label

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use

KADIAN safely and effectively.

See full prescribing information for KADIAN.

KADIAN

(morphine sulfate) Extended-Release Capsules, for oral use, CII

Initial U.S. Approval: 1941

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-

THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL

INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME;

INTERACTION WITH ALCOHOL; and RISKS FROM

CONCOMITANT USE WITH BENZODIAZEPINES AND OTHER

CNS DEPRESSANTS

See full prescribing information for complete boxed warning.

• KADIAN exposes users to risks of addiction, abuse, and misuse,

which can lead to overdose and death. Assess each patient’s risk

before prescribing, and monitor regularly for these behaviors and

conditions. (5.1

)

• Serious, life-threatening, or fatal respiratory depression may occur.

Monitor closely, especially upon initiation or following a dose

increase. Instruct patients to swallow KADIAN capsules whole to

avoid exposure to a potentially fatal dose of morphine. (5.2

)

• Accidental ingestion of KADIAN, especially by children, can result

in fatal overdose of morphine. (5.2)

• Prolonged use of KADIAN during pregnancy can result in neonatal

opioid withdrawal syndrome, which may be life-threatening if not

recognized and treated. If prolonged opioid use is required in a

pregnant woman, advise the patient of the risk of neonatal opioid

withdrawal syndrome and ensure that appropriate treatment will

be available (5.3).

• Instruct patients not to consume alcohol or any products containing

alcohol while taking KADIAN because co-ingestion can result in

fatal plasma morphine levels. (5.4)

•

Concomitant use of opioids with benzodiazepines or other central

nervous system (CNS) depressants, including alcohol, may result in

profound sedation, respiratory depression, coma, and death.

Reserve concomitant prescribing for use in patients for whom

alternative treatment options are inadequate; limit dosages and

durations to the minimum required; and follow patients for signs

and symptoms of respiratory depression and sedation. (5.4, 7)

RECENT MAJOR CHANGES

Boxed Warning 12/2016

Warnings and Precautions (5) 12/2016

INDICATIONS AND USAGE

KADIAN is an opioid agonist indicated for the management of pain severe

enough to require daily, around-the-clock, long-term opioid treatment and for

which alternative treatment options are inadequate.

Limitations of Use

• Because of the risks of addiction, abuse, and misuse with opioids, even at

recommended doses, and because of the greater risks of overdose and death

with extended-release opioid formulations, reserve KADIAN for use in

patients for whom alternative treatment options (e.g., non-opioid analgesics

or immediate-release opioids) are ineffective, not tolerated, or would be

otherwise inadequate to provide sufficient management of pain.

• KADIAN is not indicated as an as-needed (prn) analgesic.

DOSAGE AND ADMINISTRATION

• To be prescribed only by healthcare providers knowledgeable in use of

potent opioids for management of chronic pain. (2.1)

• KADIAN 100 mg and 200 mg capsules, a single dose greater than 60 mg, or

a total daily dose greater than 120 mg, are only for use in patients in whom

tolerance to an opioid of comparable potency has been established.

• Patients considered opioid-tolerant are those taking, for one week or longer,

at least 60 mg of morphine per day, 25 mcg transdermal fentanyl per hour,

30 mg of oral oxycodone per day, 8 mg of oral hydromorphone per day, 25

mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an

equianalgesic dose of another opioid. (2.1)

• Use the lowest effective dosage for the shortest duration consistent with

individual patient treatment goals (2.1).

• Individualize dosing based on the severity of pain, patient response, prior

analgesic experience, and risk factors for addiction, abuse, and misuse. (2.1)

• Instruct patients to swallow KADIAN capsules intact, or to sprinkle the

capsule contents on applesauce and immediately swallow without chewing.

(2.1, 2.5)

• Instruct patients not to cut, break, chew, crush, or dissolve the pellets in

KADIAN capsules to avoid the risk of release and absorption of potentially

fatal dose of morphine. (2.1, 2.5, 5.1)

• For opioid-naïve patients, initiate treatment using an immediate-release

morphine formulation and then convert patients to KADIAN. For opioid

non-tolerant patients, initiate with a 30 mg capsule orally every 24 hours.

Dosage adjustments may be made every one to two days. (2.2. 2.3)

• Do not abruptly discontinue KADIAN in a physically dependent patient.

(2.3, 5.11)

DOSAGE FORMS AND STRENGTHS

Extended-release capsules: 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 80 mg,

100 mg, 200 mg (3)

CONTRAINDICATIONS

• Significant respiratory depression (4)

• Acute or severe bronchial asthma in an unmonitored setting or in the

absence of resuscitative equipment (4)

• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs

within the last 14 days (4)

• Known or suspected gastrointestinal obstruction, including paralytic ileus

(4)

• Hypersensitivity to morphine (4)

WARNINGS AND PRECAUTIONS

• Life-Threatening Respiratory Depression in Patients with Chronic

Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients:

Monitor closely, particularly during initiation and titration. (5.5)

• Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of

corticosteroids, and wean patient off the opioid. (5.7)

• Severe Hypotension: Monitor during dosage initiation and titration Avoid

use of KADIAN in patients with circulatory shock,(5.8)

• Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors,

Head Injury, or Impaired Consciousness: Monitor for sedation and

respiratory depression. Avoid use of KADIAN in patients with impaired

consciousness or coma. (5.9)

ADVERSE REACTIONS

Most common adverse reactions (>10%): constipation, nausea, and somnolence.

(6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Allergan at 1-

800-

433-8871 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

DRUG INTERACTIONS

• Serotonergic Drugs: Concomitant use may result in serotonin syndrome.

Discontinue KADIAN if serotonin syndrome is suspected. (7.)

• Monoamine Oxidase Inhibitors (MAOIs): Can potentiate effects of

morphine. Avoid concomitant use in patients taking MAOIs or within 14

days of stopping =treatment with an MAOI. (7)

• Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid

use with KADIAN because they may reduce analgesic effect of KADIAN

or precipitate withdrawal symptoms. (5.12,7)

USE IN SPECIFIC POPULATIONS

• Pregnancy: May cause fetal harm. (8.1)

• Lactation: Not recommended. (8.2)

See 17 for PATIENT COUNSELING INFORMATION and Medication

Guide.

Revised: 12/2016

Reference ID: 4028194

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-

THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL

INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME;

INTERACTION WITH ALCOHOL

; and RISKS FORM

CONCOMITANT USE WITH BENZODIAZEPINES AND OTHER

CNS DEPRESSANTS

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage and Administration Instructions

2.2 Initial Dosage

2.3 Titration and Maintenance of Therapy

2.4 Discontinuation of KADIAN

2.5 Administration of Kadian

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Addiction, Abuse, and Misuse

5.2 Life Threatening Respiratory Depression

5.3 Neonatal Opioid Withdrawal Syndrome

5.4 Risk from Concomitant Use with Benzodiazepines or Other

CNS Depressants

5.5 Life-Threatening Respiratory Depression in Patients with

Chronic Pulmonary Disease or in Elderly, Cachectic, or

Debilitated Patients

5.6 Interaction with Monoamine Oxidase Inhibitors

5.7 Adrenal Insufficiency

5.8 Severe Hypotension

5.9 Risk of Use in Patients with Increased Intracranial Pressure

Brain Tumors, Head Injury, or Impaired Consciousness

5.10 Risk of Use in Patients with Gastrointestinal Conditions

5.11 Increased Risk of Seizures in Patients with Seizure Disorders

5.12 Withdrawal

5.13 Risk of Driving and Operating Machinery

6 ADVERSE REACTIONS

6.1 Clinical Trial Experience

6.2 Post-Marketing Experience

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4

Pediatric Use

8.5 Geriatric Use

8.6 Hepatic Impairment

8.7 Renal Impairment

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

9.2 Abuse

9.3 Dependence

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

*Sections or subsections omitted from the full prescribing information are

not listed

Reference ID: 4028194

FULL PRESCRIBING INFORMATION

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING

RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID

WITHDRAWAL SYNDROME; INTERACTION WITH ALCOHOL; and RISKS FROM

CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Addiction, Abuse, and Misuse

KADIAN exposes patients and other users to the risks of opioid addiction, abuse, and

misuse, which can lead to overdose and death. Assess each patient’s risk prior to

prescribing KADIAN, and monitor all patients regularly for the development of these

behaviors and conditions [see Warnings and Precautions (5.1)].

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of KADIAN.

Monitor for respiratory depression, especially during initiation of KADIAN or following a

dose increase. Instruct patients to swallow KADIAN capsules whole or to sprinkle the

contents of the capsule on applesauce and swallow immediately without chewing. Crushing,

chewing, or dissolving the pellets in KADIAN capsules can cause rapid release and

absorption of a potentially fatal dose of morphine [see Warnings and Precautions (5.2)].

Accidental Ingestion

Accidental ingestion of even one dose of KADIAN, especially by children, can result in a

fatal overdose of morphine [see Warnings and Precautions (5.2)].

Neonatal Opioid Withdrawal Syndrome

Prolonged use of KADIAN during pregnancy can result in neonatal opioid withdrawal

syndrome, which may be life-threatening if not recognized and treated, and requires

management according to protocols developed by neonatology experts. If opioid use is

required for a prolonged period in a pregnant woman, advise the patient of the risk of

neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be

available [see Warnings and Precautions (5.3)].

Interaction with Alcohol

Instruct patients not to consume alcoholic beverages or use prescription or nonprescription

products that contain alcohol while taking KADIAN. The co-ingestion of alcohol with

KADIAN may result in increased plasma levels and a potentially fatal overdose of

morphine [see Warnings and Precautions (5.4)].

