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MILNACIPRAN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Milnacipran is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI), with higher affinity for norepinephrine inhibition than serotonin, that enhances noradrenergic and serotonergic neurotransmission through reuptake inhibition at presynaptic sites.

Specific Substances

    1) (+/-)-[1R(S),2S(R)]-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide hydrochloride
    2) Molecular formula: C15H22N2O
    3) CAS 92623-85-3
    1.2.1) MOLECULAR FORMULA
    1) C15H23ClN2O (Prod Info Savella(R) oral tablets, 2013)

Available Forms Sources

    A) FORMS
    1) Milnacipran is available as 12.5 mg, 25 mg, 50 mg, and 100 mg film-coated tablets for oral administration (Prod Info SAVELLA(R) oral tablets, 2009).
    B) USES
    1) Milnacipran is indicated for the management of fibromyalgia in patients age 17 and older (Prod Info SAVELLA(R) oral tablets, 2009).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Selective serotonin and norepinephrine reuptake inhibitor (SSNRI) used in the management of fibromyalgia.
    B) PHARMACOLOGY: Inhibits neuronal norepinephrine and serotonin reuptake; thus potentiating the serotonergic and noradrenergic activity in the CNS.
    C) TOXICOLOGY: Primarily sympathomimetic activity, potential for serotonin syndrome.
    D) EPIDEMIOLOGY: Several deliberate poisonings with milnacipran have been reported in postmarketing experience. Fatalities are rare.
    E) WITH THERAPEUTIC USE
    1) COMMON: Headache, nausea and vomiting, constipation, hypertension, tachycardia and palpitations. Elevated liver enzymes have been reported.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Somnolence, nausea and vomiting are common. Tachycardia and hypertension have been reported.
    2) SEVERE TOXICITY: Milnacipran may cause seizures and serotonin syndrome. Acute stress cardiomyopathy developed in a woman after ingesting 3000 mg of milnacipran.
    0.2.20) REPRODUCTIVE
    A) Milnacipran is classified as FDA pregnancy category C. Skeletal variations were seen in rabbits exposed to milnacipran during organogenesis, and an increased incidence of fetal death was seen in rat studies.

Laboratory Monitoring

    A) Serum milnacipran concentrations are not clinically useful in guiding therapy after overdose.
    B) Monitor vital signs, serum electrolytes, and liver enzyme levels in symptomatic patients.
    C) Obtain an ECG and institute continuous cardiac monitoring in symptomatic patients.
    D) Monitor neurologic exam for evidence of mental status depression and serotonin syndrome.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Manage mild hypotension with IV fluids. For mild/moderate asymptomatic hypertension (no end organ damage), pharmacologic treatment is generally not necessary.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. For severe hypotension, administer intravenous fluids and vasopressors. For severe hypertension, nitroprusside is preferred. Labetalol, nitroglycerin, and phentolamine are alternatives.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital activated charcoal is not recommended because of the potential for somnolence and rarely, seizures.
    2) HOSPITAL: Consider activated charcoal in a patient with a potentially toxic ingestion who is able to maintain airway or if airway is protected.
    D) AIRWAY MANAGEMENT
    1) Endotracheal intubation may be necessary if significant CNS depression or severe serotonin syndrome develop.
    E) ANTIDOTE
    1) None.
    F) SEIZURES
    1) Administer IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
    G) SEROTONIN SYNDROME
    1) Sedate with benzodiazepines. Consider cyproheptadine in patients with more severe manifestations who are able to take oral medications: ADULT: 12 mg orally initially, then 2 mg every 2 hours if manifestations persist (maximum 32 mg in 24 hours), maintenance dose 8 mg every 6 hours. CHILDREN: 0.25 mg/kg/day divided every 6 hours, maximum 12 mg/day. If hyperthermic, control agitation/rigidity (benzodiazepines) and initiate external cooling measures (undress patient, cover with wet sheet and direct fan at skin). In severe cases, neuromuscular blockade (non-depolarizing agents) may be necessary. Treat hypotension with intravenous 0.9% saline, if pressors are necessary direct acting (norepinephrine, phentolamine) are preferred.
    H) ENHANCED ELIMINATION
    1) Due to the fairly large volume of distribution of milnacipran, hemodialysis, hemoperfusion, and exchange transfusion are NOT likely to be beneficial.
    I) PATIENT DISPOSITION
    1) OBSERVATION CRITERIA: All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions who are symptomatic should be observed in a healthcare facility.
    2) ADMISSION CRITERIA: Patients with a deliberate ingestions demonstrating cardiotoxicity, seizure activity, or other persistent neurotoxicity should be admitted.
    3) CONSULT CRITERIA: Consult a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    J) PITFALLS
    1) When managing a suspected milnacipran overdose, the treating physician should be cognizant of the possibility of multi-drug involvement. May cause serotonin syndrome, particularly if ingested with other drugs that increase CNS serotonin levels (SSRI, MAOI etc).
    K) PHARMACOKINETICS
    1) Tmax: about 2 to 4 hours after ingestion. Protein binding: 13%. Vd: Fairly large (5 to 8 L/kg). Metabolism: glucuronidation is the primary metabolism mechanism. Elimination half-life: 8 hours.
    L) DIFFERENTIAL DIAGNOSIS
    1) Includes sympathomimetic poisoning, drug withdrawal.

