5 WARNINGS AND PRECAUTIONS

5.1 Risks with Neuraxial Administration

Control of pain by neuraxial opiate delivery, using a continuous microinfusion device, is always accompanied by considerable risk to the patients and requires a high level of skill to be successfully accomplished. The task of treating these patients must be undertaken by experienced clinical teams, well-versed in patient selection, evolving technology and emerging standards of care.

MITIGO ® should be administered by or under the direction of a physician experienced in the techniques of epidural or intrathecal administration and familiar with the patient management problems associated with epidural or intrathecal drug administration. The physician should be familiar with patient conditions (such as infection at the injection site, bleeding diathesis, anticoagulant therapy, etc.) which call for special evaluation of the benefit versus risk potential.

Because of the risk of severe adverse effects when the epidural or intrathecal route of administration is employed, patients must be observed in a fully equipped and staffed environment for at least 24 hours after the initial dose.

The facility must be equipped to resuscitate patients with severe opioid overdosage, and the personnel must be familiar with the use and limitations of specific narcotic antagonists (naloxone, naltrexone) in such cases.

For safety reasons, it is recommended that administration of MITIGO ® 200 mg/20 mL and 500 mg/20 mL (10 and 25 mg/mL, respectively) by the intrathecal route be limited to the lumbar area.

5.2 Addiction, Abuse, and Misuse

MITIGO ® contains morphine, a Schedule II controlled substance. As an opioid, MITIGO ® exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence ( 9)]. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed MITIGO ®. Addiction can occur at recommended dosages and if the drug is misused

or abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing MITIGO ®, and monitor all patients receiving MITIGO ® 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 MITIGO ® but use in such patients necessitates intensive counseling about the risks and proper use of MITIGO ® along with intensive monitoring for signs of addiction, abuse, and misuse.

Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing MITIGO ®. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity. 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.

Each vial of MITIGO ® contains a large amount of a potent narcotic which has been associated with abuse and dependence among health care providers. Due to the limited indications for this product, the risk of overdosage and the risk of its diversion and abuse, it is recommended that special measures must be taken to control this product within the hospital or clinic. MITIGO ® should be subject to rigid accounting, rigorous control of wastage, and restricted access.

5.3 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 MITIGO ®, the risk is greatest during the initiation of therapy or following a dosage increase. This respiratory depression and/or respiratory arrest may be severe and could require intervention.

Because of the risk of severe adverse effects, patients must be observed in a fully equipped and staffed environment for at least 24 hours after the initial (single) test dose and, as appropriate, for the first several days after catheter implantation. The facility must be equipped to resuscitate patients with severe opioid overdosage, and the personnel must be familiar with the use and limitations of specific narcotic antagonists (naloxone, naltrexone) in such cases
Severe respiratory depression up to 24 hours following epidural or intrathecal administration has been reported.
Intrathecal use has been associated with a higher incidence of respiratory depression than epidural use.
Parenteral administration of narcotics in patients receiving epidural or intrathecal morphine may result in overdosage.

To reduce the risk of respiratory depression, proper dosing and titration of MITIGO ® are essential [see Dosage and Administration (2)]. Overestimating the MITIGO ® dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.

IMPROPER OR ERRONEOUS SUBSTITUTION OF MITIGO® 200 mg/20 mL and 500 mg/20 mL (10 or 25 mg/mL, respectively) FOR REGULAR MORPHINE SULFATE INJECTION, USP (0.5 or 1 mg/mL) IS LIKELY TO RESULT IN SERIOUS OVERDOSAGE, LEADING TO SEIZURES, RESPIRATORY DEPRESSION, AND DEATH.

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-relatedhypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration ( 2.6)] .

5.4 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Profound sedation, respiratory depression, coma, and death may result from concomitant use of MITIGO ® with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non- benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Use of neuroleptics in conjunction with neuraxial morphine may increase the risk of respiratory depression.

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. Monitor patients closely for signs and symptoms of respiratory depression and sedation.

5.5 Neonatal Opioid Withdrawal Syndrome

Use of MITIGO ® for an extended period of time 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 an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that management by neonatology experts will be available at delivery [see Use in Specific Populations ( 8.1) ].

