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`

`)DUCT INFORMATION
`
`NTNGS
`
`athadone Hydrochloride Tablets are for oral adnoin-
`ration only and must not be used for injection. It is
`commended that Methadone Hydrochloride Tab-
`s if dispensed, be packaged in child-resistant con-
`jeers and kept out of the reach of children to pre-
`nt accidental ingestion.
`
`aadone Hydrochloride, a narcotic, is a Schedule II con-
`ed substance under the Federal Controlled Substances
`
`G DEPENDENCE - METHADONE CAN PRODUCE
`IG DEPENDENCE OF THE MORPHINE TYPE AND,
`BEFORE, HAS THE POTENTIAL FOR BEING ABUSED.
`CHIC DEPENDENCE, PHYSICAL DEPENDENCE, AND
`ERAIOICE MAY DEVELOP UPON REPEATED ADMINIS-
`iIor’j OF METHADONE, AND IT SHOULD BE PRE-
`IBEO AND ADMINISTERED WITH THE SAME DEGREE
`IAUTION APPROPRIATE TO THE USE OF MORPHINE.
`raction with Other Central-Nervous-System Depres-
`s_(cid:150)Methadone should be used with caution and in re-
`vi dosage in patients who are concurrently receiving
`a narcotic analgesics, general anesthetics, phenothia-
`s, other tranquilizers, sedative-hypnotics, tricyclic anti-
`-essants. and other C.N.S. depressants (including alco-
`Respiratory depression, hvpotension, and profound se-
`en or coma may result.
`jeff (cid:151)Since methadone, as used by tolerant subjects at
`oetant maintenance dosage, is not a tranquilizer, pa-
`ts who are maintained on this drug will react to life
`)lems and stresses with the same symptoms of anxiety
`jo other individuals. The physician should net confuse
`I symptoms with those of narcotic abstinence and
`old net attempt to treat anxiety by increasing the dosage
`iethadone. The action of methadone in maintenance
`tment is limited to the control of narcotic symptoms and
`,effective for relief of general anxiety.
`d Injury and Increased Intracranial Pressure (cid:151)The res-
`tory depressant effects of methadone and its rapacity to
`ate cerebrospinal-fluid pressure may be markedly exag-
`ded in the presence of increased intracranial pressure.
`thermore. narcotics produce side effects that may oh-
`-e the clinical course of patients with head injuries. In
`I patients, methadone must be used with caution and
`if it is deemed essential.
`’once and Other Respiratory Conditions (cid:151)Methadone
`Ad be used with caution in patients having an acute
`imatic attack, in those with chronic obstructive pulme-
`y disease or ccc pulmonale, and in individuals with a
`stantiallv decreased respiratory reserve, preexisting rec-
`tory depression. hypoxia, or hypercapnia. In such pa.
`is. even usual therapeutic doses of narcotics may de-
`we respiratory drive while simultaneously increasing
`ray resistance to the point of apnea.
`otensive Effect (cid:151)The administration of methadone may
`alt in corers Iovpotension in an individual whose ability
`oaintain his blood pressure has already been compro-
`ed by a depleted blood volume or concurrent administra-
`- of such drugs as the phenothiazines or certain rues-
`:.lcs.
`in Ambulatory Patients (cid:151)Methadone nosy impair the
`otal and/or physical abilities required for the perfor.
`0cc of potentially hazardous tasks, such as driving scar
`perating machinery , The patient should be cautioned ar-
`lingly.
`diadone. like other narcotics. may produce orthostatic
`’atonsion in ambulatory patients.
`in Pregnancy (cid:151)Safe use in pregnancy has not been cc-
`hshed in relation to possible adverse effects on fetal de-
`)pnoent. Therefore, methadone should not be used in
`grant women unless, in the judgment of the physician,
`Potential benefits outweigh the possible hazards.
`thadone is not recommended for obstetric analgesia be-
`se its long duration of action increases the probability of
`Piratoo-s, depression in the newborn.
