Mutagenesis, Impairment of Fertility Morphine is without known carcinogenic or mutagenic effects and is not known to impair fertility at non-narcotic doses in animals, but studies of the carcinogenic and mutagenic potential or the effect on fertility of DURAMORPH (morphine injection) have not been conducted. Pregnancy
Teratogenic EffectsPregnancy Category C

Morphine sulfate is not teratogenic in rats at 35 mg/kg/day (thirty-five times the usual human dose) but does result in increased pup mortality and growth retardation at doses that narcotize the animal ( > 10 mg/kg/day, ten times the usual human dose). DURAMORPH (morphine injection) should only be given to pregnant women when no other method of controlling pain is available and means are at hand to manage the delivery and perinatal care of the opiate-dependent infant.
Nonteratogenic Effects

Infants born to mothers who have been taking morphine chronically may exhibit withdrawal symptoms. Labor and Delivery Intravenous morphine readily passes into the fetal circulation and may result in respiratory depression in the neonate. Naloxone and resuscitative equipment should be available for reversal

of narcotic-induced respiratory depression in the neonate. In addition, intravenous morphine may reduce the strength, duration and frequency of uterine contraction resulting in prolonged labor. Epidurally and intrathecally administered morphine readily passes into the fetal circulation and may result in respiratory depression of the neonate. Controlled clinical studies have shown that epidural administration has little or no effect on the relief of labor pain. Nursing Mothers Morphine is excreted in maternal milk. Effects on the nursing infant are not known. Pediatric Use Adequate studies, to establish the safety and effectiveness of spinal morphine in pediatric patients, have not been performed, and usage in this population is not recommended. Geriatric Use The pharmacodynamic effects of neuraxial morphine in the elderly are more variable than in the younger population. Patients will vary widely in the effective initial dose, rate of development of tolerance and the frequency and magnitude of associated adverse effects as the dose is increased. Initial doses should be based on careful clinical observation following "test doses", after making due allowances for the effects of the patient's age and infirmity on his/her ability to clear the drug, particularly in patients receiving epidural morphine. Elderly patients may be more susceptible to respiratory depression and/or respiratory arrest following administration of morphine. Last reviewed on RxList: 10/29/2010 This monograph has been modified to include the generic and brand name in many instances.
OVERDOSE

PARENTERAL ADMINISTRATION OF NARCOTICS IN PATIENTS RECEIVING EPIDURAL OR INTRATHECAL MORPHINE MAY RESULT IN OVERDOSAGE. Overdosage of morphine is characterized by respiratory depression, with or without concomitant CNS depression. In severe overdosage, apnea, circulatory collapse, cardiac arrest and death may occur. Since respiratory arrest may result either through direct depression of the respiratory center or as the result of hypoxia, primary attention should be given to the establishment of adequate respiratory exchange through provision of a patent airway and institution of assisted, or controlled, ventilation. The narcotic antagonist, naloxone, is a specific antidote. An initial dose of 0.4 to 2 mg of naloxone should be administered intravenously, simultaneously with respiratory resuscitation. If the desired degree of counteraction and improvement in respiratory function is not obtained, naloxone may be repeated at 2- to 3-minute intervals. If no response is observed after 10 mg of naloxone has been administered, the diagnosis of narcotic-induced, or

partial narcotic-induced, toxicity should be questioned. Intramuscular or subcutaneous administration may be used if the intravenous route is not available. As the duration of effect of naloxone is considerably shorter than that of epidural or intrathecal morphine, repeated administration may be necessary. Patients should be closely observed for evidence of renarcotization.
CONTRAINDICATIONS

DURAMORPH (morphine injection) is contraindicated in those medical conditions which would preclude the administration of opioids by the intravenous routeallergy to morphine or other opiates, acute bronchial asthma, upper airway obstruction. DURAMORPH (morphine injection) , like all opioid analgesics, may cause severe hypotension in an individual whose ability to maintain blood pressure has already been compromised by a depleted blood volume or a concurrent administration of drugs, such as phenothiazines or general anesthetics. (See also PRECAUTIONS: Use with Other Central Nervous System Depressants.) Last reviewed on RxList: 10/29/2010 This monograph has been modified to include the generic and brand name in many instances.
CLINICAL PHARMACOLOGY