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS)

depressants, including alcohol, may result in profound sedation, respiratory depression,

coma, and death [see Warnings and Precautions (5.4), Drug Interactions (7)]

• Reserve concomitant prescribing of KADIAN Injection and benzodiazepines or other

CNS depressants for use in patients for whom alternative treatment options are

inadequate.

• Limit dosages and durations to the minimum required.

• Follow patients for signs and symptoms of respiratory depression and sedation.

Page 3 of 35

Reference ID: 4028194

1 INDICATIONS AND USAGE

KADIAN is indicated for the management of pain severe enough to require daily, around-the-

clock, long-term opioid treatment and for which alternative treatment options are inadequate.

Limitations of Use

• Because of the risks of addiction, abuse, and misuse with opioids, even at recommended

doses, and because of the greater risks of overdose and death with extended-release

opioid formulations [see Warnings and Precautions (5.1)], reserve KADIAN for use in

patients for whom alternative treatment options (e.g., non-opioid analgesics or

immediate-release opioids) are ineffective, not tolerated, or would be otherwise

inadequate to provide sufficient management of pain.

• KADIAN is not indicated as an as-needed (prn) analgesic.

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage and Administration Instructions

KADIAN should be prescribed only by healthcare professionals who are knowledgeable in the

use of potent opioids for the management of chronic pain.

KADIAN 100 mg and 200 mg capsules, a single dose greater than 60 mg, or a total daily dose

greater than 120 mg, are only for use in patients in whom tolerance to an opioid of comparable

potency has been established. Patients considered opioid-tolerant are those taking, for one week

or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg

oral oxycodone per day, 8 mg oral hydromorphone daily, 25 mg oral oxymorphone per day, 60

mg oral hydrocodone per day, or an equianalgesic dose of another opioid.

• Use the lowest effective dosage for the shortest duration consistent with individual

patient treatment goals [see Warnings and Precautions (5)].

• Initiate the dosing regimen for each patient individually, taking into account the patient's

severity of pain, prior analgesic treatment experience, and risk factors for addiction,

abuse, and misuse [see Warnings and Precautions (5.1)].

• Monitor patients closely for respiratory depression, especially within the first 24 to 72

hours of initiating therapy and following dosage increases with KADIAN and adjust the

dosage accordingly [see Warnings and Precautions (5.2)].

Instruct patients to swallow KADIAN capsules whole [see Patient Counseling Information

(17)].Crushing, chewing, or dissolving the pellets in KADIAN capsules will result in

uncontrolled delivery of morphine and can lead to overdose or death [see Warnings and

Precautions (5.1)].

Instruct patients who are unable to swallow KADIAN capsules to sprinkle the capsule contents

on applesauce and immediately swallow without chewing [see Dosage and Administration

(2.5)].

KADIAN is administered orally at a frequency of either once daily (every 24 hours) or twice

daily (every 12 hours).

Page 4 of 35

Reference ID: 4028194

2.1 Initial Dosage

Use of KADIAN as the First Opioid Analgesic (opioid-naïve patients)

There has been no evaluation of KADIAN as an initial opioid analgesic in the management of

pain. Because it may be more difficult to titrate a patient to adequate analgesia using an

extended-release morphine, begin treatment using an immediate-release morphine formulation

and then convert patients to KADIAN as described below.

Use of KADIAN in Patients who are not Opioid Tolerant (opioid non-tolerant patients)

The starting dose for patients who are not opioid tolerant is KADIAN 30 mg orally every 24

hours.

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory

depression.

Conversion from Other Opioids to KADIAN

Discontinue all other around-the-clock opioid drugs when KADIAN therapy is initiated.

There are no established conversion ratios from other opioids to KADIAN defined by clinical

trials. Initiate dosing using KADIAN 30 mg orally every 24 hours.

It is safer to underestimate a patient's 24-hour oral morphine dosage and provide rescue

medication (e.g. immediate-release morphine) than to overestimate the 24-hour oral morphine

dosage and manage an adverse reaction due to an overdose. While useful tables of opioid

equivalents are readily available, there is inter-patient variability in the potency of opioid drugs

and formulations.

Close observation and frequent titration are warranted until pain management is stable on the

new opioid. Monitor patients for signs and symptoms of opioid withdrawal and for signs of

oversedation/toxicity after converting patients to KADIAN.

Conversion from Other Oral Morphine Formulations to KADIAN

Patients receiving other oral morphine formulations may be converted to KADIAN by

administering one-half of the patient's total daily oral morphine dose as KADIAN twice daily or

by administering the total daily oral morphine dose as KADIAN once daily. There are no data to

support the efficacy or safety of prescribing KADIAN more frequently than every 12 hours.

KADIAN is not bioequivalent to other extended-release morphine preparations. Conversion

from the same total daily dose of another extended-release morphine product to KADIAN may

lead to either excessive sedation at peak or inadequate analgesia at trough. Therefore, monitor

patients closely when initiating KADIAN therapy and adjust the dosage of KADIAN as needed.

Conversion from Parenteral Morphine, or Other Opioids to KADIAN

When converting from parenteral morphine or other non-morphine opioids (parenteral or oral) to

KADIAN, consider the following general points:

Page 5 of 35

Reference ID: 4028194

Parenteral to Oral Morphine Ratio

Between 2 mg and 6 mg of oral morphine may be required to provide analgesia

equivalent to 1 mg of parenteral morphine. Typically, a dose of oral morphine that is

three times the daily parenteral morphine requirement is sufficient.

Other Oral or Parenteral Opioids to Oral Morphine Ratios

Specific recommendations are not available because of a lack of systematic evidence for

these types of analgesic substitutions. Published relative potency data are available, but

such ratios are approximations. In general, begin with half of the estimated daily

morphine requirement as the initial dose, managing inadequate analgesia by

supplementation with immediate-release morphine.

Conversion from Methadone to KADIAN

Close monitoring is of particular importance when converting from methadone to other opioid

agonists. The ratio between methadone and other opioid agonists may vary widely as a function

of previous dose exposure. Methadone has a long half-life and can accumulate in the plasma.

2.3 Titration and Maintenance of Therapy

Individually titrate KADIAN to a dose that provides adequate analgesia and minimizes adverse

reactions. Continually reevaluate patients receiving KADIAN to assess the maintenance of pain

control and the relative incidence of adverse reactions, as well as monitoring for the development

of addiction, abuse, or misuse [see Warnings and Precautions (5.1)]. Frequent communication

is important among the prescriber, other members of the healthcare team, the patient, and the

caregiver/family during periods of changing analgesic requirements, including initial titration.

During chronic therapy, periodically reassess the continued need for the use of opioid analgesics.

Patients who experience breakthrough pain may require a dosage adjustment of KADIAN, or

may need rescue medication with an appropriate dose of an immediate-release analgesic. If the

level of pain increases after dose stabilization, attempt to identify the source of increased pain

before increasing the KADIAN dosage. In patients experiencing inadequate analgesia with once

daily dosing of KADIAN, consider a twice daily regimen. Because steady-state plasma

concentrations are approximated within 24 to 36 hours, KADIAN dosage adjustments may be

done every 1 to 2 days.

If unacceptable opioid-related adverse reactions are observed, consider reducing the

dosage. Adjust the dosage to obtain an appropriate balance between management of pain and

opioid-related adverse reactions.

2.4 Discontinuation of KADIAN

When a patient no longer requires therapy with KADIAN, taper the dose gradually, by 25% to 50

%, every 2 to 4 days, , while monitoring for signs and symptoms of withdrawal. If the patient

develops these signs or symptoms, raise the dose to the previous level and taper more slowly,

either by increasing the interval between decreases, decreasing the amount of change in dose, or

both. Do not abruptly discontinue KADIAN [see Warnings and Precautions (5.12), Drug Abuse

and Dependence (9.3).

Page 6 of 35

Reference ID: 4028194

2.5 Administration of KADIAN

KADIAN capsules must be taken whole. Crushing, chewing, or dissolving the pellets in

KADIAN capsules will result in uncontrolled delivery of morphine and can lead to overdose or

death [see Warnings and Precautions (5.1)].

Alternatively, the contents of the KADIAN capsules (pellets) may be sprinkled over applesauce

and then swallowed. This method is appropriate only for patients able to reliably swallow the

applesauce without chewing. Other foods have not been tested and should not be substituted for

applesauce. Instruct the patient to:

• Sprinkle the pellets onto a small amount of applesauce and consume immediately without

chewing.

• Rinse the mouth to ensure all pellets have been swallowed.

• Discard any unused portion of the KADIAN capsules after the contents have been

sprinkled on applesauce.

The contents of the KADIAN capsules (pellets) may be administered through a 16 French

gastrostomy tube.

1. Flush the gastrostomy tube with water to ensure that it is wet.

2. Sprinkle the KADIAN Pellets into 10 mL of water.

3. Use a swirling motion to pour the pellets and water into the gastrostomy tube through a

funnel.

4. Rinse the beaker with a further 10 mL of water and pour this into the funnel.

5. Repeat rinsing until no pellets remain in the beaker.

Do not administer KADIAN pellets through a nasogastric tube.

3 DOSAGE FORMS AND STRENGTHS

Extended-release capsules: 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, , 200

mg. KADIAN contains white to off-white or tan colored polymer coated pellets, have an outer

opaque capsule with colors as identified below and are available in nine dose strengths:

Each 10 mg extended-release capsule has a light blue opaque cap printed with “KADIAN” and a

light blue opaque body printed with “10 mg”.