`in Children ----Methadone is not recommended for use
`III analgesic in children, since documented clinical expe-
`ice has been insufficient to establish a suitable dosage
`boon for the pediatric age group.
`
`ministered over the course of several hours while the
`patient’s condition and vital signs are under careful obser-
`vation.
`Special-Risk Patients (cid:151)Methadone should be given with
`caution and the initial dose should be reduced in certain pa-
`tients, such as the elderly or debilitated and those with se-
`vere impairment of hepatic or renal function, hypothyroid-
`ism, Addison’s disease, prostatic hypertrophy, or urethral
`stricture.
`
`ADVERSE REACTIONS
`THE MAJOR HAZARDS OF METHADONE. AS OF
`OTHER NARCOTIC ANALGESICS, ARE RESPIRATORY
`DEPRESSION AND, TO A LESSER DEGREE. CIRCULA-
`TORY DEPRESSION. RESPIRATORY ARREST. SHOCK,
`AND CARDIAC ARREST HAVE OCCURRED.
`The most frequently observed adverse reactions include
`lightheadedness, dizziness, sedation, nausea, vomiting, and
`sweating. These effects seem to be more prominent in am-
`bulatory patients and in those who are not suffering severe
`chronic pain. In such individuals, lower doses are advisable.
`Some adverse reactions may be alleviated in the ambula-
`tory patient if he lies down.
`Other adverse reactions include the following:
`Central Nervous System (cid:151)Euphoria, dysphoria, weakness,
`headache, insomnia, agitation, disorientation, and visual
`disturbances-
`Gastrointestinal (cid:151)Dry mouth, anorexia, constipation, and
`biliary tract spasm.
`Cardiovascular (cid:151)Flushing of the face, bradycardia, palpi-
`tation, faintness, and syncope.
`Genitourinary (cid:151)Urinary retention or hesitancy, antidi-
`uretic effect, and reduced libido and/or potency.
`Allergic (cid:151)Pruritus, urticaria. other skin rashes, edema.
`and, rarely hemorrhagic urticaria,
`Hematologic (cid:151)Reversible thrembocytopenia has been de-
`scribed in a narcotics addict with chronic hepatitis.
`DOSAGE AND ADMINISTRATION
`For relief of Severe Pain (cid:151)Dosage should be adjusted ac-
`cording to the severity of the pain and the response of the
`patient. Occasionally it may be necessary to exceed the
`usual dosage recommended in cases of exceptionally severe
`chronic pain or in those patients who have become tolerant
`to the analgesic effect of narcotics.
`The usual adult dose is 2.5 mg to 10 mg every three to four
`hours as necessary
`For Detoxification 7l -eatmenf (cid:151) THE DRUG SHALL BEAD-
`MINISTERED DAILY UNDER CLOSE SUPERVISION AS
`FOLLOWS:
`A detoxification treatment course shall not exceed 21 days
`and ma,, not be repeated earlier than four weeks after com-
`pletion of the preceding course.
`The oral fm-rn of administration is preferred. However, if the
`patient is unable to ingest oral medication, he may be
`started on the parenteral ferns initially.
`In detoxification, the patient may receive methadone when
`there are significant symptoms of withdrawal. The dosage
`schedules indicated below are recommended but could be
`varied in accordance with clinical judgment. Initially, a sin-
`gle dose of 15 to 20 mg of methadone will often be sufficient
`to suppress withdrawal symptoms. Additional methadone
`may be provided if withdrawal symptoms are not sup-
`pressed or if symptoms reappear. When patients are physi-
`cally dependent on high doses, it maybe necessary to exceed
`these levels. Forty nog per day in single or divided doses will
`usually constitute an adequate stabilizing dosage level. Sta-
`bilization call be continued for two to three days, and then
`the amount of methadone normally will be gradually de-
`creased. The rate at which methadone is decreased will be
` of metha-
`determined separately for each patient. The Nr
`done can be decreased on a daily basis or at two-day inter-
`vals. but the amount of intake shall always be sufficient to
`keep withdrawal symptoms at a tolerable level. In hospital-
`ized patients, a daily reduction of 20 percent of the total
`dose may be tolerated and may cause little discomfort. In
`ambulatory patients, a somewhat slower schedule may be
`needed. If methadone is administered for more than three
`weeks, the procedure is considered to have progressed from
`detoxification or treatment of the acute withdrawal syn-
`drome to maintenance treatment, even though the goal and
`intent may be eventual total withdrawal.
