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`
`Faulding Laboratories Inc.
`5511 CAPITAL CENTER DRIVE
`SUITE 550
`RALEIGH, INC 27606
`
`(919) 233-5788
`Direct Inquiries to:
`Customer Service
`(800) 432-8534
`
`KADIANfi
`Morphine Sulfate Sustained Release
`KADIANfi 20 mg Capsules
`KADIANfi 50 mg Capsules
`KADIANfi 100 mg Capsules
`
`DESCRIPTION
`KADIANfi capsules 20. 50 and 100 mg contain identical
`polymer coated sustained release pellets of morphine sul-
`fate for oral administration.
`Chemically, morphine sulfate is 7.8-didehydro-4,5 a- epoxy-
`17-methyl-morphinan-3,6 a- diol sulfate (2:1) (salt) penta-
`hydrate and has the following structural formula:
`
`CH
`
`::HI HiSO,
`
`[H
`
`Morphine sulfate is an odorless, white, crystalline powder
`with a bitter taste and a molecular weight of 755 as the
`sulfate). It has a solubility of 1 in 21 parts of water and 1 in
`1000 parts of alcohol, but is practically insoluble in chloro-
`form or ether. The octanol: water partition coefficient of
`morphine is 1.42 at physiologic pH and the pK, is 7.9 for the
`tertiary nitrogen (mostly ionized at pH 7.4).
`Each RADIANfi sustained release capsule contains either
`20, 50 or 100 mg of Morphine Sulfate USP and the following
`inactive ingredients common to all strengths: Hydroxvpro-
`pvl Methylcellulose, Ethvlcellulose, Methacrylic Acid Co-
`polymer, Polyethylene Glycol, Diethyl Phthalate, Talc,
`Black Ink SW-9009, Corn Starch and Sucrose.
`CLINICAL PHARMACOLOGY
`Morphine is a natural product that is the prototype for the
`class of natural and synthetic opioid analgesics. Opioids
`produce a wide spectrum of pharmacologic effects including
`analgesia. dysphoria, euphoria, somnolence, respiratory de-
`pression, diminished gastrointestinal motility, altered circu-
`latory dynamics, histamine release and physical depen-
`dence.
`Morphine produces both its therapeutic and its adverse ef-
`fects by interaction with one or more classes of specific
`opioid receptors located throughout the body Morphine acts
`as a pure agonist, binding with and activating opioid recep-
`tors at sites in the peri.aqueductal and pen-ventricular grey
`matter, the ventro-medial medulla and the spinal cord to
`produce analgesia.
`Effects on the Central Nervous System
`The principal therapeutic actions of morphine are analge-
`sia. sedation and alterations of mood. Opioids of this class
`do not usually eliminate pain, but they do reduce the per-
`ception of pain by the central nervous system.
`Morphine produces respiratory depression by reducing the
`responsiveness of the brain stem respiratory centers to in-
`creases in carbon dioxide tension (Or to direct electrical
`stimulation).
`Morphine depresses the cough reflex by direct effect on the
`cough center in the medulla. Antitussive effects may occur
`with doses lower than those usually required for analgesia.
`Morphine causes miosis, even in total darkness, and little
`tolerance develops to this effect. Pinpoint pupils are a sign
`of opoosd overdose but are not pathognomonic (e.g. pontine
`lesions of hemorrhagic or ischemic origins may produce sim-
`ilar findings). Marked mydriasis rather than miosis may be
`seen due to severe hypoxia in overdose situations.
`
`Effects on the Gastrointestinal Tract
`Gastric, biliary and pancreatic secretions are decreased by
`morphine. Morphine causes a reduction in motility associ-
`ated 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. Propul-
`sive peristaltic waves in the colon are decreased, while tone
`is increased to the point of spasm. The end result is consti-
`pation. Morphine can cause a marked increase in biliary
`tract pressure as a result of spasm of the sphincter of Oddi.
`Effects on the Cardiovascular System
`Morphine produces peripheral vasodilation which may re-
`sult in orthostatic hypotension or svncope. Release of hista-
`mine may be induced by morphine and can contribute to
`opioid-induced hypotension. Manifestations of histamine re-
`lease and/or peripheral vasodilation may include rruritus,
`flushing. red eyes and sweating.
`Pharmacodynamics
`The relationship between the blood level of morphine and
`the analgesic response will depend on the patient’s age,
`state of health, medical condition, and the extent of previ-
`ous opioid treatment.