Each 20 mg extended-release capsule has a yellow opaque cap printed with “KADIAN” and a

yellow opaque body printed with “20 mg”.

Each 30 mg extended-release capsule has a blue violet opaque cap printed with “KADIAN” and

a blue violet opaque body printed with “30 mg”.

Each 40 mg extended-release capsule has a yellow opaque cap printed with “KADIAN” and a

blue violet opaque body printed with “40 mg”.

Each 50 mg extended-release capsule has a blue opaque cap printed with “KADIAN” and a blue

opaque body printed with “50 mg”.

Page 7 of 35

Reference ID: 4028194

Each 60 mg extended-release capsule has a pink opaque cap printed with “KADIAN” and a pink

opaque body printed with “60 mg”.

Each 80 mg extended-release capsule has a light orange opaque cap printed with “KADIAN” and

a light orange opaque body printed with “80 mg”.

Each 100 mg extended-release capsule has a green opaque cap printed with “KADIAN” and a

green opaque body printed with “100 mg”.

Each 200 mg extended-release capsule has a light brown opaque cap printed with “KADIAN”

and light brown opaque body printed with “200 mg”.

4 CONTRAINDICATIONS

KADIAN is contraindicated in patients with

• Significant respiratory depression [see Warnings and Precautions (5.2)]

• Acute or severe bronchial asthma in an unmonitored setting or in the absence of

resuscitative equipment [see Warnings and Precautions (5.5)]

• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the

last 14 days [see Warnings and Precautions (5.6)/Drug Interactions (7))].

• Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings

and Precautions (5.10)]

• Hypersensitivity (e.g., anaphylaxis) to morphine [see Adverse Reactions (6.2)]

5 WARNINGS AND PRECAUTIONS

5.1 Addiction, Abuse, and Misuse

KADIAN contains morphine, a Schedule II controlled substance. As an opioid, KADIAN

exposes users to the risks of addiction, abuse, and misuse. Because extended-release products

such as KADIAN deliver the opioid over an extended period of time, there is a greater risk for

overdose and death due to the larger amount of morphine present [see Drug Abuse and

Dependence (9)].

Although the risk of addiction in any individual is unknown, it can occur in patients

appropriately prescribed KADIAN. Addiction can occur at recommended doses and if the drug is

misused or abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing KADIAN,

and monitor all patients receiving KADIAN for the development of these behaviors and

conditions. Risks are increased in patients with a personal or family history of substance abuse

(including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The

potential for these risks should not, however, prevent the proper management of pain in any

given patient. Patients at increased risk may be prescribed opioids such as KADIAN, but use in

such patients necessitates intensive counseling about the risks and proper use of KADIAN along

with intensive monitoring for signs of addiction, abuse, and misuse.

Page 8 of 35

Reference ID: 4028194

Abuse or misuse of KADIAN by crushing, chewing, snorting, or injecting the dissolved product

will result in the uncontrolled delivery of morphine and can result in overdose and death [see

Overdosage (10)].

Opioids are sought by drug abusers and people with addiction disorders and are subject to

criminal diversion. Consider these risks when prescribing or dispensing KADIAN. Strategies to

reduce these risks include prescribing the drug in the smallest appropriate quantity and advising

the patient on the proper disposal of unused drug [see Patient Counseling Information (17)].

Contact local state professional licensing board or state controlled substances authority for

information on how to prevent and detect abuse or diversion of this product.

5.2 Life Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of

opioids, even when used as recommended. Respiratory depression, if not immediately

recognized and treated, may lead to respiratory arrest and death. Management of respiratory

depression may include close observation, supportive measures, and use of opioid antagonists,

depending on the patient’s clinical status [see Overdosage (10)]. Carbon dioxide (CO

) retention

from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the

use of KADIAN, the risk is greatest during the initiation of therapy or following a dosage

increase. Monitor patients closely for respiratory depression, especially within the first 24-72

hours of initiating therapy and following dosage increases of KADIAN.

To reduce the risk of respiratory depression, proper dosing and titration of KADIAN are

essential [see Dosage and Administration (2)]. Overestimating the KADIAN dosage when

converting patients from another opioid product can result in fatal overdose with the first dose.

Accidental ingestion of even one dose of KADIAN, especially by children, can result in

respiratory depression and death due to an overdose of morphine.

5.3 Neonatal Opioid Withdrawal Syndrome

Prolonged use of KADIAN during pregnancy can result in withdrawal in the neonate. Neonatal

opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-

threatening if not recognized and treated, and requires management according to protocols

developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal

syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged

period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment

will be available [see Use in Specific Populations (8.1), Patient Counseling Information (17)].

5.4 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Profound sedation, respiratory depression, coma, and death may result from the concomitant use

of KADIAN with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine

sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics,

Page 9 of 35

Reference ID: 4028194

antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing

of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and

benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics

alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with

the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug

Interactions (7)].

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly

with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of

concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose

of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and

titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a

benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic,

and titrate based on clinical response. Follow patients closely for signs and symptoms of

respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when

KADIAN is used with benzodiazepines or other CNS depressants (including alcohol and illicit

drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant

use of the benzodiazepine or other CNS depressant have been determined. Screen patients for

risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for

overdose and death associated with the use of additional CNS depressants including alcohol and

illicit drugs [see Drug Interactions (7), Patient Counseling Information (17)].

Patients must not consume alcoholic beverages or prescription or non-prescription products

containing alcohol while on KADIAN therapy. The co-ingestion of alcohol with KADIAN may

result in increased plasma levels and a potentially fatal overdose of morphine.

5.5 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary

Disease or in Elderly, Cachectic, or Debilitated Patients

The use of KADIAN in patients with acute or severe bronchial asthma in an unmonitored setting

or in the absence of resuscitative equipment is contraindicated.

Patients with Chronic Pulmonary Disease: KADIAN-treated patients with significant chronic

obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased

respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased

risk of decreased respiratory drive including apnea, even at recommended dosages of KADIAN

[see Warnings and Precautions (5.2)].

Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely

to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics

Page 10 of 35

Reference ID: 4028194

or altered clearance compared to younger, healthier patients [see Warnings and Precautions

(5.2)].

Monitor such patients closely, particularly when initiating and titrating KADIAN and when

KADIAN is given concomitantly with other drugs that depress respiration [see Warnings and

Precautions (5.2)]. Alternatively, consider the use of non-opioid analgesics in these patients.

5.6 Interaction with Monoamine Oxidase Inhibitors

Monoamine oxidase inhibitors (MAOIs) may potentiate the effects of morphine, including

respiratory depression, coma, and confusion. KADIAN should not be used in patients taking

MAOIs or within 14 days of stopping such treatment.

5.7 Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater

than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms

and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood

pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as

soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses

of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and

continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as

some cases reported use of a different opioid without recurrence of adrenal insufficiency. The

information available does not identify any particular opioids as being more likely to be

associated with adrenal insufficiency.

5.8 Severe Hypotension

KADIAN may cause severe hypotension including orthostatic hypotension and syncope in

ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure

has already been compromised by a reduced blood volume or concurrent administration of

certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions

(7)]. Monitor these patients for signs of hypotension after initiating or titrating the dosage of

KADIAN. In patients with circulatory shock, KADIAN may cause vasodilation that can further

reduce cardiac output and blood pressure. Avoid the use of KADIAN in patients with circulatory

shock.

5.9 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head

Injury, or Impaired Consciousness

In patients who may be susceptible to the intracranial effects of CO

retention (e.g., those with

evidence of increased intracranial pressure or brain tumors), KADIAN may reduce respiratory

drive, and the resultant CO

retention can further increase intracranial pressure. Monitor such

patients for signs of sedation and respiratory depression, particularly when initiating therapy with

KADIAN.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of

KADIAN in patients with impaired consciousness or coma.

Page 11 of 35

Reference ID: 4028194

5.10 Risks of Use in Patients with Gastrointestinal Conditions

KADIAN is contraindicated in patients with known or suspected gastrointestinal obstruction,

including paralytic ileus.

The morphine in KADIAN may cause spasm of the sphincter of Oddi. Opioids may cause

increases in the serum amylase. Monitor patients with biliary tract disease, including acute

pancreatitis, for worsening symptoms.

5.11 Increased Risk of Seizures in Patients with Seizure Disorders

The morphine in KADIAN may increase the frequency of seizures in patients with seizure

disorders, and may increase the risk of seizures occurring in other clinical settings associated

with seizures. Monitor patients with a history of seizure disorders for worsened seizure control

during KADIAN therapy.

5.12 Withdrawal

Avoid the use of mixed agonist/antagonist analgesics (e.g., pentazocine, nalbuphine, and

butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a

full opioid agonist analgesic, including KADIAN. In these patients, mixed agonists/antagonists

and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal

symptoms [see Drug Interactions (7)].

When discontinuing KADIAN, gradually taper the dosage [see Dosage and Administration

(2.3)]. Do not abruptly discontinue KADIAN [see Drug Abuse and Dependence (9.3)].

5.13 Risks of Driving and Operating Machinery

KADIAN may impair the mental or physical abilities needed to perform potentially hazardous

activities such as driving a car or operating machinery. Warn patients not to drive or operate

dangerous machinery unless they are tolerant to the effects of KADIAN and know how they will

react to the medication [see Patient Counseling Information (17)].