`
`ECATJTIONS
`iraction with Pen tazocjrie (cid:151)Patients who are addicted
`-leroin or who are on the methadone maintenance pro-
`111 may experience withdrawal symptoms when given
`ItaZocifle
`O.raction with Rifampin (cid:151)The concurrent administration
`ofanopin may possibly reduce the blood concentration of
`thadone. The mechanism by which rifampin may de-
`as blood concentrations of methadone is not fully under-
`ad, although enhanced microsomal drug-metabolized en-
`(cid:176)es may influence drug disposition.
`etc Abdominal Conditions (cid:151)The administration of meth-
`Ole or other narcotics may obscure the diagnosis or din-
`tours5 in patients with acute abdominal conditions.
`erOctt0 with Monoamine Oxidase (MAO) Inhibitors -
`orapeutic doses of mepea’idine have precipitated severe
`Otiona in patients concurrently receiving monoamine ox-
`inhibitors or those who have received such agents
`’in 14 days. Similar reactions thus far have not been re-
`ed With methadone; but if the use of methadone is nec-
`O’y such patients, a sensitivity test should be per-
`
`OVERDOSAGE
`Symptoms (cid:151)Serious overdosage of methadone is character-
`ized by respiratory demession (a decrease in respiratory
`rate and/or tidal volume, Cheyne-Stokes respiration, cyano-
`sis), extreme somnolence progressing to stupor or coma,
`maximally constricted pupils, skeletal-muscle flaccidity,
`cold and clammy skin, and sometimes. bradvcardia and by-
`potension. In severe overdosago, particularly by the intra-
`venous route, apnea, circulatory collapse, cardiac arrest,
`and death may occur.
`Ih’eat,nent (cid:151)Primary attention should be given to the rees-
`tablishment of adequate respiratory exchange through pro-
`vision of a patent airway and institution of assisted or con-
`trolled ventilation. If a nontolerant person, especially a
`child, takes a large dose of methadone, effective narcotic an-
`tagonists are available to counteract the potentially lethal
`respiratory depression. The physician must remember,
`however, that methadone is a long-acting depressant (36
`to 48 hours), whereas the antagonists act for much shorter
`periods (one to three hours). The patient must, therefore,
`be monitored continuously for recurrence of respiratory de-
`
`ROXANE/2713
`
`rust as needed. If the diagnosis is correct and respiratory
`depression is due only to overdosage of methadone, the use
`of other respiratory stimulants is not indicated.
`An antagonist should not be administered in the absence of
`clinically significant respiratory or cardiovascular depres-
`sion. Intravenously administered narcotic antagonists (nal-
`oxone and nalorphine) are the drugs of choice to reverse
`signs of intoxication. These agents should be given repeat-
`edly until the patient’s status remains satisfactory. The ha-
`zard that the narcotic agent will further depress respiration
`is less likely with the use of naloxone.
`Oxygen, intravenous fluids, vasopressors, and other sup-
`portive measures should be employed as indicated.
`
`Note
`IN AN INDIVIDUAL PHYSICALLY DEPENDENT ON
`NARCOTICS, THE ADMINISTRATION OF THE
`USUAL DOSE OF A NARCOTIC ANTAGONIST WILL
`PRECIPITATE AN ACUTE WITHDRAWAL SYN -
`DROME. THE SEVERITY OF THIS SYNDROME
`WILL DEPEND ON THE DEGREE OF PHYSICAL DE-
`PENDENCE AND THE DOSE OF THE ANTAGONIST
`ADMINISTERED. THE USE OF A NARCOTIC AN-
`TAGONIST IN SUCH A PERSON SHOULD BE
`AVOIDED IF POSSIBLE. IF IT MUST BE USED TO
`TREAT SERIOUS RESPIRATORY DEPRESSION IN
`THE PHYSICALLY DEPENDENT PATIENT, THE AN-
`TAGONIST SHOULD BE .ADMINISTERED WITH EX-
`TREME CARE AND BY TITRATION WITH SMALLER
`THAN USUAL DOSES OF THE ANTAGONIST.