5.6 Risk of Inflammatory Masses

Inflammatory masses such as granulomas, some of which have resulted in serious neurologic impairment including paralysis, have been reported to occur in patients receiving continuous infusion of opioid analgesics including MITIGO ® via indwelling intrathecal catheter. Patients receiving continuous infusion of MITIGO ® via indwelling intrathecal catheter should be carefully monitored for new neurologic signs or symptoms. Further assessment or intervention should be based on the clinical condition of the individual patient.

5.7 Risk of Tolerance and Myoclonic Activity

Patients sometimes manifest unusual acceleration of neuraxial morphine requirements, which may cause concern regarding systemic absorption and the hazards of large doses; these patients may benefit from hospitalization and detoxification. Two cases of myoclonic-like spasm of the lower extremities have been reported in patients receiving more than 20 mg/day of intrathecal morphine. After detoxification, it might be possible to resume treatment at lower doses, and some patients have been successfully changed from continuous epidural morphine to continuous intrathecal morphine. Repeat detoxification may be indicated at a later date. The upper daily dosage limit for each patient during continuing treatment must be individualized.

5.8 Opioid-Induced Hyperalgesia and Allodynia

Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see Dependence ( 9.3)] . Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.

Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation (safety switching the patient to a different opioid moiety) [see Dosage and Administration ( 2), Warnings and Precautions ( 5.16)].

5.9 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

The use of MITIGO® 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: 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 doses of MITIGO ®[see Warnings and

Precautions ( 5.3)] .

Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have alteredpharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions ( 5.3)] .

Monitor such patients closely, particularly when initiating and titrating MITIGO ® and when MITIGO ® is given concomitantly with other drugs that depress respiration [see Warnings and Precautions ( 5.3, 5.4), Drug Interactions ( 7)] . Alternatively, consider the use of non-opioid analgesics in these patients.

5.10 Interaction with Monoamine Oxidase Inhibitors

Monoamine oxidase inhibitors (MAOIs) may potentiate the effects of morphine, including respiratory depression, coma, and confusion. Morphine Sulfate Injection should not be used in patients taking MAOIs or within 14 days of stopping such treatment [see Drug Interactions ( 7)].

5.11 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 nonspecific 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.

5.12 Severe Hypotension

MITIGO ® 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 MITIGO ®. In patients with circulatory shock, MITIGO ® may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of MITIGO ® in patients with circulatory shock.

5.13 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), MITIGO ® 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

MITIGO ®. MITIGO ® should be used with extreme caution in patients with head injury or increased intracranial pressure. Pupillary changes (miosis) from morphine may obscure the existence, extent and course of intracranial pathology. High doses of neuraxial morphine may produce myoclonic events [see Warnings and Precautions ( 5.7)] . Clinicians should maintain a high index of suspicion for adverse drug reactions when evaluating altered mental status or movement abnormalities in patients receiving this modality of treatment. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of MITIGO ® in patients with impaired consciousness or coma.

5.14 Risks of Use in Patients with Gastrointestinal Conditions

MITIGO ® is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The morphine in MITIGO ® may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms. As significant morphine is released into the systemic circulation from neuraxial administration, the ensuing smooth muscle hypertonicity may result in biliary colic.

5.15 Increased Risk of Seizures in Patients with Seizure Disorders
The morphine in MITIGO ® may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical setting associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during MITIGO ® therapy.

5.16 Withdrawal

Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including MITIGO ®. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [Drug

Interactions ( 7)].

When discontinuing MITIGO ®, gradually taper the dosage [see Dosage and Administration ( 2.6)].

Do not abruptly discontinue MITIGO ®[see Drug Abuse and Dependence ( 9.3)].

5.17 Risks of Driving and Operating Machinery

MITIGO ® 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 MITIGO ® and know how they will react to the medication.

5.18 Risks of Use in Patients with Urinary System Disorders

Urinary retention, which may persist 10 to 20 hours following single epidural or intrathecal administration, is frequently associated with neuraxial opioid administration and must be anticipated, more frequently in male patients than female patients. Urinary retention may also occur during the first several days of hospitalization for the initiation of continuous intrathecal or epidural morphine therapy. Early recognition of difficulty in urination and prompt intervention in cases of urinary retention is indicated. Patients who develop urinary retention have responded to cholinomimetic treatment and/or judicious use of catheters.

5.19 Risks of Use in Ambulatory Patients

Patients with reduced circulating blood volume, impaired myocardial function or on sympatholytic drugs should be monitored for the possible occurrence of orthostatic hypotension, a frequent complication in single-dose neuraxial morphine analgesia.