6 ADVERSE REACTIONS

The following serious adverse reactions are described, or described in greater detail, in other

sections:

• Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]

• Life Threatening Respiratory Depression [see Warnings and Precautions (5.2)]

• Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.3)]

• Interactions with Benzodiazepine or Other CNS Depressants [see Warnings and

Precautions (5.4)]

• Adrenal Insufficiency [see Warnings and Precautions (5.7)]

Page 12 of 35

Reference ID: 4028194

• Severe Hypotension [see Warnings and Precautions (5.8)]

• Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.10)]

• Seizures [see Warnings and Precautions (5.11)]

• Withdrawal [see Warnings and Precautions (5.12)]

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates

observed in the clinical trials of a drug cannot be directly compared with rates in the clinical

trials of another drug and may not reflect the rates observed in practice.

In the randomized study, the most common adverse reactions with KADIAN therapy were

drowsiness, constipation, nausea, dizziness, and anxiety. The most common adverse reactions

leading to study discontinuation were nausea, constipation (may be severe), vomiting, fatigue,

dizziness, pruritus, and somnolence.

Clinical trial patients with chronic cancer pain (n=227)

(AE by Body System as seen in 2% or more of patients)

Percentage %

CENTRAL NERVOUS SYSTEM

Drowsiness

Dizziness

Anxiety

Confusion

Dry mouth

Tremor

GASTROINTESTINAL

Constipation

Nausea

Diarrhea

Anorexia

Abdominal pain

Vomiting

BODY AS A WHOLE

Pain

Disease progression

Chest pain

Diaphoresis

Fever

Asthenia

Accidental injury

RESPIRATORY

Page 13 of 35

Reference ID: 4028194

Dyspnea

SKIN & APPENDAGES

Rash

METABOLIC & NUTRITIONAL

Peripheral edema

HEMIC & LYMPHATIC

Anemia

Leukopenia

In clinical trials in patients with chronic cancer pain, the most common adverse events reported

by patients at least once during therapy were drowsiness (9%), constipation (9%), nausea (7%),

dizziness (6%), and anxiety (6%). Other less common side effects expected from KADIAN or

seen in less than 2% of patients in the clinical trials were:

• Body as a Whole: Headache, chills, flu syndrome, back pain, malaise, withdrawal

syndrome

• Cardiovascular: Tachycardia, atrial fibrillation, hypotension, hypertension, pallor, facial

flushing, palpitations, bradycardia, syncope

• Central Nervous System: Confusion, anxiety, abnormal thinking, abnormal dreams,

lethargy, depression, loss of concentration, insomnia, amnesia, paresthesia, agitation,

vertigo, foot drop, ataxia, hypesthesia, slurred speech, hallucinations, vasodilation,

euphoria, apathy, seizures, myoclonus

• Endocrine: Hyponatremia due to inappropriate ADH secretion, gynecomastia

• Gastrointestinal: Dysphagia, dyspepsia, stomach atony disorder, gastro-esophageal

reflux, delayed gastric emptying, biliary colic

• Hemic and Lymphatic: Thrombocytopenia

• Metabolic and Nutritional: Hyponatremia, edema

• Musculoskeletal: Back pain, bone pain, arthralgia

• Respiratory: Hiccup, rhinitis, atelectasis, asthma, hypoxia, respiratory insufficiency,

voice alteration, depressed cough reflex, non-cardiogenic pulmonary edema

• Skin and Appendages: Decubitus ulcer, pruritus, skin flush

• Special Senses: Amblyopia, conjunctivitis, miosis, blurred vision, nystagmus, diplopia

• Urogenital: Urinary abnormality, amenorrhea, urinary retention, urinary hesitancy,

reduced libido, reduced potency, prolonged labor

Page 14 of 35

Reference ID: 4028194

Four-Week Open-Label Safety Study

In the open-label, 4-week safety study, 1418 patients ages 18 to 85 with chronic, non-malignant

pain (e.g., back pain, osteoarthritis, neuropathic pain) were enrolled. The most common adverse

events reported at least once during therapy were constipation (12%), nausea (9%), and

somnolence (3%). Other less common side effects occurring in less than 3% of patients were

vomiting, pruritus, dizziness, sedation, dry mouth, headache, fatigue, and rash.

6.2 Post-Marketing Experience

The following adverse reactions have been identified during post approval use of morphine.

Because these reactions are reported voluntarily from a population of uncertain size, it is not

always possible to reliably estimate their frequency or establish a causal relationship to drug

exposure.

Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have

been reported during concomitant use of opioids with serotonergic drugs.

Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more

often following greater than one month of use.

Anaphylaxis: Anaphylaxis has been reported with ingredients contained in KADIAN.

Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids

[see Clinical Pharmacology (12.2)].

7 DRUG INTERACTIONS

Table 1 includes clinically significant drug interactions with KADIAN.

Table 1: Clinically Significant Drug Interactions with KADIAN

Alcohol

Clinical Impact:

Concomitant use of alcohol with KADIAN can result in an increase of morphine

plasma levels and potentially fatal overdose of morphine.

Intervention:

Instruct patients not to consume alcoholic beverages or use prescription or non-

prescription products containing alcohol while on KADIAN therapy [see

Warnings and Precautions (5.4)].

Benzodiazepines and Other Central Nervous System (CNS) Depressants

Clinical Impact:

Due to additive pharmacologic effect, the concomitant use of benzodiazepines or

other CNS depressants, including alcohol, can increase the risk of hypotension,

respiratory depression, profound sedation, coma, and death.

Intervention:

Reserve concomitant prescribing of these drugs for use in patients for whom

alternative treatment options are inadequate. Limit dosages and durations to the

minimum required. Follow patients closely for signs of respiratory depression

and sedation [see Warnings and Precautions (5.2)].

Examples:

Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle

relaxants, general anesthetics, antipsychotics, other opioids, alcohol.

Serotonergic Drugs

Clinical Impact:

The concomitant use of opioids with other drugs that affect the serotonergic

neurotransmitter system has resulted in serotonin syndrome.

Intervention:

If concomitant use is warranted, carefully observe the patient, particularly during

treatment initiation and dose adjustment. Discontinue KADIAN if serotonin

syndrome is suspected.

Page 15 of 35

Reference ID: 4028194

Examples:

Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine

reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3

receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g.,

mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those

intended to treat psychiatric disorders and also others, such as linezolid and

intravenous methylene blue).

Monoamine Oxidase Inhibitors (MAOIs)

Clinical Impact:

MAOI interactions with opioids may manifest as serotonin syndrome or opioid

toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions

(5.6)].

Intervention:

Do not use KADIAN in patients taking MAOIs or within 14 days of stopping

such treatment.

Examples:

phenelzine, tranylcypromine, linezolid

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics

Clinical Impact:

May reduce the analgesic effect of KADIAN and/or precipitate withdrawal

symptoms.

Intervention:

Avoid concomitant use.

Examples:

butorphanol, nalbuphine, pentazocine, buprenorphine

Muscle Relaxants

Clinical Impact:

Morphine may enhance the neuromuscular blocking action of skeletal muscle

relaxants and produce an increased degree of respiratory depression.

Intervention:

Monitor patients for signs of respiratory depression that may be greater than

otherwise expected and decrease the dosage of KADIAN and/or the muscle

relaxant as necessary.

Cimetidine

Clinical Impact:

The concomitant use of cimetidine can potentiate morphine effects and increase

risk of hypotension, respiratory depression, profound sedation, coma, and death.

Intervention:

Monitor patients for signs of respiratory depression that may be greater than

otherwise expected and decrease the dosage of KADIAN and/or cimetidine as

necessary.

Diuretics

Clinical Impact:

Opioids can reduce the efficacy of diuretics by inducing the release of

antidiuretic hormone.

Intervention:

Monitor patients for signs of diminished diuresis and/or effects on blood pressure

and increase the dosage of the diuretic as needed.

Anticholinergic Drugs

Clinical Impact:

The concomitant use of anticholinergic drugs may increase risk of urinary

retention and/or severe constipation, which may lead to paralytic ileus.

Intervention:

Monitor patients for signs of urinary retention or reduced gastric motility when

KADIAN is used concomitantly with anticholinergic drugs.

P-Glycoprotein (P-gp) Inhibitors

Clinical Impact:

The concomitant use of PGP-inhibitors can increase the exposure to morphine by

about two-fold and can increase risk of hypotension, respiratory depression,

profound sedation, coma, and death.

Intervention:

Monitor patients for signs of respiratory depression that may be greater than

Page 16 of 35

Reference ID: 4028194

otherwise expected and decrease the dosage of KADIAN and/or the PGP-inhibitor

as necessary.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Prolonged use of opioid analgesics during pregnancy can cause neonatal opioid withdrawal

syndrome [see Warnings and Precautions (5.3)]. There are no available data with KADIAN in

pregnant women to inform a drug-associated risk for major birth defects and miscarriage.

Published studies with morphine use during pregnancy have not reported a clear association with

morphine and major birth defects [see Human Data]. In published animal reproduction studies,

morphine administered subcutaneously during the early gestational period produced neural tube

defects (i.e., exencephaly and cranioschisis) at 5 and 16 times the human daily dose of 60 mg

based on body surface area (HDD) in hamsters and mice, respectively, lower fetal body weight

and increased incidence of abortion at 0.4 times the HDD in the rabbit, growth retardation at 6

times the HDD in the rat, and axial skeletal fusion and cryptorchidism at 16 times the HDD in

the mouse. Administration of morphine sulfate to pregnant rats during organogenesis and

through lactation resulted in cyanosis, hypothermia, decreased brain weights, pup mortality,

decreased pup body weights, and adverse effects on reproductive tissues at 3-4 times the HDD;

and long-term neurochemical changes in the brain of offspring which correlate with altered

behavioral responses that persist through adulthood at exposures comparable to and less than the

HDD [see Animal Data]. Based on animal data, advise pregnant women of the potential risk to a

fetus.