`A minimum effective concentration (MEC) of morphine for
`pain relief has been reported as 27.2 14.5 ng/mL (mean –
`SD) in cancer patients treated with morphine solution.
`These results compare with the AMC for plasma morphine
`reported as 14.7 4.8 ng/mL (mean x SD) in patients with
`postoperative pain. The high degree of variation is of clini-
`cal significance as it may result in either under-dosing or
`over-dosing if the dosage is not adjusted to the patient’s clin-
`ical status and analgesic response (see PRECAUTIONS
`and DOSAGE AND ADMINISTRATION),
`For opioid-tolerant patients the situation is much more
`complex. Some patients will become rapidly tolerant to the
`analgesic effects of morphine, and will require high daily ,
`oral morphine doses for adequate pain control. Since the de-
`velopment of tolerance to both the therapeutic and adverse
`effects of opioids is highly individualized, the dose of mor-
`phine should be individualized to the patient’s condition
`and should not be based on an arbitrary choice of a dose or
`blood level to be achieved.
`Pharmacokinetics
`KADIANfi capsules contain polymer coated sustained re-
`lease pellets of morphine sulfate that release morphine sig-
`nificantly more slowly than from morphine sulfate tablets
`and shorter-acting controlled-release oral morphine sulfate
`preparations. RADIAN(D activity is primarily due to mor-
`phine. One metabolite, morphine-6-glucuronide, has been
`shown to have analgesic activity, but poorly crosses the
`blood-brain barrier.
`Following oral administration, the extent of absorption is
`essentially the same for immediate or sustained release for-
`mulations, although the time to peak blood level T o,,,5 ) will
`be longer and the Cmi,, will be lower for formulations that
`delay the release of morphine in the gastrointestinal tract.
`Elimination of morphine is primarily via hepatic metabo-
`lism to glucuronide metabolites (55 to 65%) which are then
`renally excreted. The terminal half-life of morphine is 2 to 4
`hours, however, a longer term half-life of about 15 hours has
`been reported in studies where blood has been sampled up
`to 48 hours.
`The single-dose pharmacokinetics of RADIANfi are linear
`over the dosage range of 30 to 100 mg. The single dose and
`multiple dose pharmacokinetic parameters of RADIANfi in
`normal volunteers are summarized in Table 1.
`[See table below]
`Absorption
`Following the administration of oral morphine solution, ap-
`proximately 50% of the morphine absorbed reaches the sys-
`temic circulation within 30 noinutes. However, following the
`administration of an equal amount of RADIANfi to healthy
`volunteers, this occurs, on average, after 8 hours. As with
`most forms of oral morphine, because of pro-systemic elim-
`ination, only about 20 to 40% of the administered dose
`reaches the systemic circulation,
`Food Effects: While concurrent administration of food
`slows the rate of absorption of KADL4Nfi. the extent of ab-
`sorption is not affected and KADIANfi can be administered
`without regard to meals.
`Steady State: When RADIANfi is given on a fixed dosing
`regimen to patients with chronic pain due to malignancy,
`steady state is achieved in about two days. At steady state,
`RADIANfi will have a significantly lower Cm,,,, and a higher
`
`Table 1: Mean pharmacokinetic parameters 1% coefficient variation) resulting from a fasting single dose study in normal
`volunteers and a multiple dose study in patients with cancer pain.
`Regiment
`Dosage Form
`
`T,,,,, (cid:9)
`(it) (cid:9)
`
`C,,,1 ,+ (cid:9)
`lng/mLl
`
`Fluctuation"
`
`AUC#,+
`lng.h/mL}
`
`C,,,,,,+
`lng/mLl
`
`Single Dose (n=24)
`IADLtNfi Capsule
`Controlled-Release Tablet
`Morphine Solution
`Multiple Dose (n=24)
`RADIANfi Capsule q24h
`Controlled-Release Tablet ql2h
`
`271,0 (19,4)
`304.3 (19.1)
`362.4 (42.6)
`
`15.6 (24,4)
`30.5 (32,1)
`64.4 (38.2)
`
`8.6 (41.1) (cid:9)
`2.5 (52.6) (cid:9)
`0.9 (55.8) (cid:9)
`
`na’ (cid:9)
`na (cid:9)
`na (cid:9)
`
`na
`no
`na
`
`500,9 (38.6)
`37.3 (37,7)
`10.1 (32.2) (cid:9)
`457.3 (40.2)
`36,9 (42,0)
`4-4(53.0) (cid:9)
`# For single dose AUC = AUC5,4010 , for multiple dose AI,JC = AUC 5.241, at steady state
`+ For single dose parameter normalized to 100 mg, for multiple dose parameter normalized to 100 mg per 24 hours
`Steady-state fluctuation in plasma concentrations =
`Not applicable
`
`9.9 (52.3) (cid:9)
`7.6 (60.3) (cid:9)
`
`3.0 (45.5)
`4.1 (51.5)
`
`Information will be superseded by supplements and subsequent editions
`
`C,,,,,, than equivalent doses of oral morphine soluti(cid:176)
`some other controlled-release preparations (see flr (cid:9)
`
`hlhtl
`
`io,phl SOst Moelsit
`Moat 1Iea0y riot, plo,,, morph,,, oo’oorrrulions 10, 6005140 (too, a 4,5 ronImli -.