`
`HOW SUPPLIED
`Methadone Hydrochloride Oral Solution USP
`Clear, orange -colored, citrus -flavored solution
`5 mg per 5 mL
`NDC 0054-3555-63: Bottles of 500 mL
`10 mg per 5 mL
`NDC 0054-3556-63: Bottles of 500 mL
`Methadone Hydrochloride Tablets USP
`5 mg white, scored identified (54 210) tablets.
`NDC 0054-4170-25: Bottle of 100 tablets.
`NBC 0054-8553-24: Unit dose, 25 tablets per card (reverse
`numbered). 4 cards per shipper.
`10 mg white, scored identified (54 142) tablets.
`NBC 0054-4571-25: Bottle of 100 tablets,
`NBC 0054-8554-24: Unit dose, 25 tablets per card (reverse
`numbered), 4 cards per shipper.
`4056301/4056401 (cid:9)
`078 (cid:9)
`
`Revised July 1998
`DELI, 1998
`
`ORAMORPHSR (cid:9)
`(morphine sulfate)
`Sustained Release Tablets
`15 mg, 30 mg, 60 mg, 100 mg
`Rx only.
`
`C11 1~
`
`NOTE
`THIS IS A SUSTAINED RELEASE DOSAGE FORM.
`PATIENT SHOULD BE INSTRUCTED TO SWALLOW
`THE TABLET AS A WHOLE; THE TABLE SHOULD
`NOT BE BROKEN IN HALF, NOR SHOULD IT BE
`CRUSHED OR CHEWED.
`THE SUSTAINED RELEASE OF MORPHINE FROM
`ORAMORPH SR SHOULD BE TAKEN INTO CONSID-
`ERATION IN EVENT OF ADVERSE REACTIONS OR
`OVEBDOSAGE.
`
`DESCRIPTION
`Each tablet for oral administration contains:
`Morphine sulfate ...........15 mg, 30 mg 60 nog, or 100 mg
`-
`in a tablet that provides for sustained release of the medi
`cation.
`Morphine sulfate occurs as white, feathery, silky crystals,
`cubical masses of crystals, or white crystalline powder; it is
`soluble in water and slightly soluble in alcohol. Morphine
`has a pKa of 7.9, with an octanohlivater partition coefficient
`of 1.42 at pH 7.4. At this pH, the tertiary amino group is
`mostly ionized, making the molecule water -soluble. Mor-
`phine is significantly more water-soluble than any other
`opioid in clinical use.
`Chemically, morphine sulfate is 7,3.didehydro.4,5a-epOxl’-
`17 -methy) -morphiian -3.6uu -diol sulfate (2:1)(salt) pentally-
`drate, and has the following structural formula:
`
`- (cid:9)
`
`CH (cid:9)
`K N(cid:151)CH
`
`1
`
`-10 (cid:9)
`
`0 4"H
`
`H2504
`
`0H20
`
`Each ORAIvIORPH SR Tablet contains 15 mg, 30 mg, 60 mg,
`or 100 mg Morphine Sulfate USE Inactive ingredients: Lac-
`tose, Hydroxypropyl Methylcellulose, Colloidal Silicon Diox-
`ide, and Stearic Acid.
`CLINICAL PHARMACOLOGY
`Morphine is the prototype of many narcotic drugs that in-
`teract predeominantly with the oploid p-receptor. These
`
`2
`
`(cid:9)
`

`

`2714/ROXANE
`
`Oramorph SR(cid:151)Cont.
