MORPHINE SULFATERECTAL SUPPOSITORIES(WARNING: MAY BE HABIT FORMING)

DESCRIPTIONEach suppository for rectal administration con-tains 5 mg, 10 mg, 20 mg, or 30 mg ofMorphine Sulfate in a bland, specially formulat-ed Hydrogenated Vegetable Oil Base with BHAand BHT as preservatives, as well as otheringredients.Chemically, Morphine Sulfate is, Morphinan-3,6-diol, 7,8-didehydro-4,5-epoxy-17-methyl-,(5a,6a)-, sulfate (2:1) (salt), pentahydrate, whichcan be represented by the following structuralformula:

CLINICAL PHARMACOLOGYMorphine is a potent narcotic analgesic; it’sprincipal therapeutic effect is relief of pain. Inaddition to analgesia, narcotics produce drowsi-ness, changes in mood, and mental clouding;although neither sensory modalities nor motoractivity are blocked at therapeutic doses. Thereis no intrinsic limit to the analgesic effect.Clinically, however, dosage limitations areimposed by the adverse effects, primarily respi-ratory depression, nausea, and vomiting, whichcan result from high doses.

Morphine has diverse additional actions. Itdepresses the respiratory center, stimulates thevomiting center, depresses the cough reflex,constricts the pupils, increases the tone of gas-trointestinal and genitourinary tracts, and pro-duces mild vasodilation. Morphine is detoxifiedin the liver by means of conjugation with glu-curonic acid. Small amounts of the free drugand larger amounts of conjugated morphine arepresent in the urine, and these account for mostof the administered drug. Ninety percent of thetotal excretion occurs within the first 24 hours.

Morphine is about two-thirds absorbed from thegastrointestinal tract with the maximum anal-gesic effect occuring 20-60 minutes postadministration.

INDICATIONS AND USAGEMorphine is indicated for the relief of severechronic pain, and severe acute pain.

CONTRAINDICATIONSHypersensitivity to morphine; respiratory insuf-ficiency or depression; severe CNS depression;attack of bronchial asthma; heart failure sec-ondary to chronic lung disease; cardiac arrhyth-mias; increased intracranial or cerebrospinalpressure; head injuries; brain tumor; acute alco-holism, delerium tremens; convulsive disorders;after biliary tract surgery; suspected surgicalabdomen; surgical anastomosis; concomitantlywith MAO inhibitors or within 14 days of suchtreatment.

WARNINGSMorphine can cause tolerance, psychologicaland physical dependence. Withdrawal will occuron abrupt discontinuation or administration of anarcotic antagonist.Interaction with Other Central-Nervous-SystemDepressants - Morphine should be used withcaution and in reduced dosage in patients whoare concurrently receiving other narcotic anal-gesics, general anesthetics, phenothiazines,other tranquilizers, sedative-hypnotics, tricyclicantidepressants, and other CNS depressants(including alcohol). Respiratory depression,hypotension, and profound sedation or coma

CII may result.PRECAUTIONSGeneral: Head Injury and Increased Intracranial Pressure-The respiratory depressant effects of morphineand its capacity to elevate cerebrospinal-fluidpressure may be markedly exaggerated in thepresence of increased intracranial pressure.Furthermore, narcotics produce side effects thatmay obscure the clinical course of patients withhead injuries. In such patients, morphine must beused with caution and only if it is deemed essen-tial.Asthma and Other Respiratory Conditions-Morphine should be used with caution in patientshaving an acute asthmatic attack, in those withchronic obstructive pulmonary disease or cor pul-monale, and in individuals with substantiallydecreased respiratory reserve, preexisting respi-ratory depression, hypoxia, or hypercapnia. Insuch patients, even usual therapeutic doses ofnarcotics may decrease respiratory drive whilesimultaneously increasing airway resistance tothe point of apnea.

Hypotensive Effect - the administration of mor-phine may result in severe hypotension in an indi-vidual whose ability to maintain his blood pres-sure has already been compromised by a deplet-ed blood volume or concurrent administration ofsuch drugs as the phenothiazines or certain anes-thetics.

Supraventricular Tachycardias - Caution shouldbe used in patients with atrial flutter and othersupraventricular tachycardias due to a possiblevagolytic action which may produce a significantincrease in the ventricular response rate.