`morphine 1,061 laIr, a day) 0,0 051 morph,,, toluOr, (ererO boa,,). plasma or ’
`0, ,om,5,,Str ISO rop ea5 it hour, (.-24).
`
`
`
`- (60)655---- M,,tphtra (cid:9)
`SoJubon (cid:9)
`
`Comes50
`morPhrns s 64os
`
`at
`30
`
`30
`
`25
`
`20
`
`15
`
`0
`
`5 6
`Time (5)
`
`When given once-daily (every 24 hours) to 24 patients
`malignancy, RADIANfi had a similar C m,,, and h(ghy
`at steady state in clinical usage, when compared to twj(cid:176)0(cid:176)(cid:176)
`daily every 12 hours) controlled-release morpbi tabl
`(MS Continfi), given at an equivalent total daily dosage
`Graph 2 and Table 1). Drug-disease interactions are see
`quently seen in the older and more gravely ill paliente
`, a
`may result in both altered absorption and re
`duced cleanM
`as compared to normal volunteers (see Geriatric, flepat’
`(cid:176)
`Failure, and Renal Insufficiency sections).
`
`th
`
`
`Owe P )SC’dot M0R’62).
`Dote ror,00laaO mao,, ,Itaoy ,Oara pirama mo ,ohom ’,roomOuOa,a to, 650104,,, 5,ou a
`
`Piro_ ,00renrru,mma,e onoapa,dt,loewsoe..o24hoa,ab,,24)
`
`CAfl,Atorta (cid:9)
`
`- - - - hIS
`
`35
`
`30
`
`25
`
`2
`O 20
`
`O 15
`
`10
`
`ra (cid:9)
`F
`
`a,
`
`524681212141618202324
`’n)
`Time
`
`Distribution
`Once absorbed, morphine is distributed to skeletal muscle,
`kidneys, liver, intestinal tract, lungs, spleen and bra)’.i.
`The volume of distribution of morphine is approximately 3
`to 4 5/kg. Morphine is 30 to 35% reversibly bound to plasma
`proteins.
`Although the primary site of action of morphine is in the
`CRS, only small quantities pass the blood-brain barrier.
`Morphine also crosses the placental membranes see PRE-
`CAUTIONS - Pregnancy) and has beem found in breast
`milk see PRECAUTIONS - Nursing Mothers).
`Metabolism
`The major pathway of the detoxification of morphine is con-
`jugation, either with D.glucuronic acid in the liver to pro-
`duce glucuronides or with sulfuric acid to give morphine-I’
`etheral sulfate. Although a small fraction (less than 5%) of
`morphine is demethylated, for all practical purposes virtu -
`ally all morphine is converted to glucuronide metabolites in -
`cluding morphine-3-glucuronide, MIG (about 50%) and
`morphine-6.glucuronide, M6G (about 5 to 15%). Studies i ll
`healthy subjects and cancer patients have shown that the
`glucuronide metabolite to morphine mean molar ral105
`(based on AUC) are similar after both single doses and at
`steady state for KADIANfi. 12-how’ controlled-release mor-
`phine sulfate tablets and morphine sulfate solution.
`M3G has no significant analgesic activity MGG has bee"
`shown to have oploid agonist and analgesic activity in ho’
`mans.
`Excretion
`
`Approximately 10% of morphine dose is excreted unchanged
`in the urine. Most of the dose is excreted in the ,’i15e 0
`M3G and 516G. A small amount of the glucuronide reetabO
`lites is excreted in the bile and there is some minor 0nteno
`(cid:176)
`hepatic cycling. Seven to 10% of administered monphu5(cid:176)
`excreted in the feces.