`
`u-binding sites are discretely distributed in the human
`brain, with high densities in the posterior amygdala, hypo-
`thalamus, thalamus, nucleus caudatus, putainsn, and cer-
`tain cortical areas. They are also found on the terminal ax-
`ons of primary afferents with laminae I and II (aubstantia
`gelatinosa) of the spinal cord and in the spinal nucleus of
`the trigeminal nerve.
`In clinical settings, morphine exerts its principal pharma-
`cological effect on the central nervous system and gastroin-
`testinal tract. Its primary actions of therapeutic value are
`analgesia and sedation. Morphine appears to increase the
`patient’s tolerance for pain and to decrease discomfort, al-
`though the presence of the pain itself may still be recog-
`nized. In addition to analgesia, alterations in mood, eupho-
`ria and dt’sphoria, and drowsiness commonly occur.
`Morphine depresses various respiratory centers, depresses
`the cough reflex, and constricts the pupils. Analgesically ef-
`fective blood levels of morphine may cause nausea and vom-
`iting directly by stimulating the chemoreceptor trigger
`zone, but nausea and vomiting are significantly more com-
`mon in ambulatory than in recumbent patients, as is postu-
`ral syncope.
`Morphine increases the tone and decreases the propulsive
`contractions of the smooth muscle of the gastrointestinal
`tract. The resultant prolongation in gastrointestinal transit
`time is responsible for the constipating effect of morphine.
`Because morphine may increase biliary-tract pressure,
`some patients with biliary colic may experience worsening
`rather than relief of pain.
`While morphine generally increases the tone of urinary-
`tract smooth muscle, the net effect tends to be variable, in
`some cases producing urinary urgency, in others, difficulty
`in urination.
`In therapeutic doses, morphine does not usually exert major
`effects on the cardiovascular system. Some patients, how-
`ever, exhibit a propensity to develop orthoetatic hypotension
`and fainting. Rapid intravenous injection is more likely to
`precipitate a fall in blood pressure than oral dosing.
`Morphine can cause histamine release, which appears to be
`responsible for dilation of cutaneous blood vessels, with re-
`sulting flushing of the face and neck, pruritus, and sweat-
`tog.
`PHARMACORLNETICS
`ORAMORPH SR Tablets are a sustained release oral dosage
`form of morphine sulfate. Only about 40% of the adminis-
`tered dose reaches the central compartment because of first-
`pass effect (i.e., metabolism in the gut wail and liver). Once
`absorbed, morphine is distributed to skeletal muscle, kid-
`neys, liver, intestinal tract, lungs, spleen and brain. Mor-
`phine also crosses the placental membrane and has been
`found in breast milk.
`For all practical purposes, virtually all morphine is con-
`verted to glucuronide metabolites: only a small fraction (less
`than 5%) of absorbed morphine is demethylated. Among
`these glucuronide metabolites, morphine-3-glucuronide is
`present in the highest plasma concentration following oral
`administration: a smaller fraction is converted to morphine-
`6-glucuronide, which has the greater analgesic activity of
`these two metabolites.
`The glucuronide system has a high capacity and is not eas-
`ily saturated, even in disease. Therefore, the rate of delivery
`of morphine to the gut and liver does not influence the total
`and/or the relative quantities of the various metabolites
`formed.
`The pharmacoidnetic parameters following oral administra-
`tion of ORAMORPH SR, presented in the table below, show
`considerable inter-subject variation, but are representative
`of average values reported in the literature. The volume of
`distribution tVd) for morphine is 4 liters per kilogram (LI
`kg). and the terminal elimination half-life is approximately
`2 to 4 hours.
`
`[See table below]
`Following the administration of conventional, immediate-
`release, oral morphine products, approximately 50 17, of the
`morphine that will ever reach the central compartment,
`reaches it within 30 minutes. Following the administration
`of an equal amount of ORAIVIORPH SR to normal volun-
`teers, however, 50% of absorption occurs, on average, after
`1.5 hours,
`The possible effect of food upon the systemic bioavallability
`of ORAMORPH SR has not been evaluated.