Morphine produces a wide spectrum of pharmacologic effects including analgesia, dysphoria, euphoria, somnolence, respiratory depression, diminished gastrointestinal motility and physical dependence. Opiate analgesia involves at least three anatomical areas of the central nervous system: the periaqueductal-periventricular gray matter, the ventromedial medulla and the spinal cord. A systematically administered opiate may produce analgesia by acting at any, all or some combination of these distinct regions. Morphine interacts predominantly with the -receptor. The -binding sites of opioids are very discretely distributed in the human brain, with high densities of sites found in the posterior amygdala, hypothalamus, thalamus, nucleus caudatus, putamen and certain cortical areas. They are also found on the terminal axons of primary afferents within laminae I and II (substantia gelatinosa) of the spinal cord and in the spinal nucleus of the trigeminal nerve. Morphine has an apparent volume of distribution ranging from 1.0 to 4.7 L/kg after intravenous dosage. Protein binding is low, about 36%, and muscle tissue binding is reported as 54%. A blood-brain barrier exists, and when morphine is introduced outside of the CNS (e.g., intravenously), plasma concentrations of morphine remain higher than the corresponding CSF morphine levels. Conversely, when morphine is injected into the intrathecal space, it diffuses out into the systemic circulation slowly, accounting for the long duration of action of morphine administered by this route. Morphine has a total plasma clearance which ranges from 0.9 to 1.2 L/kg/h (liters/kilogram/hour) in postoperative patients, but shows considerable interindividual variation. The major pathway of

clearance is hepatic glucuronidation to morphine-3-glucuronide, which is pharmacologically inactive. The major excretion path of the conjugate is through the kidneys, with about 10% in the feces. Morphine is also eliminated by the kidneys, 2 to 12% being excreted unchanged in the urine. Terminal half-life is commonly reported to vary from 1.5 to 4.5 hours, although the longer half-lives were obtained when morphine levels were monitored over protracted periods with very sensitive radioimmunoassay methods. The accepted elimination half-life in normal subjects is 1.5 to 2 hours. "Selective" blockade of pain sensation is possible by neuraxial application of morphine. In addition, duration of analgesia may be much longer by this route compared to systemic administration. However, CNS effects, associated with systemic administration, are still seen. These include respiratory depression, sedation, nausea and vomiting, pruritus and urinary retention. In particular, both early and late respiratory depression (up to 24 hours post dosing) have been reported following neuraxial administration. Circulation of the spinal fluid may also result in high concentrations of morphine reaching the brain stem directly. The incidence of unwanted CNS effects, including delayed respiratory depression, associated with neuraxial application of morphine, is related to the circulatory dynamics of the epidural venous plexus and the spinal fluid. The lipid solubility and degree of ionization of morphine plays an important part in both the onset and duration of analgesia and the CNS effects. Morphine has a pKa 7.9, with an octanol/water partition coefficient of 1.42 at pH 7.4. At this pH, the tertiary amino group in each of the opioids is mostly ionized, making the molecule water soluble. Morphine, with additional hydroxyl groups on the molecule, is significantly more water soluble than any other opioid in clinical use. Morphine, injected into the epidural space, is rapidly absorbed into the general circulation. Absorption is so rapid that the plasma concentration-time profiles closely resemble those obtained after intravenous or intramuscular administration. Peak plasma concentrations averaging 33^1-0 ng/mL (range 5-62 ng/mL) are achieved within 10 to 15 minutes after administration of 3 mg of morphine. Plasma concentrations decline in a multiexponential fashion. The terminal half-life is reported to range from 39 to 249 minutes (mean of 9034.3 min) and, though somewhat shorter, is similar in magnitude as values reported after intravenous and intramuscular administration (1.5-4.5 h). CSF concentrations of morphine, after epidural doses of 2 to 6 mg in postoperative patients, have been reported to be 50 to 250 times higher than corresponding plasma concentrations. The CSF levels of morphine exceed those in plasma after only 15 minutes and are detectable for as long as 20 hours after the injection of 2 mg of epidural morphine. Approximately 4% of the dose injected epidurally reaches the CSF. This corresponds to the relative minimum effective epidural and intrathecal doses of 5 mg and 0.25 mg, respectively. The disposition of morphine in the CSF follows a biphasic pattern, with an early half-life of 1.5 h and a late phase half-life of about 6 h. Morphine crosses the dura slowly, with an absorption half-life across the dura averaging 22 minutes. Maximum CSF concentrations are seen 60-90 minutes after injection. Minimum effective CSF concentrations for postoperative analgesia average 150 ng/mL (range < 1-380 ng/mL). The intrathecal route of administration circumvents meningeal diffusion barriers and, therefore, lower doses of morphine produce comparable analgesia to that induced by the epidural route.