`The mean adult plasma clearance is about 20-30 iiDoris
`IV
`utelkg. The effective terminal half-life of morphine a5
`administration is reported to be approximately 2 0 lie
`Longer plasma sampling in some studies suggests 150 or
`terminal half-life of morphine of about 15 hours.
`Special Populations (cid:9)
`.tv to
`Geriatric: The elderly may have increased sensius’t ’
`51
`morphine and may achieve higher and more variable se
`levels than younger patients. In adults, the durat100 0 fo-
` ee
`a’
`(cid:9) increases progressively with age, though the de_
`of analgesia remains unchanged. RADIANfi pham .(cid:176) (cid:176) ,65
`netics have not been investigated in elderly pat1s 05 .
`
`years) although such patients were included in tile cli0afl
`col
`studies, (cid:9)
`Nursing Mothers: Morphine is excreted in the
`milk, and the milk to plasma morphine AUC ratio
`inr5501 51
`2.5:1. The amount of morphine received by the
`ponds on the maternal plasma concentration, art(cid:176) 0
`milk ingested by the infant, and the extent of first 5SC5
`tabolism. (cid:9)
`Infants under 1 month of age have a pt’01
`Pediatric:
`)1
`elimination half-life and decreased clearance re)
`
`god
`(0
`
`.
`
`2
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`V, (cid:9)
`
`N FoRMATION
`
`dirts (cid:9)
`
`by (cid:9)
`
`atric patients. The clearance of mo
`0ination half-life begin to approach adult
`5end month of life. Pediatric patients old
`’capsules should have pharmacokinetic pa-
`o adults, used on a per kilogram basis
`- Pediatric Usel,
`differences between male and fe-
`ore demonstrated in the analysis of the
`’tie (cid:9)
`data from clinical studies.
`sr51scekitwtc differences due to race may exist.
`ts given intravenous morphine in one study
`eccIearsn ce when compared to caucasian sub-
`ie 5
`la + 16 PlUnition versus 1495 – 80 mI/mini.
`The pharmacokinetics of morphine were
`- (cid:9)
`l
`Failure.
`558-0jfican y altered in individuals with alco-
`be
`The clearance was found to decrease with a
`increase in half-life. The M3G and MSG to
`ili el increase
`0 vO 00 plasma A1..IC ratios also decreased in these pa-
`0rrP dicetin8 a decrease in metabolic activity.
`coOl 050fficieneY The pharmacokmetics of morphine
`d in renal failure patients. AUG is increased and
`.1tere is decreased The metabolites, M3G and M6G
`eseral fold in renal failure patients compared
`chsltbY subjects.
`jo (cid:9)
`interactions: The known drug interactions in-
`egrnrn.phiu are pharmacodynaimc, not pharmacoki-
`Pr
`1gige"AUTIONS - Drug Interactions).
`- (cid:9)
`
`(cid:176)3
`t0
`
`
`
`nealthy subjects and 337 patients with cancer
`psr mdipat5d in a total of 15 studies 10 pharmacoki-
`ru
`one study reported both pharmacoki-
`ric and 8 chrnC(cid:176)
`and clinical data). Of these individuals, 158 healthy
`ii’tIC
`mhjects and 268 patients received KADIANfi. In the con-
`lini- studies patients were followed for a median
`1iled c
`.jarotis(cid:176) of 7 days and in the open label studies patients
`., ere followed tot up to 12-24 months. KADIANfi was corn-
`pored to oral morphine solution and to either MS Continfi
`or to a 12-hour controlled-release morphine tablet
`hiseqUival5llt to MS Continfi using trial designs that fol-
`lowed the clinical and pharmacokinetic performance of each
`treatment in cancer patients receiving chronic opioid ther -
`apy.
`lu two controlled studies, patients with moderate to severe
`cancer pain were titrated with immediate-release morphine
`IRM i solution or tablets to a stable total daily dose of mor-
`phine for at least three consecutive days, then randomized
`to KADllbNfi or 12-hour controlled-release morphine for
`seven days of observation. KADInNfi given once a day
`proved similar to the same total dose of morphine given in
`divided doses in a 12-hour dosage form, with respect to pain
`relict use of rescue medication, patient and investigator
`global assessment, and quality of sleep. Individual patient
`differences in the pattern of pain control emphasize the
`need to individualize both dose and dosing interval (see
`DOSAGE AND ADMINISTRATION).