`Although variation in the physico.mechanical properties of
`a formulation of an oral morphine drug product can affect
`both its absolute bioavailabilitv and its absorption rate con-
`stant )k), morphine distribution and cleat’ar.se are un-
`changed, as they are fundamental properties of morphine in
`the organism. However, in chronic use. (he possibility of
`shifts in metabolite-to-parent drug a atios cannot be ex-
`cluded.
`When immediate-release oral morphine or ORAMORPH SR
`is given on a fixed dosing regimen, steady-state is achieved
`in about one or two days.
`For a given dose and dosing interval, the Area-Under-the-
`Curve (A(JC) and average blood concentration of morphine
`at steady-state (C 50) will be independent of the type of oral
`formulation administered, as long as the formulations have
`the same absolute bioavaiabilitv. The absorption rate of a
`formulation will, however, affect the maximum (C) and
`minimum (C mo) plasma concentrations and the time be-
`tween administration and their occurrence. For any fixed
`dose and dosing interval. ORAMORPH SR will have, at
`steady-state, a lower C m and a higher C than conven-
`tional immediate-release morphine, which might bea ther-
`apeutic advantage in chronic pain control (see also PHAB-
`MACODYNAMICS).
`The clearance of morphine occurs primarily as renal excre-
`tion of morphine-3-glucuronide. A small amount of the glue-
`uronide conjugate is excreted in the bile, and there is some
`minor enterohepatic recycling: about 10% of the glucuronide
`conjugate is excreted in the feces. Because morphine is es-
`sentially metabolized in the liver, the effects of renal disease
`on morphine’s clearance are not likely to be pronounced. As
`with any drug, however, caution should be taken to guard
`against unanticipated accumulation if renal and/or hepatic
`function is seriously impaired.
`PHARMACODYNAMICS
`In clinical settings, morphine’s primary actions of therapeu-
`tic value are analgesia and sedation. Opiate analgesia in-
`volves at least three anatomical areas of the central nervous
`system: the periaquednctal-periventriculm gray , matter, the
`ventromedial medulla, and the spinal cord. Morphine ap-
`pears to increase the patient’s tolerance for pain, and to de-
`crease the discomfort, although the presence of pain itself
`may still be recognized.
`While there is considerable variability in the relationship
`between morphine blood concentration and analgesic re-
`sponse, effective analgesia probably will not occur below
`some minimum blood level in a given patient. The minimum
`effective blood level for analgesia will vary among patients,
`especially among patients who have been previously treated
`with potent p-agonist opioids. Similarly, there is a consider-
`able variability in the relationship between morphine
`plasma concentration and untoward clinical responses. but
`higher concentrations are more likely to be toxic.
`In contrast to immediate-release morphine, after dosing
`with ORAMORPH SR. the morphine blood levels show re-
`duced fluctuation between peak and trough plasma levels;
`that means that they are more centered within the theoret-
`ical therapeutic window’. On the other hand, the reduced
`fluctuation in morphine plasma concentration might con-
`ceivably affect other phenomena, as for example, the rate of
`tolerance induction.
`ORAMORPH SR is an analgesic intended for patients who
`require chronic morphine analgesia and who will have, in
`
`TABLE OF APPROXIMATE’ AVERAGE PHARMACOKINETIC
`PARAMETERS FOLLOWING ORAL DOSING OF ORAMORPH SR
`
`Pharmacokinetic Parameter
`(scientific notationl
`
`(unit)
`
`Bloavailability
`(oral compared to injectable)
`
`Time-to-peak plasma
`concentration {Tmx}(h)
`
`Peak plasma con-
`centration
`(ng/mL) [single dose]
`
`Volume of distribution
`(calculated from mean
`clearance and terminal half
`life) {VdIItl} (11kg)
`
`Dose of ORAMORPH SR
`
`Dose of
`2 X 15 mg
`
`30 mg (cid:9)
`
`60 mg (cid:9)
`
`100 mg
`
`approximately 40 1t
`
`3.7
`(1-6)
`
`3.8 (cid:9)
`(1-7) (cid:9)
`
`3.8 (cid:9)
`(2-7) (cid:9)
`
`3.6
`(1.5-12)
`
`11.1
`(6.5-16.2)
`
`9.9 (cid:9)
`(5.0-18.6) (cid:9)
`
`16.1 (cid:9)
`10.0-25.3) (cid:9)
`
`27.4
`14,1-46.1
`
`411kg..........................