Range Of Toxicity

    A) TOXICITY: Ingestions up to 2800 mg milnacipran, alone or in combination with other drugs, have resulted in CNS depression. A 59-year-old woman developed coma, respiratory failure, autonomic instability, fever, tremor, and acute cardiac dysfunction after ingesting 3000 mg of milnacipran. Following supportive care, she recovered gradually. Fatalities have been reported rarely, but the ingested dose was unknown.
    B) THERAPEUTIC DOSE: The recommended dose of milnacipran for the management of fibromyalgia is 50 mg orally twice daily. Depending on the patient's clinical response, dose maybe increased up to 200 mg/day (100 mg twice daily).

Clinical Effects

Summary Of Exposure

    A) USES: Selective serotonin and norepinephrine reuptake inhibitor (SSNRI) used in the management of fibromyalgia.
    B) PHARMACOLOGY: Inhibits neuronal norepinephrine and serotonin reuptake; thus potentiating the serotonergic and noradrenergic activity in the CNS.
    C) TOXICOLOGY: Primarily sympathomimetic activity, potential for serotonin syndrome.
    D) EPIDEMIOLOGY: Several deliberate poisonings with milnacipran have been reported in postmarketing experience. Fatalities are rare.
    E) WITH THERAPEUTIC USE
    1) COMMON: Headache, nausea and vomiting, constipation, hypertension, tachycardia and palpitations. Elevated liver enzymes have been reported.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Somnolence, nausea and vomiting are common. Tachycardia and hypertension have been reported.
    2) SEVERE TOXICITY: Milnacipran may cause seizures and serotonin syndrome. Acute stress cardiomyopathy developed in a woman after ingesting 3000 mg of milnacipran.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Clinical trials demonstrated an increased risk of mydriasis with the use of milnacipran (Prod Info SAVELLA(R) oral tablets, 2009).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CARDIOTOXICITY
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 59-year-old woman with a past medical history of hypertension, hypothyroidism, ADHD, depression, and fibromyalgia, developed mental status changes and hypotension (BP 70/50 mmHg) approximately 1 hour after ingesting milnacipran 3000 mg (42.6 mg/kg). Although she was also taking methylphenidate, paroxetine, carisoprodol, methadone, and levothyroxine, pill counts showed only milnacipran was missing. An initial ECG revealed sinus bradycardia with a heart rate of 58 bpm, QRS of 104 ms, with a corrected QT interval of 488 ms. Physical examination in the ED showed an obtunded, diaphoretic patient with no gag reflex, and shallow respirations. At this time, she was intubated and received a norepinephrine infusion for persistent hypotension. A urine drug screen was positive for tetrahydrocannabinol and benzodiazepines. During the transport to a tertiary care medical center, she received a single dose of 10 mg vecuronium and norepinephrine was titrated off. In the ICU approximately 1 hour later (about 6 hours postingestion), She developed atrial fibrillation with a ventricular rate of approximately 130 bpm, and hypertension (BP 249/145 mm Hg). Approximately 15 minutes after treatment with IV diltiazem, her blood pressure decreased to 66/54 mm Hg. At this time, she received norepinephrine after treatment with IV crystalloid, calcium gluconate, and magnesium sulfate failed to improve her persistent hypotension. An ECG showed a sinus dysrhythmia with an average rate of 130 bpm and QRS of 94 ms and upright T waves. A second ECG showed T wave flattening/inversion throughout the precordium. A left ventricular ejection fraction (LVEF) of 30% to 35% with moderate to severe diastolic dysfunction was observed in an echocardiogram. She was treated with an additional 32 hours of norepinephrine and 66 hours of dobutamine. Her troponin levels peaked at 0.45 ng/mL. Physical examination revealed a fever of 38.9 degrees C and tremor of bilateral upper extremities, with no clonus or rigidity. Although urine drug testing showed the presence of paroxetine, nicotine, and milnacipran, no sympathomimetic agents such as amphetamine or methylphenidate were detected. Plasma milnacipran concentration 5 hours postingestion was 8400 ng/mL. Her condition improved gradually and an echocardiogram 2 days later showed resolution of the cardiac dysfunction with an LVEF of 60% to 65% which increased to greater than 70% 4 days postingestion. It is suggested that the combination of paroxetine taken therapeutically and milnacipran overdose could have caused serotonin syndrome in this patient (Levine et al, 2011).