After intrathecal bolus injection of morphine, there is a rapid initial distribution phase lasting 1530 minutes and a half-life in the CSF of 42-136 min (mean 9016 min). Derived from limited data, it appears that the disposition of morphine in the CSF, from 15 minutes postintrathecal administration to the end of a six-hour observation period, represents a combination of the distribution and elimination phases. Morphine concentrations in the CSF averaged 332137 ng/mL at 6 hours, following a bolus dose of 0.3 mg of morphine. The apparent volume of distribution of morphine in the intrathecal space is about 228 mL. Time-to-peak plasma concentrations, however, are similar (5-10 min) after either epidural or intrathecal bolus administration of morphine. Maximum plasma morphine concentrations after 0.3 mg intrathecal morphine have been reported from < 1 to 7.8 ng/mL. The minimum analgesic morphine plasma concentration during Patient-Controlled Analgesia (PCA) has been reported as 20-40 ng/mL, suggesting that any analgesic contribution from systemic redistribution would be minimal after the first 30-60 minutes with epidural administration and virtually absent with intrathecal administration of morphine. Last reviewed on RxList: 10/29/2010 This monograph has been modified to include the generic and brand name in many instances.
Duramorph Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs. MORPHINE - INJECTION (MORE-feen) WARNING: Morphine has a high risk for abuse and severe, possibly fatal, breathing problems. The risk for harm is higher if you use the wrong dose/strength, or if you use it along with other drugs that might also affect breathing. Be sure you know how to use morphine and what other drugs you should avoid taking with it. Get immediate help if you notice unusual slow/shallow breathing. Keep this medicine in a safe place to prevent theft, misuse, or abuse. If a child accidentally swallows this drug, get emergency medical help right away. USES: This medication is used to treat severe pain. It acts on certain centers in the brain to give you pain relief. This medication is a narcotic pain reliever (opiate-type). HOW TO USE: Depending on your specific product, this medication is given by injection into a vein, into a muscle, or under the skin. Use this product exactly as directed by your doctor. Read

and learn all of the manufacturer's instructions for preparation and use. If you have any questions about using this medication properly, consult your doctor or pharmacist. Preservative-free morphine may also be given by a doctor as an injection into the area around the spinal cord (epidural) or into the fluid-filled space that contains the spinal cord (intrathecal). In this case, the medication is first given in the hospital where you can be monitored closely. If your doctor directs you to continue using this medication at home, it is usually given as a continuous injection using an infusion pump placed under your skin. The dosage is based on your medical condition and response to treatment. For children, the dosage may also be based on weight. Do not increase your dose, use the medication more frequently, or use it for a longer time than prescribed. Properly stop the medication when so directed. Pain medications work best if they are used when the first signs of pain occur. If you wait until the pain has worsened, the medication may not work as well. Before using, check this product visually for particles or discoloration. If either is present, do not use the liquid. Before injecting each dose, clean the injection site with rubbing alcohol. If this medication is given into a muscle or under the skin, it is important to change the location of the injection site with each dose to avoid problem areas under the skin. Learn how to store and discard needles and medical supplies safely. Consult your pharmacist for more details. If nausea occurs, consult your doctor or pharmacist for ways to decrease it (such as taking antihistamines, lying down for 1 to 2 hours with as little head movement as possible). This medication may cause withdrawal reactions, especially if it has been used regularly for a long time or in high doses. In such cases, withdrawal symptoms (such as restlessness, watery eyes, widened pupils, sweating, runny nose) may occur if you suddenly stop using this medication. To prevent withdrawal reactions, your doctor may reduce your dose gradually. Consult your doctor or pharmacist for more details, and report any withdrawal reactions immediately. When this medication is used for a long time, it may not work as well. Your doctor may need to increase your dose or change your medication. Talk with your doctor if this medication stops working well. Along with its benefits, this medication may rarely cause abnormal drug-seeking behavior (addiction). This risk may be increased if you have abused alcohol or drugs in the past. Use this medication exactly as prescribed to lessen the risk of addiction. Tell your doctor if your pain persists or worsens.