`
`mean
`(ranget
`
`mean
`(range)
`
`mean
`
`Dose metabolized = approximately 90%
`Morphine metabolites
`tr) = morphine-3-glucuronide (55-75%).
`morphine-6-glucuronide (1-5%)
`
`’Derived from pharmacokinetic studies in 24 normal volunteers
`
`PHYSICIANS’ DESK REFEREN
`
`4
`’i
`
`consequence, markedly different degrees of ph (cid:9)
`namic tolerance for opioid drugs. Morphine a0g(cid:176)td
`opioids induce tolerance to their effects, so that a
`of the duration of satisfactory analgesia may be the Ing
`sign of an increase in tolerance.
`Once patients are started on morphine. the dote
`for satisfactory analgesia will rise, with the rate e , ~quire -
`mont of tolerance varying, depending on the pat
`Orior
`narcotic use, level of pain, degree of anxiety, u5
`CNS-active drugs, circulatory status, total daila- d (cid:176)f 0th50
`O5
`the dosing interval. (cid:9)
`INDICATIONS AND USAGE
`ORAMORPH SR is indicated for the relief of
`tients who require opioid analgesics for more
`days. (cid:9)
`CONTRAINDICATIONS
`ORAMORPH SR is contraindicated in patients with r espi-
`ratory depression in the absence ofresuscitative s quip
`in patients with acute or severe bronchial aethnna
`patients with known hypersensitivity to morphjtae (cid:9)
`ORAMORPH SR is contraindicated in any patient \vho h
`as
`or is suspected of having a paralytic ileus, (cid:9)
`
`"
`
`Ifl
`
`(cid:176)
`
`WARNINGS
`IMPAIRED RESPIRATION:
`Respiratory depression is the chief hazard of all morphine
`preparations. Respiratory depression occurs more fr
`quently in the elderly and debilitated patients, as \’eell as
`those stiffering from conditions accompanied by h’spsxi a
`hypercapuia when even moderate therapeutic doses may
`dangerously decrease pulmonary ventiliation.
`Morphine should be used with extreme caution in patie nts
`who have a decreased respiratory reserve (e.g.. emphyse ma
`severe obesity. kyphoscoliosie. or paralysis of the phreni c
`nervel. ORA.SIORPH SR should not be given in cases of
`chronic asthma, upper airway obstruction, or is any other
`chronic pulmonary disorder without due consIderatio n of
`the known risk of acute respiratory failure following mor-
`phine administration in such patients.
`DRUG ABUSE AND DEPENDENCE -
`CONTROLLED SUBSTANCE:
`Morphine sulfate is a Schedule II narcotic under the United
`States Controlled Substance Act (21 U.S.C. 801-856;
`Morphine is the most commonly cited prototype for narcotic
`substances that possess an addiction-forming or addition-
`sustaining liability. A patient may be at risk for developing
`a dependence to morphine if used improperly or 1i’ overly
`long periods of time. As with all potent opioids,s -hich are
`p-agonists, tolerance as well as psychological and physical
`dependence to morphine may develop irrespective sf the
`route of administration )oral, intravenous, intramuscular,
`intrathecal, epidural). Individuals with a prior histoiy of
`opisid or other substance abuse or dependence, being more
`apt to respond to eurphorogenic and reinforcing properties
`of morphine, would be considered to be at greater risk.
`Care must be taken to avert withdraw-al symptoms when
`morphine is discontinued abruptly or upon administration
`of a narcotic antagonist.