`INDICATIONS AND USAGE
`KADiANfi is indicated for the management of moderate to
`veers pain where treatment with an opiold analgesic is in-
`dicated for more than a few days (see CLINICAL PHAR-
`MACOLOGy. Clinical Studies.
`RADIfi,jifi was developed for use in patients with chronic
`Pain who require repeated dosing with a potent oprood an-
`ilossuc, and has been tested in patients with pain due to
`orolirvant conditions KADIANfi has not been tested as an
`analgesic for the treatment of acute pain or in the PO5tOP
`statics setting and is net recommended for such use.
`COPq’IpICATIONS
`
`KADIANfi is contraindicated in patients with a known by -
`llrrsensitwity to morphine, morphine salts or any of the
`torn snents.
`is Contraindicated in patients with respiratory
`depression to the absence of resuscitative equipment. and in
`POti0ts with acute or severe bronchial asthma.
`15 contraindicated in any patient who has or is
`(cid:176)’Pscted of having paralytic ileus.
`
`\KARMNGS See also CLINICAL PHARMACOLOGY)
`rpaired
`
`spirstotr depression is the chief hazard of all morphine
`repsrations Respira
`tory depression occurs more fre-
`50fltly
`in elderly and debilitated patients, and these suf-
`(cid:176)(cid:176) from conditions accompanied by hypoxia, hypercap-
`UPPer airnay obstruction when even moderate then
`sentii5tduses may significantly decrease pulmonary
`
`r. (cid:9)
`
`should be used with extreme caution in patients
`tip chtrn0 obstructive pulmonary disease or cor pulmo-
`Pir M lfl Patients having a substantially decreased res-
`P res.0 (e.g. severe kyphoscoliosis), hypoxia, hyper-
`sr Pre-existing respiratory depression. In such pa-
`mncres5 5 h5 Usual therapeutic doses of morphine may
`sY resistance and decrease respiratory drive to
`te (cid:9)
`tit of ap050
`JUry nd Increased Intracranial Pressure
`(cid:176)5Piraton depressant effects of morphine with carbon
`floi ret515o0 and secondary elevation of cerebrospinal
`’ b0(cid:176)0Ure may be markedly exaggerated in the presence
`’Oct5 tRury Other intracranial lesions, or a pro-existing
`10
`intracrawial pressure. Morphine produces effects
`ss s ? 5bscure neurologic signs of further increases in
`Patients with head injuries. Morphine should
`adm inistered under such circumstances when con-
`55Sson_u
`
`i: 5fds
`
`(See also CLINICAL PHARMACOL-
`
`Hypotensive Effect
`KADLANfi, like all opioid analgesics, may cause severe hy-
`potension in an individual whose ability to maintain blood
`pressure has already been compromised by a reduced blood
`volume, or a concurrent administration of drugs such as
`phenothiazines or general anesthetics. (see also PRECAU-
`TIONS - Drug Interactions). KADIANfi may produce orthe-
`static hypotension and syncope in ambulatory patients.
`KADIANfi, like all opioid analgesics, should be adminis-
`tered with caution to patients in circulatory shock, as vaso-
`dilation produced by the drug may further reduce cardiac
`output and blood pressure.
`Gastrointestinal Obstruction
`KADIANfi should not be given to patients with gastrointes-
`tinal obstruction, particularly paralytic ileus, as there is a
`risk of the product remaining in the stomach for an ex-
`tended period and the subsequent release of a bolus of mor-
`phine when normal gut motility is restored. As with other
`solid morphine formulations diarrhea may reduce morphine
`absorption.
`PRECAUTIONS
`OGY)
`General
`KADIANfi is intended for use in patients who require con-
`tinuous treatment with a potent opioid analgesic. As with
`any potent opioid, it is critical to adjust the dosing regimen
`for KADIANfi for each patient, taking into account the pa-
`tient’s prior analgesic treatment experience. Although it is
`clearly impossible to enumerate every consideration that is
`important to the selection of the initial dose of KADIANfi.
`attention should be given to the points under DOSAGE
`AND ADMINISTRATION.
