Morphine Sulfate: Package Insert and Label Information (Page 3 of 4)

12 CLINICAL PHARMACOLOGY

12.1 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 drowsiness, changes in mood, respiratory depression, decreased gastrointestinal motility, nausea, vomiting, and alterations of the endocrine and autonomic nervous system.

Effects on the Central Nervous System (CNS)

The principal therapeutic action of morphine sulfate is analgesia. Other therapeutic effects of morphine sulfate include anxiolysis, euphoria and feelings of relaxation. Although the precise mechanism of the analgesic action is unknown, specific CNS opiate receptors and endogenous compounds with morphine sulfate-like activity have been identified throughout the brain and spinal cord and are likely to play a role in the expression and perception of analgesic effects. In common with other opioids, morphine sulfate causes respiratory depression, in part by a direct effect on the brainstem respiratory centers. Morphine sulfate and related opioids depress the cough reflex by direct effect on the cough center in the medulla.

Morphine sulfate causes miosis, even in total darkness.

Effects on the Gastrointestinal Tract and on Other Smooth Muscle

Gastric, biliary and pancreatic secretions are decreased by morphine sulfate. Morphine sulfate causes a reduction in motility and is associated with an increase in tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone is increased to the point of spasm. The end result may be constipation. Morphine sulfate can cause a marked increase in biliary tract pressure as a result of spasm of the sphincter of Oddi. Morphine sulfate may also cause spasm of the sphincter of the urinary bladder.

Effects on the Cardiovascular System

In therapeutic doses, morphine sulfate does not usually exert major effects on the cardiovascular system. Morphine sulfate produces peripheral vasodilation which may result in orthostatic hypotension and fainting. Release of histamine can occur, which may play a role in opioid-induced hypotension. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating.

Endocrine System

Opioid agonists have been shown to have a variety of effects on the secretion of hormones. Opioids inhibit the secretion of ACTH, cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon in humans and other species, rats and dogs. Thyroid stimulating hormone (TSH) has been shown to be both inhibited and stimulated by opioids.

Immune System

Opioids have been shown to have a variety of effects on components of the immune system in and animal models. The clinical significance of these findings is unknown. in vitro

12.2 Pharmacodynamics

Morphine sulfate concentrations are not predictive of analgesic response, especially in patients previously treated with opioids. The minimum effective concentration varies widely and is influenced by a variety of factors, including the extent of previous opioid use, age and general medical condition. Effective doses in tolerant patients may be significantly higher than in opioid-naïve patients.

12.3 Pharmacokinetics

Absorption

Morphine sulfate is about two-thirds absorbed from the gastrointestinal tract with the maximum analgesic effect occurring 60 minutes post-administration. The oral bioavailability of morphine sulfate is less than 40% and shows large inter-individual variability due to extensive pre-systemic metabolism.

Food Effects

Although the presence of a food effect was not assessed with morphine sulfate oral solution, significant food effect is not expected with a solution formulation.

Steady-State

Administration of the 30 mg Morphine Sulfate Tablet and 30 mg of Morphine Sulfate Oral Solution every six hours for 5 days resulted in a comparable 24-hour exposure (AUC). The steady-state levels were achieved within 48 hours for both tablets and solution. The mean steady state Cmax values were about 78 and 58 ng/mL for tablet and solution, respectively.

Distribution

Once absorbed, morphine sulfate 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 sulfate also crosses the placental membranes and has been found in breast milk. The volume of distribution of morphine sulfate is approximately 1 to 6 L/kg, and morphine sulfate is 20 to 35% reversibly bound to plasma proteins.

Metabolism

The major pathway of morphine sulfate detoxification is conjugation, either with D-glucuronic acid to produce glucuronides or with sulfuric acid to produce morphine-3-etheral sulfate. While a small fraction (less than 5%) of morphine sulfate is demethylated, virtually all morphine sulfate is converted by hepatic metabolism to the 3- and 6-glucuronide metabolites (M3G and M6G; about 50% and 15%, respectively). M6G has been shown to have analgesic activity but crosses the blood-brain barrier poorly, while M3G has no significant analgesic activity.