The estimated background risk of major birth defects and miscarriage for the indicated

population is unknown. All pregnancies have a background risk of birth defect, loss, or other

adverse outcomes. In the U.S. general population, the estimated background risk of major birth

defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can

result in physical dependence in the neonate and neonatal opioid withdrawal syndrome

shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability,

hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and

failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal

syndrome vary based on the specific opioid used, duration of use, timing and amount of last

maternal use, and rate of elimination of the drug by the newborn. Observe newborns for

symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings

and Precautions (5.3)].

Labor or Delivery

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic

effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of

opioid-induced respiratory depression in the neonate. KADIAN is not recommended for use

Page 17 of 35

Reference ID: 4028194

in pregnant women during or immediately prior to labor, when use of shorter-acting

analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including

KADIAN, can prolong labor through actions which temporarily reduce the strength, duration,

and frequency of uterine contractions. However, this effect is not consistent and may be

offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor

neonates exposed to opioid analgesics during labor for signs of excess sedation and

respiratory depression.

Data

Human Data

The results from a population-based prospective cohort, including 70 women exposed to

morphine during the first trimester of pregnancy and 448 women exposed to morphine at any

time during pregnancy, indicate no increased risk for congenital malformations. However, these

studies cannot definitely establish the absence of any risk because of methodological limitations,

including small sample size and non-randomized study design.

Animal Data

Formal reproductive and developmental toxicology studies for morphine have not been

conducted. Exposure margins for the following published study reports are based on human

daily dose of 60 mg morphine using a body surface area comparison (HDD).

Neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous

administration of morphine sulfate (35-322 mg/kg) on Gestation Day 8 to pregnant hamsters (4.7

to 43.5 times the HDD). A no adverse effect level was not defined in this study and the findings

cannot be clearly attributed to maternal toxicity. Neural tube defects (exencephaly), axial

skeletal fusions, and cryptorchidism were reported following a single subcutaneous (SC)

injection of morphine sulfate to pregnant mice (100-500 mg/kg) on Gestation Day 8 or 9 at 200

mg/kg or greater (16 times the HDD) and fetal resorption at 400 mg/kg or higher (32 times the

HDD). No adverse effects were noted following 100 mg/kg morphine in this model (8 times the

HDD). In one study, following continuous subcutaneous infusion of doses greater than or equal

to 2.72 mg/kg to mice (0.2 times the HDD), exencephaly, hydronephrosis, intestinal hemorrhage,

split supraoccipital, malformed sternebrae, and malformed xiphoid were noted. The effects were

reduced with increasing daily dose; possibly due to rapid induction of tolerance under these

infusion conditions. The clinical significance of this report is not clear.

Decreased fetal weights were observed in pregnant rats treated with 20 mg/kg/day morphine

sulfate (3.2 times the HDD) from Gestation Day 7 to 9. There was no evidence of malformations

despite maternal toxicity (10% mortality). In a second rat study, decreased fetal weight and

increased incidences of growth retardation were noted at 35 mg/kg/day (5.7 times the HDD) and

there was a reduced number of fetuses at 70 mg/kg/day (11.4 times the HDD) when pregnant rats

were treated with 10, 35, or 70 mg/kg/day morphine sulfate via continuous infusion from

Gestation Day 5 to 20. There was no evidence of fetal malformations or maternal toxicity.

An increased incidence of abortion was noted in a study in which pregnant rabbits were treated

with 2.5 (0.8 times the HDD) to 10 mg/kg morphine sulfate via subcutaneous injection from

Gestation Day 6 to 10. In a second study, decreased fetal body weights were reported following

Page 18 of 35

Reference ID: 4028194

treatment of pregnant rabbits with increasing doses of morphine (10-50 mg/kg/day) during the

pre-mating period and 50 mg/kg/day (16 times the HDD) throughout the gestation period. No

overt malformations were reported in either publication; although only limited endpoints were

evaluated.

In published studies in rats, exposure to morphine during gestation and/or lactation periods is

associated with: decreased pup viability at 12.5 mg/kg/day or greater (2 times the HDD);

decreased pup body weights at 15 mg/kg/day or greater (2.4 times the HDD); decreased litter

size, decreased absolute brain and cerebellar weights, cyanosis, and hypothermia at 20

mg/kg/day (3.2 times the HDD); alteration of behavioral responses (play, social-interaction) at 1

mg/kg/day or greater (0.2 times the HDD); alteration of maternal behaviors (e.g., decreased

nursing and pup retrievals) in mice at 1 mg/kg or higher (0.08 times the HDD) and rats at 1.5

mg/kg/day or higher (0.2 times the HDD); and a host of behavioral abnormalities in the offspring

of rats, including altered responsiveness to opioids at 4 mg/kg/day (0.7 times the HDD) or

greater.

Fetal and/or postnatal exposure to morphine in mice and rats has been shown to result in

morphological changes in fetal and neonatal brain and neuronal cell loss, alteration of a number

of neurotransmitter and neuromodulator systems, including opioid and non-opioid systems, and

impairment in various learning and memory tests that appear to persist into adulthood. These

studies were conducted with morphine treatment usually in the range of 4 to 20 mg/kg/day (0.7

to 3.2 times the HDD).

Additionally, delayed sexual maturation and decreased sexual behaviors in female offspring at

20 mg/kg/day (3.2 times the HDD), and decreased plasma and testicular levels of luteinizing

hormone and testosterone, decreased testes weights, seminiferous tubule shrinkage, germinal cell

aplasia, and decreased spermatogenesis in male offspring were also observed at 20 mg/kg/day

(3.2 times the HDD). Decreased litter size and viability were observed in the offspring of male

rats that were intraperitoneally administered morphine sulfate for 1 day prior to mating at 25

mg/kg/day (4.1 times the HDD) and mated to untreated females. Decreased viability and body

weight and/or movement deficits in both first and second generation offspring were reported

when male mice were treated for 5 days with escalating doses of 120 to 240 mg/kg/day morphine

sulfate (9.7 to 19.5 times the HDD) or when female mice treated with escalating doses of 60 to

240 mg/kg/day (4.9 to 19.5 times the HDD) followed by a 5-day treatment-free recovery period

prior to mating. Similar multigenerational findings were also seen in female rats pre-

gestationally treated with escalating doses of 10 to 22 mg/kg/day morphine (1.6 to 3.6 times the

HDD).

8.2 Lactation

Risk Summary

Morphine is present in breast milk. Published lactation studies report variable concentrations of

morphine in breast milk with administration of immediate-release morphine to nursing mothers

in the early postpartum period with a milk-to-plasma morphine AUC ratio of 2.5:1 measured in

one lactation study. However, there is insufficient information to determine the effects of

Page 19 of 35

Reference ID: 4028194

morphine on the breastfed infant and the effects of morphine on milk production. Lactation

studies have not been conducted with extended –release morphine, including KADIAN.

Because of the potential for serious adverse reactions, including excess sedation and respiratory

depression in a breastfed infant, advise patients that breastfeeding is not recommended during

treatment with KADIAN.

Clinical Considerations

Monitor infants exposed to KADIAN through breast milk for excess sedation and respiratory

depression. Withdrawal symptoms can occur in breastfed infants when maternal administration

of morphine is stopped, or when breastfeeding is stopped.

8.3 Females and Males of Reproductive Potential

Infertility

Chronic use of opioids may cause reduced fertility in females and males of reproductive

potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions

(6.2), Clinical Pharmacology (12.2)].

In published animal studies, morphine administration adversely effected fertility and

reproductive endpoints in male rats and prolonged estrus cycle in female rats [See Nonclinical

Toxicology (13)].

8.4 Pediatric Use

The safety and efficacy of KADIAN in patients less than 18 years have not been established.

8.5 Geriatric Use

Clinical studies of KADIAN did not include sufficient numbers of subjects aged 65 and over to

determine whether they respond differently from younger subjects.

Elderly patients (aged 65 years or older) may have increased sensitivity to morphine. In general,

use caution when selecting a dosage for an elderly patient, usually starting at the low end of the

dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and

of concomitant disease or other drug therapy.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred

after large initial doses were administered to patients who were not opioid-tolerant or when

opioids were co-administered with other agents that depress respiration. Titrate the dosage of

KADIAN slowly in geriatric patients and monitor for signs of central nervous system and

respiratory depression [see Warnings and Precautions (5.5)].

Morphine is known to be substantially excreted by the kidney, and the risk of adverse reactions

to this drug may be greater in patients with impaired renal function. Because elderly patients are

more likely to have decreased renal function, care should be taken in dose selection, and it may

be useful to monitor renal function.

Page 20 of 35

Reference ID: 4028194

8.6 Hepatic Impairment

Morphine pharmacokinetics have been reported to be significantly altered in patients with

cirrhosis. Start these patients with a lower than usual dosage of KADIAN and titrate slowly

while monitoring for signs of respiratory depression, sedation, and hypotension [see Clinical

Pharmacology (12.3)].