`Cordotomy
`Patients taking RADIANfi who are scheduled for cordotomy
`or other interruption of pain transmission pathways should
`have KADLANfi ceased 24 hours prior to the procedure and
`the pain controlled by parenteral short-acting opioids. In
`addition, the post-procedure titration of analgesics for such
`patients should be individualized to avoid either overseda-
`tion or withdrawal syndromes.
`Use in Pancreatic/Biliary Tract Disease
`RADIANfi may cause spasm of the sphincter of Oddi and
`should be used with caution in patients with biliary tract
`disease, including acute pancreatitis. Opioids may cause in-
`creases in the serum amylase level.
`Special risk groups
`RADIANfi should be administered with caution, and in re-
`duced dosages in elderly or debilitated patients: patients
`with severe renal or hepatic insufficiency: patients with Ad-
`dison’s disease: mvxederna: hypothyroidism; prostatic hy-
`pertrophy or urethral stricture.
`Caution should also be exercised in the administration of
`KADIANfi to patients with CNS depression, tame psycho-
`sis, acute alcoholism and delirium tremens. and convulsive
`disorders.
`Driving and operating machinery
`Morphine may impair the mental and/or physical abilities
`needed to perform potentially hazardous activities such as
`driving a car or operating machinery. Patients must be cau-
`tioned accordingly. Patients should also be warned about
`the potential combined effects of morphine with other CNS
`depressants, including other opioids, phenothiazines, seda-
`tive/hvpustiCs and alcohol toes Drug Interactions).
`Information for Patients
`If clinically advisable. patients receiving RADIANfi should
`be given the following instructions by the physician:
`1. RADIANfi capsules should be swallowed whole (not
`chewed, crushed, or dissolved). Alternatively, RADIANfi
`capsules may be opened and the entire contents sprin-
`kled on a entail amount of applesauce immediately prior
`to ingestion. The pellets should NOT he chewed crushed.
`or dissolved due to risk of overdose. When prescribing
`RADIAN, fi by the sprinkle method, details of proper tech-
`nique should be explained to the patient. RADIAN-0 cap-
`sules may also be opened and the entire contents sprin-
`kled over about 10 mL of water in a beaker then flushed
`with swirling through a pre-wetted 16-French gastroo-
`tomy tube fitted with a plastic funnel at the port end. The
`beaker is rinsed with additional aliquots of water as nec-
`essary to transfer all of the pellets to flush the tube. NA-
`SOGASTRIC TUBES SHOULD NOT BE USED. also see
`DOSAGE AND ADMINISTRATION)
`2. The dose of KAPlANfi should not be adjusted without
`consulting the physician.
`3. Morphine may impair mental and/or physical ability re-
`quired for the performance of potentially hazardous tasks
`e.g. driving, operating machinery). Patients started on
`KA.DLANfi or whose dose has been changed should cc-
`fraiou from dangerous activity until it is established that
`they are not adversely affected.
`4. Morphine should not be taken with alcohol or other CNS
`depressants (sleeping medication, tranquilizers) because
`additive effects including CNS depression may occur. A
`physician should be consulted if other medications are
`currently being used or are prescribed for future use.
`5. Women of childbearing potential who become or are plan-
`ning to become pregnant, should consult a physician.
`6. Upon completion of therapy, it may be appropriate to ta-
`per the morphine dose, rather than abruptly discontinu-
`ing it.
`7. While psychological dependence ("addiction") to mor-
`phine used in the treatment of pain is very rare, mor-
`phineis one of a class of drugs known to be abused and
`
`FAULDING/1051
`
`8. As with other opioids, patients taking RADIANfi should
`be advised that severe constipation could occur and ap-
`propriate laxatives, stool softeners and other appropriate
`treatments should be initiated from the beginning of
`opioid therapy.
`Drug Interactions
`CNS Depressants: Morphine should be used with great
`caution and in reduced dosage in patients who are concur -
`rently receiving other central nervous system (CNS) depres-
`sants including sedatives, hypnotics, general anesthetics,
`antiemetics, phenothiazines, other tranquilizers and alcohol
`because of the risk of respiratory depression, hypotension
`and profound sedation or coma. When such combined ther-
`apy is contemplated, the initial dose of one or both agents
`should be reduced by at least 50%.
`Muscle Relaxants: Morphine may enhance the neuromus-
`cular blocking action of skeletal relaxants and produce an
`increased degree of respiratory depression.