Excretion

Most of a dose of morphine sulfate is excreted in urine as M3G and M6G, with elimination of morphine sulfate occurring primarily as renal excretion of M3G. Approximately 10% of the dose is excreted unchanged in urine. A small amount of glucuronide conjugates are excreted in bile, with minor enterohepatic recycling. Seven to 10% of administered morphine sulfate is excreted in the feces.

The mean adult plasma clearance is approximately 20 to 30 mL/min/kg. The effective terminal half-life of morphine sulfate after IV administration is reported to be approximately 2 hours. In some studies involving longer periods of plasma sampling, a longer terminal half-life of morphine sulfate of about 15 hours was reported.

Race

There may be some pharmacokinetic differences associated with race. In one published study, Chinese subjects given intravenous morphine sulfate had a higher clearance when compared to Caucasian subjects (1852 +/- 116 mL/min compared to 1495 +/- 80 mL/min).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Studies in animals to evaluate the carcinogenic potential of morphine sulfate 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 increasing DNA fragmentation in human T-cells. Morphine was reported to be mutagenic in the mouse micronucleus assay and positive for the induction of chromosomal aberrations in mouse spermatids and murine lymphocytes. Mechanistic studies suggest that the 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, studies in the literature have also shown that morphine did not induce chromosomal aberrations in human leukocytes or translocations or lethal mutations in . in vitro in vivo in vivo in vitro 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.

16 HOW SUPPLIED/STORAGE AND HANDLING

NDC:17856-0238-5 in a CUP, UNIT-DOSE of 5 SOLUTIONS

17 PATIENT COUNSELING INFORMATION

See Medication Guide

Provide the following information to patients receiving morphine sulfate or their caregivers:

•Advise patients that morphine sulfate is a narcotic pain reliever, and should be taken only as directed.•Advise patients that Morphine Sulfate Oral Solution is available in three concentrations: 10 mg per 5 mL, 20 mg per 5 mL and 100 mg per 5 mL (20 mg/mL). Carefully instruct patients about which concentration they have been prescribed and how to measure and take the correct dose of Morphine Sulfate Oral Solution. Advise patients whenever the prescribed concentration is changed to avoid dosing errors which could result in accidental overdose and death.•Advise patients to always use the enclosed calibrated oral syringe when administering Morphine Oral Solution 100 mg per 5 mL (20 mg/mL) to ensure the dose is measured and administered accurately.•The 100 mg per 5 mL (20 mg/mL) formulation is only for patients who are already receiving opioid-therapy and have demonstrated opioid-tolerance. Use of this formulation may cause fatal respiratory depression when administered to patients who have not had previous exposure to opioids.•Advise patients not to adjust the dose of morphine sulfate without consulting with a physician or other healthcare professional.•Advise patients that morphine sulfate may cause drowsiness, dizziness, or lightheadedness and may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating machinery). Advise patients started on morphine sulfate or patients whose dose has been adjusted to refrain from any potentially dangerous activity until it is established that they are not adversely affected.•Instruct patients not to combine morphine sulfate with central nervous system depressants (such as sleep aids, tranquilizers, antihistamines, general anesthetics, phenothiazines, other opioids, and monoamine oxidase [MAO] inhibitors) except by the orders of the prescribing physician, and not to combine with alcohol because dangerous additive effects may occur, resulting in serious injury or death.•Instruct women of childbearing potential who become or are planning to become pregnant to consult a physician prior to initiating or continuing therapy with morphine sulfate.•Advise patients that safe use in pregnancy has not been established and that prolonged use of opioid analgesics during pregnancy may cause fetal-neonatal physical dependence, Neonatal withdrawal may also occur.•If patients have been receiving treatment with morphine sulfate for more than a few weeks and cessation of therapy is indicated, counsel them on the importance of safely tapering the dose as abrupt discontinuation of the medication could precipitate withdrawal symptoms. Provide a dose schedule to accomplish a gradual discontinuation of the medication.•Advise patients that morphine sulfate is a potential drug of abuse. They must protect it from theft. It should never be given to anyone other than the individual for whom it was prescribed.•Instruct patients to keep morphine sulfate in a secure place out of the reach of children. When morphine sulfate is no longer needed, the unused oral solution should be destroyed by flushing down the toilet.•Advise patients taking morphine sulfate of the potential for severe constipation; appropriate laxatives and/or stool softeners as well as other appropriate treatments should be initiated from the onset of opioid therapy.•Advise patients of the most common adverse events that may occur while taking morphine sulfate: constipation, nausea, somnolence, lightheadedness, dizziness, sedation, vomiting, and sweating.

