FDA

Mitigo

Approved 16 Jul 2018InjectionInjectable

The FDA lists this product in 2 strengths and forms.

Indications

MITIGO ® is for use in continuous microinfusion devices and indicated only for intrathecal or epidural infusion in the management of intractable chronic pain severe enough to require an opioid analgesic and for which less invasive means of controlling pain are inadequate. Limitations of Use Not for single-dose intravenous, intramuscular, or subcutaneous administration due to the risk of overdose. Not for single-dose neuraxial injection because MITIGO ® is too concentrated for accurate delivery of the smaller doses used in this setting.

MITIGO ® is an opioid agonist, for use in continuous microinfusion devices and indicated only for intrathecal or epidural infusion in the management of intractable chronic pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. ( 1 ) Limitations of Use : ( 1 ) Not for single-dose intravenous, intramuscular, or subcutaneous administration due to the risk of overdose. Not for single-dose neuraxial injection because MITIGO ® is too concentrated for accurate delivery of the smaller doses used in this setting.

Contraindications

MITIGO ® 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 ( 5.9 )]
Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see Warnings and Precautions ( 5.10 ), Drug Interactions ( 7 )]
Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.14 ]
Hypersensitivity to morphine (e.g., anaphylaxis) [see Adverse Reactions ( 6 )] Neuraxial administration of MITIGO ® is contraindicated in patients with:
Infection at the injection microinfusion site [see Warnings and Precautions ( 5.1 )]
Concomitant anticoagulant therapy [see Warnings and Precautions ( 5.1 ) ]
Uncontrolled bleeding diathesis [see Warnings and Precautions ( 5.1 )]
The presence of any other concomitant therapy or medical condition which would render epidural or intrathecal administration of medication especially hazardous. Significant respiratory depression ( 4 ) Acute or severe bronchial asthma in an unmonitored setting in 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 or intolerance to morphine ( 4 ) Neuraxial administration of MITIGO ® is contraindicated in patients with: Infection at the injection microinfusion site ( 4 ) Concomitant anticoagulant therapy ( 4 ) Uncontrolled bleeding diathesis ( 4 ) The presence of any other concomitant therapy or medical condition which would render epidural or intrathecal administration of medication especially hazardous. ( 4 )

At a glance

Brand name: Mitigo
Active substance: morphine sulfate
Route: Injection
Dosage form: Injectable
Applicant: Piramal Critical
Status: Prescription
FDA approval: 16 Jul 2018
Application: ANDA204393-002

Indications

Contraindications

MITIGO ® 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 ( 5.9 )]
Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see Warnings and Precautions ( 5.10 ), Drug Interactions ( 7 )]
Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.14 ]
Hypersensitivity to morphine (e.g., anaphylaxis) [see Adverse Reactions ( 6 )] Neuraxial administration of MITIGO ® is contraindicated in patients with:
Infection at the injection microinfusion site [see Warnings and Precautions ( 5.1 )]
Concomitant anticoagulant therapy [see Warnings and Precautions ( 5.1 ) ]
Uncontrolled bleeding diathesis [see Warnings and Precautions ( 5.1 )]
The presence of any other concomitant therapy or medical condition which would render epidural or intrathecal administration of medication especially hazardous. Significant respiratory depression ( 4 ) Acute or severe bronchial asthma in an unmonitored setting in 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 or intolerance to morphine ( 4 ) Neuraxial administration of MITIGO ® is contraindicated in patients with: Infection at the injection microinfusion site ( 4 ) Concomitant anticoagulant therapy ( 4 ) Uncontrolled bleeding diathesis ( 4 ) The presence of any other concomitant therapy or medical condition which would render epidural or intrathecal administration of medication especially hazardous. ( 4 )

Warnings and precautions

5.1Risks 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.

5.2Addiction, 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. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy.

In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see Adverse Reactions ( 6.2 ) ]. 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.

5.3Life-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 overdose reversal agents (e.g., naloxone, nalmefene), 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 DURAMORPH (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 )] .

5.4Risks 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, gabapentinoids [gabapentin or pregabalin], and 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 abse

Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA

Interactions

Table 1 includes clinically significant drug interactions with MITIGO ® . Table 1. Clinically Significant Drug Interactions with MITIGO ® 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.

The depressant effects of morphine are potentiated by the presence of other CNS depressants. Use of neuroleptics in conjunction with neuraxial morphine may increase the risk of respiratory depression [see Warnings and Precautions ( 5.4 )]. 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.

Monitor patients closely for signs of respiratory depression and sedation [see Warnings and Precautions ( 5.4 ] . Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, psychotropic drugs, antihistamines, neuroleptics, gabapentinoids (gabapentin or pregabalin), 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 MITIGO ® if serotonin syndrome is suspected. 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), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase 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 ( 5.10 )] . Intervention: Do not use MITIGO ® in patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of other opioids (such as oxycodone, hydromorphone, oxymorphone, hydrocodone, or buprenorphine) to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.

Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of MITIGO ® 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 MITIGO ® and/or the muscle relaxant as necessary. Examples: Cyclobenzaprine, metaxalone. 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 MITIGO ® is used concomitantly with anticholinergic drugs. Oral P2Y 12 Inhibitors Clinical Impact: The co-administration of oral P2Y 12 inhibitors and intravenous morphine sulfate can decrease the absorption and peak concentration of oral P2Y 12 inhibitors and delay the onset of the antiplatelet effect.