`Mixed Agonist/Antagonist Opioid Analgesics: From a the-
`oretical perspective, mixed agonist/antagonist analgesics
`(i.e. pens.azocine, nalbuphine and butorphanol) should NOT
`be administered to patients who have received or are receiv-
`ing a course of therapy with a pure opioid agonist analgesic.
`In these patients, mixed agonist/antagonist analgesics may
`reduce the analgesic effect and/or may precipitate with-
`drawal symptoms.
`Monoamine Oxidase Inhibitors (MAOIs): MAOIs have
`been reported to intensify the effects of at least one opioid
`drug causing anxiety, confusion and significant depression
`of respiration or coma. We do not recommend the use of
`KADJANfi in patients taking MAOIs or within 14 days of
`stopping such treatment.
`Cimetidine: There is an isolated report of confusion and
`severe respiratory depression when a hemodialysis patient
`was concurrently administered morphine and cimetidine.
`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 prosta-
`tiem.
`Food: RADIANfi capsules should be swallowed whole (not
`chewed, crushed, or dissolved). Alternatively. KAI)IANfi
`capsules may be opened and the entire contents sprinkled
`on a small amount of applesauce immediately prior to in-
`gestion. The pellets in KAPLANfi should NOT be chewed,
`crushed, or dissolved due to risk of overdose. (see DOSAGE
`AND ADMINISTRATION, and INFORMATION FOR PA-
`TIENTS)
`Carcinogenicity/Mutagenicity/Impairment of Fertility
`Long-term studies in animals to evaluate the carcinogenic
`potential of morphine have net been conducted. There are
`no reports of carcinogenic effects in humans.
`In c’)tco studies have reported that morphine is non-muta-
`genic in the Ames test with Salmonella, and induces chro-
`mosomal aberrations in human leukocytes and lethal muta-
`tion induction in Drosophila. Morphine was found to be mu-
`tagenir in vitro in human T-cells, increasing the DNA
`fragmentation. in rico, morphine was mutagenic in the
`mouse micronucleus test and induced chromosomal aberra-
`tions in spermatids and murine lymphocytes.
`Chronic epioid abusers (e.g.. heroin abusersi and their off-
`spring display higher rates of chromosomal damage. How-
`ever. the rates of chromosomal abnormalities were similar
`in noneyposed individuals and in heroin users enrolled in
`long term apioid maintenance programs.
`Pregnancy
`Teratogertie effects (Pregnancy Category C)
`Teratogenic effects of morphine have been reported in the
`animal literature. High parental doses during the second
`trimester were teratogenic in nem-ological, soft and skeletal
`tissue. The abnormalities included encephalopathy and ax-
`ial skeletal fusions These doses were often maternally toxic
`and were 0.3 to 3-fold the maximum recommended human
`dose (SIRED) on a Mg/M2 basis. The relative contribution of
`morphine-induced maternal hypoxia and malnutrition, each
`of which can be teratogenic, has not been clearly defined.
`Treatment of male rats with approximately 3-fold the
`MRHD for 10 days prior to mating decreased litter size and
`viability.
`Nonteratogenic effects
`Morphine given subcutaneously, at non-maternally toxic
`doses, to rats during the third trimester with approximately
`0.15-fold the MRHD caused reversible reductions in brain
`and spinal cord volume, and testes size and body weight in
`the offspring, and decreased fertility in female offspring.
`The offspring of rats and hamsters treated orally or intra-
`peritoneallv throughout pregnancy with 0.04- to 0.3-fold the
`MRHD of morphine have demonstrated delayed growth,
`motor and sexual maturation and decreased male fertility.
`Chronic morphine exposure of fetal animals resulted in mild
`withdrawal, altered reflex and motor skill development, and
`altered responsiveness to morphine that persisted into
`adulthood.
`There are no well-controlled studies of chi’onic in utero ex-
`posure to morphine sulfate in human subjects. However, ran-
`controlled retrospective studies of human neonates chroni-
`cally exposed to other opioids in rutero, demonstrated re-
`duced brain volume which normalized over the first month
`of life. Infants born to opioid-abusing mothers are more of-
`ten small for gestational age, have a decreased ventilatory
`response to CO2 and increased risk of sudden infant death
`syndrome.
`
`(nntin,,ed nn next neon
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`3
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`Kadian(cid:151)Cont.
`
`Morphine should only be used during pregnancy if the need
`ibr strong oploid analgesia justifies the potential risk to the
`fetus.
`Labor and Delivery
`KADIANfi is not recommended for use in women during
`and immediately prior to la