DISTRIBUTED BY:

ATLANTIC BIOLOGICALS CORP

20101 N.E 16TH PLACE

MIAMI, FL 33179

Medication Guide

MORPHINE SULFATE (mor-pheen) (CII)

Oral Solution

. IMPORTANT: Keep Morphine Sulfate Oral Solution in a safe place away from children. Accidental use by a child is a medical emergency and can cause death. If a child accidentally takes Morphine Sulfate Oral Solution, get emergency help right away

Read the Medication Guide that comes with Morphine Sulfate Oral Solution before you start taking it and each time you get a new prescription. There may be new information. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or your treatment.

What is the most important information I should know about Morphine Sulfate Oral Solution?

Morphine Sulfate Oral Solution can cause serious side effects, including death.


Take Morphine Sulfate Oral Solution exactly as prescribed by your healthcare provider. If you take the wrong dose or strength of Morphine Sulfate Oral Solution, you could overdose and die.

It is especially important when you take Morphine Sulfate Oral Solution that you know exactly what dose and strength to take, and the right way to measure your medicine. Your healthcare provider or pharmacist should show you the right way to measure your medicine.

Always use the oral syringe provided with Morphine Sulfate Oral Solution, 100 mg per 5 mL (20 mg/mL) to help make sure you measure the right amount.

The oral solution comes in several different doses (amount of medicine per mL) and strengths (number of mgs).

Do not take the strongest dose of Morphine Sulfate Oral Solution, 100 mg per 5 mL (20 mg/mL), unless you are “opioid tolerant.” Opioid tolerant means that you have been regularly using Morphine Sulfate Oral Solution or another opioid medicine for your constant (around the clock) pain and your body is used to it.
What is Morphine Sulfate Oral Solution?

Morphine Sulfate Oral Solution is in a group of drugs called narcotic pain relievers. Morphine Sulfate Oral Solution is only for adults who have moderate to severe pain.


Morphine Sulfate Oral Solution is a prescription medicine that is used to manage moderate to severe pain that is expected to last a short period of time (acute), and pain that continues around-the-clock and is expected to last for a long period of time (chronic).

Morphine Sulfate Oral Solution is a federally controlled substance (CII) because it is a strong opioid pain medicine that can be abused by people who abuse prescription medicines or street drugs.

Prevent theft, misuse or abuse. Keep Morphine Sulfate Oral Solution in a safe place to keep it from being stolen. Morphine Sulfate Oral Solution can be a target for people who misuse or abuse prescription medicines or street drugs.

Never give Morphine Sulfate Oral Solution to anyone else, even if they have the same symptoms you have. It may harm them or even cause death.

Selling or giving away this medicine is against the law.

It is not known if Morphine Sulfate Oral Solution is safe and effective in children under age 18 years of age.

Morphine Sulfate Oral Solution 100 mg per 5 mL (20 mg/mL) is only for adults with moderate to severe pain who are already using an opioid narcotic pain medicine and have been using this medicine continuously for several weeks or longer.

Who should not take Morphine Sulfate Oral Solution?


Do not take Morphine Sulfate Oral Solution if you:

See the end of this Medication guide for a complete list of ingredients in Morphine Sulfate Oral Solution. are allergic to morphine, morphine salts or any of the ingredients in Morphine Sulfate Oral Solution.

are having an asthma attack or have severe asthma, trouble breathing, or lung problems

have a bowel blockage called paralytic ileus
What should I tell my healthcare provider before taking Morphine Sulfate Oral Solution?