    B) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) In controlled clinical trials of non-hypertensive fibromyalgia patients, hypertension (BP 140/90 or higher) was reported in 19.5% and 16.6% of patients who received milnacipran 100 mg/day and 200 mg/day, respectively, compared with 7.2% of patients who received placebo. Among fibromyalgia patients who were pre-hypertensive (SBP of 120 to 139 mmHg) at baseline, 14% of patients in both the 100 mg/day and 200 mg/day treatment arms became hypertensive by study end, compared with 9% of patients who received placebo. Among baseline hypertensive fibromyalgia patients, SBP increases of greater than 15 mmHg and DBP increases of greater than 10 mmHg were observed in 7% and 8%, respectively, of patients who received milnacipran hydrochloride 100 mg/day and 2% and 6%, respectively, of patients who received milnacipran hydrochloride 200 mg/day, compared with 1% and 3% of patients in the placebo group (Prod Info SAVELLA(R) oral tablets, 2009).
    2) WITH POISONING/EXPOSURE
    a) Hypertension may occur with milnacipran overdose (Levine et al, 2011).
    C) TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) During controlled clinical trials, pulse increases of 20 beats per minute or greater were reported in 8% of patients in both the milnacipran 100 mg/day and 200 mg/day treatment arms compared with 0.3% of patients in the placebo arm (Prod Info SAVELLA(R) oral tablets, 2009).
    2) WITH POISONING/EXPOSURE
    a) Tachycardia may occur with milnacipran overdose (Levine et al, 2011).
    b) CASE REPORT: Fanton et al (2008) reports a case of intentional milnacipran overdose that resulted in somnolence and sinus tachycardia. The victim ingested 700 mg milnacipran and had serum milnacipran levels of 1.6 mg/L. Details of clinical management were not provided, but a favorable outcome was noted (Fanton et al, 2008).
    D) PALPITATIONS
    1) WITH THERAPEUTIC USE
    a) During controlled clinical trials, palpitations were reported in 7% of fibromyalgia patients who received milnacipran (n=1557) compared with 2% of patients who received placebo (n=652) and was one of the most commonly-reported adverse reactions (Prod Info SAVELLA(R) oral tablets, 2009).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache was reported in 18% of fibromyalgia patients who received milnacipran (n=1557) compared with 14% of patients who received placebo (n=652) during controlled clinical trials (Prod Info SAVELLA(R) oral tablets, 2009).
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness was reported in 10% of fibromyalgia patients who received milnacipran (n=1557) compared with 6% of patients who received placebo (n=652) during controlled clinical trials (Prod Info SAVELLA(R) oral tablets, 2009).
    C) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Seizures, including grand mal, have been reported in postmarketing experience (Prod Info SAVELLA(R) oral tablets, 2009).
    2) WITH POISONING/EXPOSURE
    a) Seizures, including grand mal, have been reported in postmarketing experience (Prod Info SAVELLA(R) oral tablets, 2009).
    D) SEROTONIN SYNDROME
    1) WITH THERAPEUTIC USE
    a) Serotonin syndrome, which may include mental status changes (eg, agitation, hallucination, coma), autonomic instability (eg, tachycardia, hyperthermia, labile blood pressure), neuromuscular aberrations (eg, myoclonus, tremor, incoordination, hyperreflexia), and gastrointestinal symptoms (eg, nausea, vomiting, diarrhea), may occur with milnacipran. This syndrome could be life-threatening. Risk is increased with concomitant use of serotonergic drugs (eg, tramadol, triptans), and drugs that impair serotonin metabolism, including MAOIs (Prod Info SAVELLA(R) oral tablets, 2009).
    2) WITH POISONING/EXPOSURE
    a) Serotonin syndrome, which may include mental status changes (eg, agitation, hallucination, coma), autonomic instability (eg, tachycardia, hyperthermia, labile blood pressure), neuromuscular aberrations (eg, incoordination, hyperreflexia), and gastrointestinal symptoms (eg, nausea, vomiting, diarrhea), may occur with milnacipran. This syndrome could be life-threatening. Risk is increased with concomitant use of serotonergic drugs (eg, tramadol, triptans), and drugs that impair serotonin metabolism, including MAOIs (Prod Info SAVELLA(R) oral tablets, 2009).