8.7 Renal Impairment

Morphine pharmacokinetics are altered in patients with renal failure. Start these patients with a

lower than usual dosage of KADIAN and titrate slowly while monitoring for signs of respiratory

depression, sedation, and hypotension [see Clinical Pharmacology (12.3)].

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

KADIAN contains morphine, a Schedule II controlled substance.

9.2 Abuse

KADIAN contains morphine, a substance with a high potential for abuse similar to other opioids

including fentanyl, hydrocodone, hydromorphone, methadone, oxycodone, oxymorphone, and

tapentadol. KADIAN can be abused and is subject to misuse, addiction, and criminal diversion

[see Warnings and Precautions (5.1)].

The high drug content in extended-release formulations adds to the risk of adverse outcomes

from abuse and misuse.

All patients treated with opioids require careful monitoring for signs of abuse and addiction,

because use of opioid analgesic products carries the risk of addiction even under appropriate

medical use.

Prescription drug abuse is the intentional non-therapeutic use of an over-the-counter or

prescription drug, even once, for its rewarding psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop

after repeated substance use and includes: a strong desire to take the drug, difficulties in

controlling its use, persisting in its use despite harmful consequences, a higher priority given to

drug use than to other activities and obligations, increased tolerance, and sometimes a physical

withdrawal.

“Drug seeking” behavior is very common in persons with substance use disorders. Drug-seeking

tactics include emergency calls or visits near the end of office hours, refusal to undergo

appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with

prescriptions, and reluctance to provide prior medical records or contact information for other

healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional

prescriptions) is common among drug abusers and people suffering from untreated addiction.

Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with

poor pain control.

Page 21 of 35

Reference ID: 4028194

Abuse and addiction are separate and distinct from physical dependence and tolerance.

Healthcare providers should be aware that addiction may not be accompanied by concurrent

tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can

occur in the absence of true addiction.

KADIAN, like other opioids, can be diverted for non-medical use into illicit channels of

distribution. Careful record-keeping of prescribing information, including quantity, frequency,

and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy,

and proper dispensing and storage are appropriate measures that help to limit abuse of opioid

drugs.

Risks Specific to Abuse of KADIAN

KADIAN is for oral use only. Abuse of KADIAN poses a risk of overdose and death. This risk is

increased with concurrent abuse of KADIAN with alcohol and other central nervous system

depressants. Taking cut, broken, chewed, crushed, or dissolved KADIAN enhances drug release

and increases the risk of over dose and death.

Due to the presence of talc as one of the excipients in KADIAN, parenteral abuse can be

expected to result in local tissue necrosis, infection, pulmonary granulomas, embolism and death,

and increased risk of endocarditis and valvular heart injury. Parenteral drug abuse is commonly

associated with transmission of infectious diseases such as hepatitis and HIV.

9.3 Dependence

Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is

the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the

absence of disease progression or other external factors). Tolerance may occur to both the

desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant

dosage reduction of a drug. Withdrawal also may be precipitated through the administration of

drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist

analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine).

Physical dependence may not occur to a clinically significant degree until after several days to

weeks of continued opioid usage

KADIAN should not be abruptly discontinued [see Dosage and Administration (2.3)]. If

KADIAN is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome

may occur. Some or all of the following can characterize this syndrome: restlessness,

lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and

symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness,

abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure,

respiratory rate, or heart rate.

Page 22 of 35

Reference ID: 4028194

Infants born to mothers physically dependent on opioids will also be physically dependent and

may exhibit respiratory difficulties and withdrawal symptoms [see Use in Specific Populations

(8.2), Warnings and Precautions (5.3)].

10 OVERDOSAGE

Clinical Presentation

Acute overdosage with KADIAN can be manifested by respiratory depression, somnolence

progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted

pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete

airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be

seen with hypoxia in overdose situations.

Treatment of Overdose

In cases of overdose, priorities are the re-establishment of a patent and protected airway and

institution of assisted or controlled ventilation, if needed. Employ other supportive measures

(including oxygen and vasopressors) in the management of circulatory shock and pulmonary

edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques.

The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression

resulting from opioid overdose. For clinically significant respiratory or circulatory depression

secondary to morphine overdose, administer an opioid antagonist. Opioid antagonists should not

be administered in the absence of clinically significant respiratory or circulatory depression

secondary to morphine overdose.

Because the duration of reversal would be expected to be less than the duration of action of

morphine in KADIAN, carefully monitor the patient until spontaneous respiration is reliably

reestablished. KADIAN will continue to release morphine add to the morphine load for 24 to 48

hours or longer following ingestion, necessitating prolonged monitoring. If the response to an

opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as

directed by the product’s prescribing information.

In an individual physically dependent on opioids, administration of the recommended usual

dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the

withdrawal symptoms experienced will depend on the degree of physical dependence and the

dose of the antagonist administered. If a decision is made to treat serious respiratory depression

in the physically dependent patient, administration of the antagonist should be initiated with care

and by titration with smaller than usual doses of the antagonist.

11 DESCRIPTION

KADIAN (morphine sulfate) extended-release capsules, an opioid agonist, are for oral use and

contain pellets of morphine sulfate.

Each KADIAN extended-release capsule contains either 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60

mg, 80 mg, 100 mg, , or 200 mg of Morphine Sulfate USP and the following inactive ingredients

common to all strengths: hypromellose, ethylcellulose, methacrylic acid copolymer, polyethylene

glycol, diethyl phthalate, talc, corn starch, and sucrose.

Page 23 of 35

Reference ID: 4028194

The capsule shells contain gelatin, silicon dioxide, sodium lauryl sulfate, titanium dioxide, and

black ink, D&C red #28, FD&C blue #1 (10 mg), D&C yellow #10 (20 mg), FD&C red #3,

FD&C blue #1 (30 mg), D&C yellow #10, FD&C blue #1, FD&C red #3 (40 mg), D&C red #28,

FD&C red #40, FD&C blue #1 (50 mg), D&C red #28, FD&C red #40, FD&C blue #1 (60 mg),

FD&C blue #1, FD&C red #40, FD&C yellow #6 (80 mg), D&C yellow #10, FD&C blue #1

(100 mg) black iron oxide, yellow iron oxide, red iron oxide (200 mg). The imprint ink contains

black iron oxide, potassium hydroxide, propylene glycol, and shellac.

The chemical name of morphine sulfate is 7,8-didehydro-4,5 α- epoxy-17-methyl-morphinan-3,6

α- diol sulfate (2:1) (salt) pentahydrate. The empirical formula is (C

)

•H

•5H

and its molecular weight is 758.85.

Morphine sulfate is an odorless, white, crystalline powder with a bitter taste. It has a solubility

of 1 in 21 parts of water and 1 in 1000 parts of alcohol, but is practically insoluble in chloroform

or ether. The octanol: water partition coefficient of morphine is 1.42 at physiologic pH and the

is 7.9 for the tertiary nitrogen (mostly ionized at pH 7.4). Its structural formula is:

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Morphine is a full opioid agonist and is relatively selective for the mu-opioid receptor, although

it can bind to other opioid receptors at higher doses. The principal therapeutic action of morphine

is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with morphine.

Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse

reactions, including respiratory and CNS depression.

The precise mechanism of the analgesic action is unknown. However, specific CNS opioid

receptors for endogenous compounds with opioid-like activity have been identified throughout

the brain and spinal cord and are thought to play a role in the analgesic effects of this drug.

12.2 Pharmacodynamics

CNS Depressant/Alcohol Interaction

Additive pharmacodynamic effects may be expected when KADIAN is used in conjunction with

alcohol, other opioids, or illicit drugs that cause central nervous system depression.

Page 24 of 35

Reference ID: 4028194

Effects on the Central Nervous System

Morphine produces respiratory depression by direct action on brainstem respiratory centers. The

respiratory depression involves a reduction in the responsiveness of the brainstem respiratory

centers to both increases in carbon dioxide tension and to electrical stimulation.

Morphine causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose

but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may

produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in

overdose situations.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Morphine causes a reduction in motility associated with an increase in smooth muscle tone in the

antrum of the stomach and 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 may be increased to the point of spasm, resulting in constipation. Other opioid-

induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter

of Oddi, and transient elevations in serum amylase.

Effects on the Cardiovascular System

Morphine produces peripheral vasodilation, which may result in orthostatic hypotension or

syncope. Manifestations of histamine release or peripheral vasodilation may include pruritus,

flushing, red eyes, sweating, and/or orthostatic hypotension.

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing

hormone (LH) in humans [see Adverse Reactions (6.2)]. They also stimulate prolactin, growth

hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to

androgen deficiency that may manifest as low libido, impotence, erectile dysfunction,

amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism

is unknown because the various medical, physical, lifestyle, and psychological stressors that may

influence gonadal hormone levels have not been adequately controlled for in studies conducted

to date [see Adverse Reactions (6.2)].

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in

vitro and animal models. The clinical significance of these findings is unknown. Overall, the

effects of opioids appear to be modestly immunosuppressive.

Concentration-Efficacy Relationships

The minimum effective analgesic concentration will vary widely among patients, especially

among patients who have been previously treated with potent agonist opioids. The minimum

effective analgesic concentration of morphine for any individual patient may increase over time

due to an increase in pain, the development of a new pain syndrome, and/or the development of

analgesic tolerance [see Dosage and Administration (2.1, 2.2)].

Page 25 of 35

Reference ID: 4028194

Concentration–Adverse Reaction Relationships

There is a relationship between increasing morphine plasma concentration and increasing

frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and

respiratory depression. In opioid-tolerant patients, the situation may be altered by the

development of tolerance to opioid-related adverse reactions [see Dosage and Administration

(2.1, 2.2, 2.3)].