Before taking Morphine Sulfate Oral Solution, tell your healthcare provider if you:

have trouble breathing or lung problems

have had a head injury

have liver or kidney problems

have had adrenal gland problems, such as Addison’s disease

have severe scoliosis that affects your breathing

have thyroid problems

have problems urinating or enlargement of your prostate

have had convulsions or seizures

have a past or present drinking problem or alcoholism

have severe mental problems or hallucinations (seeing or hearing things that are not really there).

have constipation or other bowel problems

have problems with your pancreas or gallbladder

have past or present substance abuse or drug addiction

plan to have surgery

have any other medical conditions

are pregnant or plan to become pregnant. It is not known if Morphine Sulfate Oral Solution will harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant.
If you take Morphine Sulfate Oral Solution regularly before your baby is born, your newborn baby may have withdrawal symptoms because their body has become used to the medicine. Symptoms of withdrawal in a newborn baby may include:


irritability

being very active

problems sleeping

high pitched cry

shaking (tremors)

vomiting

diarrhea or more stools than normal

weight loss

fever
If you take Morphine Sulfate right before your baby is born, your baby could have breathing problems.


are breast-feeding or plan to breast-feed. Some Morphine Sulfate passes into your breast milk. A nursing baby could become very sleepy and have problems breathing or feeding well. If you stop breast-feeding, your baby may have withdrawal symptoms. See the list of withdrawal symptoms above. You and your healthcare provider should decide if you will take Morphine Sulfate Oral Solution or breast-feed.

, including prescription and non-prescription medicines, vitamins, and herbal supplements. Sometimes the doses of medicines that you take with Morphine Sulfate Oral Solution may need to be changed if used together. Be especially careful about taking other medicines that make you sleepy such as: Tell your healthcare provider about all the medicines you take


sleeping pills

other pain medicines

anti-nausea medicines

tranquilizers

muscle relaxants

antihistamines

anti-anxiety medicines

anti-depressants

anticholinergic medicines

antibiotic or antifungal medicines

heart medicines

anti-seizure medicines

Tell your healthcare provider if you take cimetidine (Tagamet).

Do not take Morphine Sulfate Oral Solution if you already take a monoamine oxidase inhibitor medicine (MAOI) or within 14 days after you stop taking an MAOI medicine.

Do not take any new medicine while using Morphine Sulfate Oral Solution until you have talked with your healthcare provider or pharmacist. They will tell you if it is safe to take other medicines with Morphine Sulfate Oral Solution.
Ask your healthcare provider if you are not sure if your medicine is one listed above.

Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I take Morphine Sulfate Oral Solution?


See “What is the most important information I should know about Morphine Sulfate Oral Solution?”

. Do not change your dose unless your healthcare provider tells you to. Your healthcare provider may change your dose after seeing how the medicine affects you. Call your healthcare provider if your pain is not well controlled with your prescribed dose of Morphine Sulfate Oral Solution. Take Morphine Sulfate Oral Solution exactly as prescribed

. You can take Morphine Sulfate Oral Solution with or without food

. Always use the oral syringe provided with your Morphine Sulfate Oral Solution, 100 mg per 5 mL (20 mg/mL) to help make sure you measure the right amount. See the Instructions for Use at the end of this Medication Guide for information about how to measure your dose the right way. Ask your healthcare provider or pharmacist if you are not sure what dose of Morphine Sulfate Oral Solution you should take or if you are not sure how to use the oral syringe. Make sure you understand exactly how to measure your dose

If you have been taking Morphine Sulfate Oral Solution for more than a few weeks, stopping Morphine Sulfate Oral Solution suddenly can make you sick with withdrawal symptoms (for example, nausea, vomiting, diarrhea, anxiety, and shivering). If your healthcare provider decides you no longer need Morphine Sulfate Oral Solution, ask how to slowly reduce this medicine. Do not stop taking Morphine Sulfate Oral Solution without talking to your healthcare provider. Do not stop taking Morphine Sulfate Oral Solution suddenly.

you can take the dose when you remember it if you have pain, or you can wait for the next dose. If you miss one dose of Morphine Sulfate Oral Solution
Talk with your healthcare provider regularly about your pain to see if you still need to take Morphine Sulfate Oral Solution.

What should I avoid while taking Morphine Sulfate Oral Solution?