Intervention: Consider the use of parenteral antiplatelet agent in the setting of acute coronary syndrome requiring co-administration of intravenous morphine sulfate. Examples: clopidogrel, prasugrel, ticagrelor Serotonergic Drugs : Concomitant use may result in serotonin syndrome. Discontinue MITIGO ® if serotonin syndrome is suspected. ( 7 ) Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics : Avoid use with MITIGO ® because they may reduce the analgesic effect of MITIGO ® or precipitate withdrawal symptoms.( 7 )

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 ( 5.2 )] Life-Threatening Respiratory Depression [see Warnings and Precautions ( 5.3 )] Interactions with CNS Benzodiazepines or Other Depressants [ see Warnings and Precautions ( 5.4 )] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.5 )] Inflammatory Masses [see Warnings and Precautions ( 5.6 )] Myoclonic Activity [see Warnings and Precautions ( 5.7 )] Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions ( 5.8 )] Adrenal Insufficiency [see Warnings and Precautions ( 5.11 )] Severe Hypotension [see Warnings and Precautions ( 5.12 )] Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.14 )] Seizures [see Warnings and Precautions ( 5.15 )] Withdrawal [see Warnings and Precautions ( 5.16 )] Urinary Retention [see Warnings and Precautions ( 5.18 )] Orthostatic Hypotension [see Warnings and Precautions ( 5.19 )] The following adverse reactions associated with the use of morphine were identified in clinical studies or postmarketing reports.

Because some of these reactions were 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. The most serious adverse reactions encountered during continuous intrathecal or epidural infusion of MITIGO ® were respiratory depression, myoclonus, and formation of inflammatory masses. Cardiovascular System: While low doses of intravenously administered morphine have little effect on cardiovascular stability, high doses are excitatory, resulting from sympathetic hyperactivity and increase in circulating catecholamines.

Excitation of the central nervous system, resulting in convulsions, may accompany high doses of morphine given intravenously. Central Nervous System: myoclonus, seizures, dysphoric reactions, toxic psychosis, dizziness, euphoria, anxiety, confusion, headache. Lumbar puncture-type headache is encountered in a significant minority of cases for several days following intrathecal catheter implantation and generally responds to bed rest and/or other conventional therapy.

Gastrointestinal System: Nausea, vomiting, constipation Skin: Pruritus, urticaria, wheals, and/or local tissue irritation. Genito-Urinary System: Urinary retention, oliguria, unexplained genital swelling in male patients, following infusion-device implant surgery. Other: Other adverse experiences reported following morphine therapy include depression of cough reflex, interference with thermal regulation, peripheral edema.

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 MITIGO ® . Androgen deficiency : Cases of androgen deficiency have occurred with use of opioids for an extended period of time. [see Clinical Pharmacology ( 12.2 )].

Hyperalgesia and Allodynia : Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions ( 5.8 )] Hypoglycemia : Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes). Opioid-induced esophageal dysfunction (OIED) : Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term [see Warnings and Precautions ( 5.14 )] .

Adverse Reactions from Observational Studies A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021. Study participants included in one or more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/longacting opioid analgesic prescriptions during a 90-day period (n=978); or 2) filled any Schedule II opioid analgesic prescriptions covering at least 70 of 90 days (n=1,244).

Those included also had no dispensing of the qualifying opioids in the previous 6 months. Over 12 months:

approximately 1% to 6% of participants across the two cohorts newly met criteria for addiction, as assessed with two validated interview-based measures of moderate-to-severe opioid use disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and
approximately 9% and 22% of participants across the two cohorts newly met criteria for prescription opioid abuse and misuse [defined in Drug Abuse and Dependence ( 9.2 )], respectively, as measured with a validated self-reported instrument. A retrospective, observational cohort study estimated the risk of opioid-involved overdose or opioid overdose-related death in patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n=220,249). Included patients had been enrolled in either one of two commercial insurance programs, one managed care program, or one Medicaid program for at least 9 months. New long-term use was defined as having Schedule II opioid analgesic prescriptions covering at least 70 days’ supply over the 3 months prior to study entry and none during the preceding 6 months. Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry. Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database. The 5-year cumulative incidence estimates for opioid-involved overdose or opioid overdose-related death ranged from approximately 1.5% to 4% across study sites, counting only the first event during follow-up. Approximately 17% of first opioid overdoses observed over the entire study period (5-11 years, depending on the study site) were fatal. Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdose-related death. Study exclusion criteria may have selected patients at lower risk of overdose, and substantial loss to follow-up (approximately 80%) also may have biased estimates. The risk estimates from the studies described above may not be generalizable to all patients receiving opioid analgesics, such as those with exposures shorter or longer than the duration evaluated in the studies. Most serious adverse reactions were respiratory depression, apnea, circulatory depression, respiratory arrest, shock, and cardiac arrest. Other common frequently observed adverse reactions include: sedation, lightheadedness, dizziness, nausea, vomiting, and constipation. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Piramal Critical Care, Inc. at 1-888-822-8431 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Mitigo

Indications

Contraindications

At a glance

Two medicines in one question?

Mitigo

Indications

Contraindications

At a glance

Two medicines in one question?

Warnings and precautions

5.1Risks with Neuraxial Administration Control

5.2Addiction, Abuse, and Misuse

5.3Life-Threatening Respiratory Depression

5.4Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Interactions

Adverse reactions

Composition

Strengths and forms

Official product information