Special Risk Patients - Morphine should be givenwith caution and the initial dose should bereduced in certain patients, such as the elderly ordebilitated and those with severe impairment ofhepatic or renal function, hypothyroidism,Addison’s disease, prostatic hypertrophy, or ure-thral stricture.

Convulsions - Morphine may aggravate preexist-ing convulsive disorders. Convulsions may occurin individuals without a history of convulsive dis-orders if dosage is substantially escalated aboverecommended levels because of tolerance devel-opment.

Acute Abdominal Conditions - The administrationof morphine or other narcotics may obscure thediagnosis or clinical course in patients with acuteabdominal conditions.

INFORMATION FOR PATIENTS

Use in Ambulatory Patients - Morphine mayimpair the mental and/or physical abilitiesrequired for the performance of potentially haz-ardous tasks, such as driving a car or operatingmachinery. The patient should be cautionedaccordingly.

Morphine, like other narcotics, may produceorthostatic hypotension in ambulatory patients.

Patients should be cautioned about the combinedeffects of alcohol or other central nervous systemdepressants with morphine.

Drug Interactions - Generally, effects of morphinemay be potentiated by alkalizing agents and antag-onized by acidifying agents. Analgesic effect ofmorphine is potentiated by chlorpromazine andmethocarbamol, CNS depressants such as anes-thetics, hypnotics, barbiturates, phenothiazines,chloral hydrate, glutethimide, sedatives, MAOinhibitors (including procarbazine hydrochloride),antihistamines, beta-blockers (propranolol), alco-hol, furazolidone and other narcotics mayenhance the depressant effects of morphine.Morphine may increase anticoagulant activity of

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ItemBarcode

2124053

placed on scheduled narcotic programs insteadof a “pain to relief of pain” cycle typical of a PRNregimen.

OVERDOSAGESigns and Symptoms: Serious overdosage is characterized by respirato-ry depression ( a decrease in respiratory rateand/or tidal volume, Cheyne-Stokes respiration,cyanosis), extreme somnolence progressing tostupor or coma, maximally constricted pupils,skeletal muscle flaccidity, cold and clammy skin,and sometimes bradycardia and hypotension. Insevere overdosage, particularly by the IV route,apnea, circulatory collapse, cardiac arrest, anddeath may occur.Treatment of Overdose:Primary attention should be given to the reestab-lishment of adequate respiratory exchangethrough provision of a patent airway and institu-tion of assisted or controlled ventilation. Ifdepressed respiration is associated with muscularrigidity, an IV neuromuscular blocking agent maybe required to facilitate assisted or controlled res-piration.The narcotic antagonists-nalorphine, naloxone,and levallorphan are specific antidotes againstrespiratory depression resulting from overdosageor unusual sensitivity to narcotics. Thus, anantagonist should be administered, preferably bythe IV route, simultaneously with efforts at respi-ratory resuscitation. Since the duration of actionof morphine may exceed that of the antagonist,repeated doses of the antagonist may be requiredto maintain adequate respiration; the patient mustbe kept under surveillance.

Oxygen, intravenous fluids, vasopressors, andother supportive measures should be employedas indicated. In cases of oral overdose, the stom-ach should be evacuated by emesis or gastriclavage if treatment can be instituted within 2hours following ingestion. The patient should beobserved closely for a rise in temperature or pul-monary complications that may signal the needfor institution of antibiotic therapy.

DOSAGE AND ADMINISTRATION FOR MOR-PHINE SULFATE SUPPOSITORIES

Usual Adult Dose: 10 to 20 mg every 4 hours oras directed by physician.Dosage is a patient dependent variable, thereforeincreased dosage may be required to achieve ade-quate analgesia.Note: Medication may suppress respiration in theelderly, the very ill, and those patients with respi-ratory problems, therefore lower doses may berequired.Morphine Dosage Reduction - During the first twoto three days of effective pain relief, the patientmay sleep for many hours. This can be misinter-preted as the effect of excessive analgesic dosingrather than the first sign of relief of a painexhausted patient. The dose, therefore, should bemaintained for at least three days before reduc-tion, if respiratory activity and other vital signs areadequate.

Following successful relief of severe pain, period-ic attempts to reduce the narcotic dose should bemade. Smaller doses or complete discontinuationof the narcotic analgesic may become feasible dueto a physiologic change or the improved mentalstate of the patient.