`
`.
`
`-
`
`PRECAUTIONS
`General Precautions: Selection of patients for t reatment
`with ORAISIORPH SR should be governed by the same pun-
`ciples that apply to the use of morphine or other potent
`opioid analgesics. Narcotic analgesics are drugs that have a
`narrow therapeutic index in the old, the sick. and the in-
`firm, i.e., the very population in which their use :5 indicated’
`Physicians should individualize t reatment with -
`ORAMORPH SR in every case, weighing the need for an al-
`the
`gesia against the risk of serious or fatal reactions to
`drug.
`with
`Use in Patients with Increased Intracranial Pressure f
`ex-
`Head Injury: ORAMORPH SR should be used wssh
`pres-
`inlr00155tS-’
`treme caution in patients with increased
`sure or with head injury. The respiratory depr5S(cid:176)’ (cid:176)er-
`of morphine (increased pCO 2 ) may result in sieVat-5 , 55g5
`ebrospinal fluid pressure and may thus be ma.rl5dl ’al
`gerated in the presence of head injury, other Lntrscmte um
`sions, or a pre-escieting increased intracrant(cid:176)1 .srelsgit
`Morphine produces effects which may obscure ulth head
`signs of further increases in pressure i n patients th msr-
`
`injuries. Pupili se ary changes (miosis), associated roe is.
`phine. may conceal the existence, extent, and eCU
`tracranial pa thology
`Use in Hepatic or Renal Disease: The clear 51tetioc a tis
`
`iii
`phine may be reduced in patients with hopatttjiressed
`while the clearance of its metabolites may be
`both-
`renal dysfunction. This will be manifested (cid:9)
`of
`longed elimination half-life and the accumtub 0t.
`hsse Pro-
`of either morphine or its metabolites m excess 0 (cid:9)
`5f
`duced in normals, with the potential for 0trt 5 0gh 1
`1
`verse effects see WARNINGS and ADt drosotSa
`TIONS). These changes in morphine phaIT10
`gid be
`0 s1- ’ -
`patients with hepatic or renal dysfunction5-
`sidez’ed when adjusting the dose and dosath horscte
`ing also into account the slow-releas(cid:176)
`ORAMORPH SR.
`Drug Interactions (cid:9)
`500 ((cid:176) rI’
`lt
`Use ailS Other Central Nervous System Pep b 1’s
`
`potentia te
`(cid:9) e’
`depressant effects of morphine are
`sues of other CNS depressants such as a:(cid:176) (cid:231) oesr0,1e
`antibistaminics, or psychotropic drugs. P5 0e 11
`g
`ci ’
`in conjunction with oral morphine may irc‘ c a
`,00
`respiratory depression, hypotension and p0 f
`or coma, (cid:9)
`
`-
`
`-
`
`3
`
`(cid:9)
`

`

`PRODUCT _INFORMATION (cid:9)
`
`1eractm with Mixed Agonist/Antagonist Opioid Analge-
`I(,, Agonistlantagonist analgesics (i.e., pentazocine, nal-
`9bjne, butorphanol, or buprenorphine) should NOT be
`bdisteredto patients who have received or are receiving
`course of therapy with a pure opioid agonist analgesic. In
`e patients, the mixed agonist/antagonist may alter the
`5
`sigesic effect or may precipitate withdrawal symptoms.
`cinoge0ed/s Muta genesis, impairment of Fertility:
`tudies of morphine sulfate in animals to evaluate the
`carcinogenic and mutagenic potential or the effect on
`fertibti have not been conducted.
`pregnancy:
`fratogeniC Effects(cid:151)Category
`C. There are no well-con-
`nflled studies in women, but marketing experience does not
`iocludr any evidence of adverse effects on the fetus follow -
`’0g routine (short-term) clinical use of morphine sulfate
`Products. Although there is no clearly defined risk, such ox-
`erience cannot exclude the possibility of infrequent or sub-
`tle damage to the human fetus.
`0 M