12.3 Pharmacokinetics

Absorption

KADIAN capsules contain polymer coated extended-release pellets of morphine sulfate that

release morphine significantly more slowly than oral morphine solution. Following the

administration of oral morphine solution, approximately 50% of the morphine absorbed reaches

the systemic circulation within 30 minutes compared to 8 hours with an equal amount of

KADIAN. Because of pre-systemic elimination, only about 20 to 40% of the administered dose

reaches the systemic circulation.

Both dose-normalized C

max

and dose-normalized AUC

0-48hr

values of morphine after a single

dose administration of KADIAN in healthy volunteers are less than those for morphine oral

solution or an extended-release tablet formulation (Table 1).

When KADIAN was given twice daily to 24 patients with chronic pain due to malignancy,

steady-state was achieved in about two days. At steady-state, KADIAN has a significantly lower

max

and a higher C

min

than equivalent doses of oral morphine solution given every 4 hrs and an

extended-release tablet given twice daily. When given once daily to 24 patients with malignancy,

KADIAN had a similar C

max

and higher C

min

at steady-state when compared to an

extended-release morphine tablets, given twice daily at an equivalent total daily dosage (see

Table 1).

The single-dose pharmacokinetics of KADIAN are linear over the dosage range of 30 to 100 mg.

Page 26 of 35

Reference ID: 4028194

Table 1: Mean pharmacokinetic parameters (% coefficient variation) resulting from a

fasting single dose study in normal volunteers and a multiple-dose study in

patients with cancer pain.

Regimen/Dosag

e Form

AUC#,+

(ng∙h/mL)

max

(ng/mL)

max

(h)

min

(ng/mL)

Fluctuation

Single Dose (n=24)

KADIAN

Capsule

271.0

(19.4)

15.6

(24.4)

8.6

(41.1)

na^

Extended-Relea

se Tablet

304.3

(19.1)

30.5

(32.1)

2.5

(52.6)

Morphine

Solution

362.4

(42.6)

64.4

(38.2)

0.9

(55.8)

Multiple Dose (n=24)

KADIAN

Capsule

Once

Daily

500.9

(38.6)

37.3

(37.7)

10.3

(32.2)

9.9

(52.3)

3.0

(45.5)

Extended-Relea

se Tablet

Twice

Daily

457.3

(40.2)

36.9

(42.0)

4.4

(53.0)

7.6

(60.3)

4.1

(51.5)

# For single dose AUC = AUC

0-48h

, for multiple dose AUC = AUC

0-24h

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 = C

max

-C

min

^ Not applicable

Food Effect:

While concurrent administration of food slows the rate of absorption of KADIAN, the extent

of absorption is not affected and KADIAN can be administered without regard to meals.

Distribution

Once absorbed, morphine is distributed to skeletal muscle, kidneys, liver, intestinal tract, lungs,

spleen and brain. The volume of distribution of morphine is approximately 3 to 4 L/kg.

Morphine is 30 to 35% reversibly bound to plasma proteins. Although the primary site of action

of morphine is in the CNS, only small quantities pass the blood-brain barrier. Morphine also

crosses the placental membranes [see Use in Specific Populations (8.1)] and has been found in

breast milk [see Use in Specific Populations (8.4)].

Elimination

Metabolism

Major pathways of morphine metabolism include glucuronidation in the liver to produce

metabolites including morphine-3-glucuronide, M3G (about 50%) and morphine-6-

glucuronide, M6G (about 5 to 15%) and sulfation in the liver to produce morphine-3-etheral

sulfate. A small fraction (less than 5%) of morphine is demethylated. M3G has no significant

contribution to the analgesic activity. Although M6G does not readily cross the blood-brain

barrier, it has been shown to have opioid agonist and analgesic activity in humans.

Studies in healthy subjects and cancer patients have shown that the glucuronide metabolite to

morphine mean molar ratios (based on AUC) are similar after both single doses and at

Page 27 of 35

Reference ID: 4028194

steady-state for KADIAN, 12-hour extended-release morphine sulfate tablets and morphine

sulfate solution.

Excretion

Approximately 10% of a morphine dose is excreted unchanged in the urine. Most of the dose

is excreted in the urine as M3G and M6G which are then renally excreted. A small amount

of the glucuronide metabolites is excreted in the bile and there is some minor enterohepatic

cycling. Seven to 10% of administered morphine is excreted in the feces.

The mean adult plasma clearance of morphine is about 20 to 30 mL/minute/kg. The effective

terminal half-life of morphine after IV administration is reported to be approximately 2

hours. The terminal elimination half-life of morphine following a single dose of KADIAN

administration is approximately 11 to 13 hours.

Specific Populations

Sex: No meaningful differences between male and female patients were demonstrated in the

analysis of the pharmacokinetic data from clinical studies.

Race/Ethnicity: Chinese subjects given intravenous morphine in one study had a higher

clearance when compared to Caucasian subjects (1852 + 116 mL/min versus 1495 + 80

mL/min).

Hepatic Impairment

Morphine pharmacokinetics are altered in patients with alcoholic cirrhosis. Clearance was

found to decrease with a corresponding increase in half-life. The M3G and M6G to morphine

AUC ratios also decreased in these patients, indicating a decrease in metabolic activity.

Adequate studies of the pharmacokinetics of morphine in patients with severe hepatic

impairment have not been conducted.

Renal Impairment

Morphine pharmacokinetics are altered in patients with renal failure. The AUC is increased

and clearance is decreased and the metabolites, M3G and M6G, may accumulate to much

higher plasma levels in patients with renal failure as compared to patients with normal renal

function. Adequate studies of the pharmacokinetics of morphine in patients with severe renal

impairment have not been conducted.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term studies in animals to evaluate the carcinogenic potential of morphine have not been

conducted.

Mutagenesis

No formal studies to assess the mutagenic potential of morphine have been conducted. In the

published literature, morphine was found to be mutagenic in vitro increasing DNA fragmentation

in human T-cells. Morphine was reported to be mutagenic in the in vivo mouse micronucleus

Page 28 of 35

Reference ID: 4028194

assay and positive for the induction of chromosomal aberrations in mouse spermatids and murine

lymphocytes. Mechanistic studies suggest that the in vivo clastogenic effects reported with

morphine in mice may be related to increases in glucocorticoid levels produced by morphine in

this species. In contrast to the above positive findings, in vitro studies in the literature have also

shown that morphine did not induce chromosomal aberrations in human leukocytes or

translocations or lethal mutations in Drosophila.

Impairment of Fertility

No formal nonclinical studies to assess the potential of morphine to impair fertility have been

conducted. Several nonclinical studies from the literature have demonstrated adverse effects on

male fertility in the rat from exposure to morphine. One study in which male rats were

administered morphine sulfate subcutaneously prior to mating (up to 30 mg/kg twice daily) and

during mating (20 mg/kg twice daily) with untreated females, a number of adverse reproductive

effects including reduction in total pregnancies and higher incidence of pseudo pregnancies at 20

mg/kg/day (3.2 times the HDD) were reported.

Studies from the literature have also reported changes in hormonal levels in male rats (i.e.

testosterone, luteinizing hormone) following treatment with morphine at 10 mg/kg/day or greater

(1.6 times the HDD).

Female rats that were administered morphine sulfate intraperitoneally prior to mating exhibited

prolonged estrous cycles at 10 mg/kg/day (1.6 times the HDD).

Exposure of adolescent male rats to morphine has been associated with delayed sexual

maturation and following mating to untreated females, smaller litters, increased pup mortality,

and/or changes in reproductive endocrine status in adult male offspring have been reported

(estimated 5 times the plasma levels at the HDD).

16 HOW SUPPLIED/STORAGE AND HANDLING

KADIAN capsules contain white to off-white or tan colored polymer coated extended-release

pellets of morphine sulfate and are available in twelve dose strengths.

KADIAN 10 mg

KADIAN 20 mg

KADIAN 30 mg

KADIAN 40 mg

Extended-

Release

Capsule

Description

size 4, light blue

opaque cap

printed with

“KADIAN” and

light blue opaque

body printed with

“10 mg”.

size 4, yellow

opaque cap printed

with “KADIAN”

and yellow opaque

body printed with

“20 mg”.

size 4, blue violet

opaque cap printed

with “KADIAN”

and blue violet

opaque body

printed with “30

mg”.

size 2, yellow

opaque cap printed

with “KADIAN”

and blue violet

opaque body

printed with “40

mg”.

Bottle Size

NDC #

NDC 0023-

6011-60

NDC 0023-6012-

NDC 0023-6013-

NDC 0023-6014-

Page 29 of 35

Reference ID: 4028194

KADIAN 50 mg

KADIAN 60 mg

KADIAN 80 mg

Extended-

Release

Capsule

Description

size 2, blue

opaque cap printed

with “KADIAN”

and blue opaque

body printed with

“50 mg”.

size 1, pink

opaque cap printed

with “KADIAN”

and pink opaque

body printed with

“60 mg”.

size 0, light orange

opaque cap printed

with “KADIAN”

and light orange

opaque body

printed with “80

mg”.

Bottle Size

NDC #

NDC 0023-6015-

NDC 0023-6016-

NDC 0023-6017-

KADIAN 100 mg

KADIAN 200 mg

Extended-

Release

Capsule

Description

size 0, green

opaque cap printed

with “KADIAN”

and green opaque

body printed with

“100 mg”.

size 0, light brown

opaque cap printed

with “KADIAN”

and light brown

opaque body

printed with “200

mg”.