You should not drink alcohol while using Morphine Sulfate Oral Solution. Drinking alcohol with Morphine Sulfate Oral Solution may increase your risk of having dangerous side effects or death.

especially when you start taking Morphine Sulfate Oral Solution and when your dose is changed, until you know how Morphine Sulfate Oral Solution affects you. Morphine Sulfate Oral Solution can make you sleepy. Ask your healthcare provider to tell you when it is okay to do these activities. Do not drive, operate heavy machinery, or do other dangerous activities,
What are the possible side effects of Morphine Sulfate Oral Solution?


See “What is the most important information I should know about Morphine Sulfate Oral Solution?”

Morphine Sulfate Oral Solution can cause serious breathing problems that can become life-threatening, especially if Morphine Sulfate Oral Solution is used the wrong way. Call your healthcare provider or get help right away if:

your breathing slows down

you have shallow breathing (little chest movement with breathing)

you feel faint, dizzy, confused, or

you have any other unusual symptoms
These can be symptoms that you have taken too much Morphine Sulfate Oral Solution (overdose) or the dose is too high for you. These symptoms may lead to serious problems or death if not treated right away.


This can make you feel dizzy if you get up too fast from sitting or lying down. Low blood pressure is also more likely to happen if you take other medicines that can also lower your blood pressure. Severe low blood pressure can happen if you lose blood or take certain other medicines. Morphine Sulfate Oral Solution can cause your blood pressure to drop.

The chance is higher if you are or have been addicted to or abused other medicines, street drugs, or alcohol, or if you have a history of mental problems. There is a risk of abuse or addiction with Morphine Sulfate Oral Solution.

Do not stop taking Morphine Sulfate or any other opioid without talking to your healthcare provider about how to slowly stop your medicine. You could become sick with uncomfortable withdrawal symptoms because your body has become used to these medicines. Physical dependence is not the same as drug addiction. Tell your healthcare provider if you have any of these symptoms of withdrawal while slowly stopping Morphine Sulfate Oral Solution: Morphine Sulfate can cause physical dependence.

feel restless

tearing eyes

runny nose

yawning

sweating

chills or hair on your arms “stand up”

muscle aches, backache

dilated pupils of your eyes

feel irritable or anxious

trouble sleeping

nausea, loss of appetite, vomiting, diarrhea, stomach-area (abdominal) cramps

increase in your blood pressure

faster breathing, or faster heart beats


Common side effects of Morphine Sulfate Oral Solution include:

constipation

nausea

sleepiness

lightheadedness

dizziness

drowsiness

vomiting

sweating
Constipation (not often enough or hard bowel movements) is a very common side effect of pain medicines (opioids). Talk to your healthcare provider about dietary changes, and the use of laxatives (medicines to treat constipation) and stool softeners to prevent or treat constipation while taking Morphine Sulfate Oral Solution.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Morphine Sulfate Oral Solution. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Morphine Sulfate Oral Solution?


Store Morphine Sulfate Oral Solution at 68º to 77º F (20º to 25º C).

After you stop taking Morphine Sulfate Oral Solution, flush the unused oral solution down the toilet.

Keep Morphine Sulfate out of the reach of children. Accidental overdose by a child is a medical emergency and can lead to death.
General information about Morphine Sulfate Oral Solution

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Morphine Sulfate Oral Solution for a condition for which it was not prescribed. Do not give your Morphine Sulfate Oral Solution to other people, even if they have the same symptoms you have. Selling or giving away Morphine Sulfate Oral Solution may harm others, may cause death, and is against the law.

This Medication Guide summarizes the most important information about Morphine Sulfate Oral Solution. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Morphine Sulfate Oral Solution that is written for healthcare professionals.

For more information about Morphine Sulfate Oral Solution, go to or call Roxane Laboratories, Inc. at 1-800-962-8364. www.roxane.com

What are the ingredients in Morphine Sulfate Oral Solution?

morphine sulfate USP Active ingredient:

citric acid, edetate disodium, glycerin, sodium benzoate, sorbitol, and water. Inactive ingredients:• The 10 mg/5 mL oral solution also contains: FD&C Green No. 3 (fast green) • The 20 mg/5 mL oral solution also contains: FD&C Green No. 3 (fast green), methylparaben, and propylparaben • The 100 mg per 5 mL tinted solution also contains D & C Red No. 33 and sucralose.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

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