HOW SUPPLIEDMorphine Sulfate Suppositories are available incartons of 12. Easy-to-open, color-coded:5 mg Suppositories (Red)12’s NDC 0574-7110-12

10 mg Suppositories (Light Blue)12’s NDC 0574-7112-12

20 mg Suppositories (Light Green)12’s NDC 0574-7114-12

30 mg Suppositories (Purple)12’s NDC 0574-7116-12

A Schedule Narcotic

DEA Order Form Required

RRxx oonnllyyCaution: Federal law prohibits transfer of thisdrug to any person other than the patient forwhom it was prescribed.

PADDOCK LABORATORIES, INC.Minneapolis, MN 55427 2124053 (07-05)

Coumadin® and other anticoagulants.

Carcinogenicity/Mutagenicity - Long-term stud-ies to determine the carcinogenic and muta-genic potential of morphine are not available.

PREGNANCYTeratogenic Effects - Pregnancy Category C:Animal reproduction studies have not been con-ducted with morphine. It is also not knownwhether morphine can cause fetal harm whenadministered to a pregnant woman or can affectreproduction capacity. Morphine should begiven to a pregnant woman only if clearly need-ed.Labor and Delivery - Morphine readily crossesthe placental barrier and if administered duringlabor may lead to respiratory depression in theneonate.

Nursing Mothers - Morphine has been detectedin human milk. For this reason, caution shouldbe exercised when morphine is administered toa nursing woman.

Pediatric Usage - Safety and effectiveness inchildren have not been established.

ADVERSE REACTIONSTHE MAJOR HAZARDS OF MORPHINE, ASWITH OTHER NARCOTIC ANALGESICS, ARERESPIRATORY DEPRESSION AND, TO A LESS-ER DEGREE, CIRCULATORY DEPRESSION,RESPIRATORY ARREST, SHOCK, AND CAR-DIAC ARREST HAVE OCCURRED.The most frequently observed adverse reac-tions include lightheadedness, dizziness, seda-tion, nausea, vomiting and sweating. Theseeffects seem to be more prominent in ambula-tory patients and in those who are not sufferingsevere pain. In such individuals, lower dosesare advisable. Some adverse reactions may bealleviated in the ambulatory patient who liesdown.Other adverse reactions include the following:

Central Nervous System - Euphoria, dysphoria,weakness, headache, insomnia, agitation, dis-orientation, and visual disturbances.

Gastrointestinal - Dry mouth, anorexia, consti-pation, and biliary tract spasm.

Cardiovascular - Flushing of the face, bradycar-dia, palpitation, faintness and syncope.

Genitourinary - Urinary retention or hesitancy,anti-diuretic effect, and reduced libido and/orpotency.

Allergic - Pruritus, urticaria, other skin rashes,edema, and rarely hemorrhagic urticaria.

Treatment of the most frequent adverse reac-tions:

Constipation - Ample intake of water or otherliquids should be encouraged. Concomitantadministration of a stool softener and a peri-staltic stimulant with the narcotic analgesic canbe an effective preventive measure for thosepatients in need of therapeutics. If eliminationdoes not occur for two days, an enema shouldbe administered to prevent impaction.

In the event diarrhea occurs, seepage around afecal impaction is a possible cause to considerbefore antidiarrheal measures are employed.

Nausea and Vomiting - Phenothiazines and anti-histamines can be effective treatments for nau-sea of the medullary and vestibular sourcesrespectively. However, these drugs may potenti-ate the side effects of the narcotic or the antin-auseant.

Drowsiness (sedation) - Once pain control isachieved, undesirable sedation can be mini-mized by titrating the dosage to a level that justmaintains a tolerable pain or pain free state.

DRUG ABUSE AND DEPENDENCEMorphine Sulfate is a Schedule II controlledsubstance. As with other narcotics, somepatients may develop a physical and psycholog-ical dependence on morphine. They mayincrease dosage without consulting a physicianand subsequently may develop a physicaldependence on the drug. In such cases, abruptdiscontinuance may precipitate typical with-drawal symptoms, including convulsions.Therefore, the drug should be withdrawn grad-ually from any patient known to be takingexcessive dosages over a long period of time.In treating the terminally ill patient the benefit ofpain relief may outweigh the possibility of drugdependence. The chance of drug dependence issubstantially reduced when the patient is

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