Bottle Size

NDC #

NDC 0023-6018-

NDC 0023-6019-

Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F)[see USP Controlled Room

Temperature]. Protect from light and moisture. Dispense in a sealed tamper-evident, childproof,

light-resistant container.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instruction

for use).

Addiction, Abuse, and Misuse

Inform patients that the use of KADIAN, even when taken as recommended, can result in

addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and

Precautions (5.1)]. Instruct patients not to share KADIAN with others and to take steps to

protect KADIAN from theft or misuse.

Life-Threatening Respiratory Depression

Inform patients of the risk of life-threatening respiratory depression, including information that

the risk is greatest when starting KADIAN or when the dosage is increased, and that it can occur

even at recommended doses [see Warnings and Precautions (5.2)]. Advise patients how to

recognize respiratory depression and to seek medical attention if breathing difficulties develop.

Accidental Ingestion

Inform patients that accidental ingestion, especially by children, may result in respiratory

depression or death [see Warnings and Precautions (5.2)]. Instruct patients to take steps to store

KADIAN securely and to dispose of unused KADIAN by flushing the unused capsules down the

toilet.

Page 30 of 35

Reference ID: 4028194

Interactions with Alcohol

Instruct patients not to consume alcoholic beverages, or prescription and non-prescription

products that contain alcohol, during treatment with KADIAN. The co-ingestion of alcohol with

KADIAN may result in increased plasma levels and a potentially fatal overdose of morphine [see

Drug Interactions (7)].

Interactions with Benzodiazepines and Other CNS Depressants

Instruct patients not to consume alcoholic beverages, as well as prescription and over-the counter

products that contain alcohol, during treatment with KADIAN. The co-ingestion of alcohol with

KADIAN may result in increased plasma levels and a potentially fatal overdose of (active

opioid) [see Warnings and Precautions (5.4)].

Serotonin Syndrome

Inform patients that opioids could cause a rare but potentially life-threatening condition

resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms

of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct

patients to inform their physicians if they are taking, or plan to take serotonergic medications

[see Drug Interactions 7].

MAOI Interaction

Inform patients not to take KADIAN while using any drugs that inhibit monoamine oxidase.

Patients should not start MAOIs while taking KADIAN [see Warnings and Precautions (5.6),

Drug Interactions (7)].

Adrenal Insufficiency

Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening

condition. Adrenal insufficiency may present with non-specific symptoms and signs such as

nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise

patients to seek medical attention if they experience a constellation of these symptoms [see

Warnings and Precautions (5.6)].

Important Administration Instructions

Instruct patients how to properly take KADIAN, including the following:

• Swallow KADIAN capsules whole or sprinkling the capsule contents on applesauce and then

swallow immediately without chewing [see Dosage and Administration (2.1, 2.5)]

• DO not crush, chew, or dissolve the pellets contained in the capsules due to a risk of fatal

morphine overdose [see Dosage and Administration (2.1)]

• Use KADIAN exactly as prescribed to reduce the risk of life-threatening adverse reactions

(e.g., respiratory depression) [see Warnings and Precautions (5.2)]

• Do not discontinue KADIAN without first discussing the need for a tapering regimen with

the prescriber [see Dosage and Administration (2.4)]

Hypotension

Inform patients that KADIAN may cause orthostatic hypotension and syncope. Instruct patients

how to recognize symptoms of low blood pressure and how to reduce the risk of serious

consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or

lying position) [see Warnings and Precautions (5.8)].

Page 31 of 35

Reference ID: 4028194

Anaphylaxis

Inform patients that anaphylaxis has been reported with KADIAN. Advise patients how to

recognize such a reaction and when to seek medical attention [see Contraindications (4),

Adverse Reactions (6)].

Pregnancy

Neonatal Opioid Withdrawal Syndrome

Inform female patients of reproductive potential that prolonged use of KADIAN during

pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening

if not recognized and treated [see Warnings and Precautions (5.3), Use in Specific

Populations (8.1)]].

Embryo-Fetal Toxicity

Inform female patients of reproductive potential that KADIAN can cause fetal harm and to

inform their healthcare provider of a known or suspected pregnancy [see Use in Specific

Populations (8.1)].

Lactation

Advise patients that breastfeeding is not recommended during treatment with KADIAN[see Use

in Specific Populations (8.2)].

Infertility

Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether

these effects on fertility are reversible [see Adverse Reactions (6.2)].

Driving or Operating Heavy Machinery

Inform patients that KADIAN may impair the ability to perform potentially hazardous activities

such as driving a car or operating heavy machinery. Advise patients not to perform such tasks

until they know how they will react to the medication [see Warnings and Precautions (5.13)].

Constipation

Advise patients of the potential for severe constipation, including management instructions and

when to seek medical attention [see Adverse Reactions (6), Clinical Pharmacology (12.2)].

Disposal of Unused KADIAN

Advise patients to flush the unused capsules down the toilet when KADIAN is no longer needed.

For all medical inquiries contact:

Allergan USA, Inc.

Medical Communications

1-800-678-1605

Distributed By: Allergan USA, Inc.

Irvine, CA 92612

Page 32 of 35

Reference ID: 4028194

Medication Guide

KADIAN

(key-dee-un) (morphine sulfate) extended-release capsules, CII

KADIAN is:

• A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage pain severe

enough to require daily around-the-clock, long-term treatment with an opioid, when other pain

treatments such as non-opioid pain medicines or immediate-release opioid medicines do not treat your

pain well enough or you cannot tolerate them.

• A long-acting (extended-release) opioid pain medicine that can put you at risk for overdose and death.

Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse

that can lead to death.

• Not for use to treat pain that is not around-the-clock.

Important information about KADIAN:

• Get emergency help right away if you take too much KADIAN (overdose). When you first start

taking KADIAN, when your dose is changed, or if you take too much (overdose), serious or life

threatening breathing problems that can lead to death may occur.

• Taking KADIAN with other opioid medicines, benzodiazepines, alcohol, or other central nervous system

depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing

problems, coma, and death.

• Never give anyone else your KADIAN. They could die from taking it. Store KADIAN away from children

and in a safe place to prevent stealing or abuse. Selling or giving away KADIAN is against the law.

Do not take KADIAN if you have:

• severe asthma, trouble breathing, or other lung problems.

• a bowel blockage or have narrowing of the stomach or intestines.

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

• head injury, seizures  liver, kidney, thyroid problems

• problems urinating

 pancreas or gallbladder problems

• abuse of street or prescription drugs, alcohol addiction, or mental health problems.

Tell your healthcare provider if you are:

• pregnant or planning to become pregnant. Prolonged use of KADIAN during pregnancy can cause

withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.

• breastfeeding. Not recommended during treatment with KADIAN. It may harm your baby.

• taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking KADIAN with

certain other medicines can cause serious side effects.

When taking KADIAN:

• Do not change your dose. Take KADIAN exactly as prescribed by your healthcare provider. Use the

lowest dose possible for the shortest time needed.

• Take your prescribed dose every 12 or 24 hours at the same time every day. Do not take more than

your prescribed dose in 24 hours. If you miss a dose, take your next dose at your usual time.

• Swallow KADIAN whole. Do not cut, break, chew, crush, dissolve, snort, or inject KADIAN because

this may cause you to overdose and die.

• You should not receive KADIAN through a nasogastric tube.

• If you cannot swallow KADIAN

capsules, see the detailed Instructions for Use.

• Call your healthcare provider if the dose you are taking does not control your pain.

• Do not stop taking KADIAN without talking to your healthcare provider.

• After you stop taking KADIAN, flush any unused capsules down the toilet.

While taking KADIAN DO NOT:

• Drive or operate heavy machinery, until you know how KADIAN affects you. KADIAN can make you

sleepy, dizzy, or lightheaded.

• Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products

containing alcohol during treatment with KADIAN may cause you to overdose and die.

The possible side effects of KADIAN are:

• constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your

healthcare provider if you have any of these symptoms and they are severe

Get emergency medical help if you have:

• trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or

throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body

temperature, trouble walking, stiff muscles, or mental changes such as confusion.

Page 33 of 35

Reference ID: 4028194

These are not all the possible side effects of KADIAN. Call your doctor for medical advice about side

effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to

dailymed.nlm.nih.gov

This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 12/2016

Page 34 of 35

Reference ID: 4028194

Instructions For Use

KADIAN

(key-dee-uhn)

(morphine sulfate) extended-release Capsules, CII

If you cannot swallow KADIAN capsules, tell your healthcare provider. There may be another

way to take KADIAN that may be right for you. If your healthcare provider tells you that you

can take KADIAN using this other way, follow these steps:

KADIAN can be opened and the pellets inside the capsule can be sprinkled over applesauce,

as follows:

Figure 1

Figure 2

• Open the KADIAN capsule and sprinkle the pellets

over about one tablespoon of applesauce (See

Figure 1).

•

Swallow all of the applesauce and pellets right

away. Do not save any of the applesauce and

pellets for another dose (See Figure 2).

• Rinse your mouth to make sure you have swallowed

all of the pellets. Do not chew the pellets (See Figure

3).

Figure 3

• Flush the empty capsule down the toilet right away

(See Figure 4).

Figure 4

You should not receive KADIAN through a nasogastric tube.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Distributed By: Allergan USA, Inc.

Irvine, CA 92612

Revised: 12/2016

Page 35 of 35

Reference ID: 4028194