Duramorph Consumer (continued) SIDE EFFECTS: Nausea, vomiting, constipation, lightheadedness, dizziness, drowsiness, increased sweating, or dry mouth may occur. Pain, redness, or swelling at the injection site may occur if this medication is given into a muscle or under the skin. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

To prevent constipation, maintain a diet adequate in fiber, drink plenty of water, and exercise. Consult your pharmacist for help in selecting a laxative (such as a stimulant type with stool softener). Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects. Tell your doctor immediately if any of these unlikely but serious side effects occur: slow/shallow breathing, fainting, mental/mood changes (such as agitation, hallucinations, confusion), difficulty urinating, vision changes, slow/fast heartbeat. Tell your doctor immediately if any of these rare but very serious side effects occur: severe stomach/abdominal pain, change in the amount of urine, seizures. A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing. This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist. In the US Call your doctor for medical advice about side effects. You may report side effects to FDA at 1800-FDA-1088. In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345. Read the Duramorph (morphine injection) Side Effects Center for a complete guide to possible side effects PRECAUTIONS: Before using morphine injection, tell your doctor or pharmacist if you are allergic to it; or to other narcotic pain medications (such as codeine); or if you have any other allergies. This product may contain inactive ingredients (such as sulfites found in some brands), which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: certain bowel diseases (paralytic ileus, infectious diarrhea). Before using this medication, tell your doctor or pharmacist your medical history, especially of: kidney disease, liver disease, lung diseases (such as asthma, chronic obstructive pulmonary disease-COPD), breathing problems (such as slow/shallow breathing, sleep apnea), a certain spinal problem (kyphoscoliosis), certain heart problems (any type of irregular heartbeat), personal or family history of regular use/abuse of drugs/alcohol, brain disorders (such as seizures, head injury, tumor, increased intracranial pressure), underactive thyroid (hypothyroidism), difficulty urinating (for example, due to enlarged prostate or narrowed urethra), disease of the pancreas (such as pancreatitis), mental/mood disorders (such as toxic psychosis), gallbladder disease, adrenal gland problem (such as Addison's disease), intestinal disorders (such as colitis, blockage). This drug may make you dizzy or drowsy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely. Avoid alcoholic beverages. To lower your risk of dizziness and lightheadedness, get up slowly when rising from a sitting or lying position. Before having surgery, tell your doctor or dentist that you are using this medication. Older adults may be more sensitive to the effects of this drug, especially slow/shallow breathing and drowsiness. Before using this medication, women of childbearing age should talk with their doctor(s) about the risks and benefits. Tell your doctor if you are pregnant or if you plan to become pregnant. During pregnancy, this medication should be used only when clearly needed. It may slightly increase the risk of birth defects if used during the first two months of pregnancy. Also, using it for a long time or in high doses near the expected delivery date may harm the unborn baby. To lessen the risk, use the smallest effective dose for the shortest possible time. Tell the doctor right away if you notice any symptoms in your newborn baby such as slow/shallow breathing, irritability, abnormal/persistent crying, vomiting, or diarrhea. This drug passes into breast milk and the effect on a nursing infant is not known. Discuss the risks and benefits with your doctor before breast-feeding.
Duramorph Consumer (continued) DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

This drug should not be used with the following medication because a very serious interaction may occur: naltrexone.

If you are currently using this medication listed above, tell your doctor or pharmacist before starting morphine. Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: cimetidine, rifampin, certain medications for pain (opiate partial agonists such as butorphanol, nalbuphine, pentazocine). The risk of serious side effects (such as slow/shallow breathing, severe drowsiness/dizziness) may be increased if this medication is used with other products that may also affect breathing or cause drowsiness. Therefore, tell your doctor or pharmacist if you are using other products such as alcohol, anti-seizure drugs (such as phenobarbital), medicine for sleep or anxiety (such as alprazolam, diazepam, zolpidem), muscle relaxants, other narcotic pain relievers (such as codeine), and psychiatric medicines (such as risperidone, amitriptyline, trazodone). Your medications or doses of your medications may need to be changed. Check the labels on all your medicines (such as cough-and-cold products) because they may contain ingredients that cause drowsiness. Ask your pharmacist about using those products safely. This medication may interfere with certain laboratory tests (including amylase and lipase levels), possibly causing false test results. Make sure laboratory personnel and all your doctors know you use this drug. This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist. OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: slow/shallow breathing, severe drowsiness, slow heartbeat, severe dizziness, pinpoint pupils. NOTES: Do not share this medication with others. It is against the law. This medication has been prescribed for your current condition only. Do not use it later for another condition unless told to do so by your doctor. A different medication may be necessary in that case. MISSED DOSE: If you use this medication regularly and miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up. STORAGE: Store at room temperature away from light. Different brands/packaging of this medication may have different storage requirements. Read the package labeling or ask your pharmacist for the storage requirements for the product you are using. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product. Information last revised January 2012. Copyright(c) 2012 First Databank, Inc.