    b) CASE REPORT: A 59-year-old woman with a past medical history of hypertension, hypothyroidism, ADHD, depression, and fibromyalgia, developed mental status changes and hypotension (BP 70/50 mmHg) approximately 1 hour after ingesting milnacipran 3000 mg (42.6 mg/kg). Although she was also taking methylphenidate, paroxetine, carisoprodol, methadone, and levothyroxine, pill counts showed only milnacipran was missing. An initial ECG revealed sinus bradycardia with a heart rate of 58 bpm, QRS of 104 ms, with a corrected QT interval of 488 ms. Physical examination in the ED showed an obtunded, diaphoretic patient with no gag reflex, and shallow respirations. At this time, she was intubated and received a norepinephrine infusion for persistent hypotension. A urine drug screen was positive for tetrahydrocannabinol and benzodiazepines. During the transport to a tertiary care medical center, she received a single dose of 10 mg vecuronium and norepinephrine was titrated off. In the ICU approximately 1 hour later (about 6 hours postingestion), She developed atrial fibrillation with a ventricular rate of approximately 130 bpm, and hypertension (BP 249/145 mm Hg). Approximately 15 minutes after treatment with IV diltiazem, her blood pressure decreased to 66/54 mm Hg. At this time, she received norepinephrine after treatment with IV crystalloid, calcium gluconate, and magnesium sulfate failed to improve her persistent hypotension. An ECG showed a sinus dysrhythmia with an average rate of 130 bpm and QRS of 94 ms and upright T waves. A second ECG showed T wave flattening/inversion throughout the precordium. A left ventricular ejection fraction (LVEF) of 30% to 35% with moderate to severe diastolic dysfunction was observed in an echocardiogram. She was treated with an additional 32 hours of norepinephrine and 66 hours of dobutamine. Her troponin levels peaked at 0.45 ng/mL. Physical examination revealed a fever of 38.9 degrees C and tremor of bilateral upper extremities, with no clonus or rigidity. Although urine drug testing showed the presence of paroxetine, nicotine, and milnacipran, no sympathomimetic agents such as amphetamine or methylphenidate were detected. Plasma milnacipran concentration 5 hours postingestion was 8400 ng/mL. Her condition improved gradually and an echocardiogram 2 days later showed resolution of the cardiac dysfunction with an LVEF of 60% to 65% which increased to greater than 70% 4 days postingestion. It is suggested that the combination of paroxetine taken therapeutically and milnacipran overdose could have caused serotonin syndrome in this patient (Levine et al, 2011).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA
    1) WITH THERAPEUTIC USE
    a) During controlled clinical trials, nausea was reported in 37% of fibromyalgia patients who received milnacipran (n=1557) compared with 20% of patients who received placebo (n=652) and was the most frequently occurring adverse reaction reported (Prod Info SAVELLA(R) oral tablets, 2009).
    B) VOMITING
    1) WITH THERAPEUTIC USE
    a) During controlled clinical trials, vomiting was reported in 7% of fibromyalgia patients who received milnacipran (n=1557) compared with 2% of patients who received placebo (n=652) and was one of the most commonly reported adverse reactions (Prod Info SAVELLA(R) oral tablets, 2009).
    2) WITH POISONING/EXPOSURE
    a) Gastrointestinal symptoms, including vomiting, are frequently reported (Fanton et al, 2008).
    b) CASE REPORT: Fanton et al (2008) reports a case of intentional milnacipran overdose of 1 gram that resulted in vomiting as the only symptom. Clinical details were not reported, but a favorable outcome was noted (Fanton et al, 2008).
    C) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) During controlled clinical trials, constipation was reported in 16% of fibromyalgia patients who received milnacipran (n=1557) compared with 4% of patients who received placebo (n=652) and was one of the most commonly reported adverse reactions (Prod Info SAVELLA(R) oral tablets, 2009).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) In controlled clinical trials, ALT increases were reported in 6% and 7% of fibromyalgia patients who received milnacipran 100 mg/day and 200 mg/day, respectively, compared with 3% of patients who received placebo. AST increases were reported in 3% and 5% of fibromyalgia patients who received milnacipran 100 mg/day and 200 mg/day, respectively, compared with 2% of patients who received placebo (Prod Info SAVELLA(R) oral tablets, 2009).
    B) CHOLESTATIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 25-year-old woman was being treated for depression with alprazolam (1 mg/day) and milnacipran (25 mg/day), and was also taking buprenorphine (12 mg/day). She had a history hepatitis C, but most recent serology testing was negative. Approximately 6 months after initiation of milnacipran, the patient presented with epigastric pain for 5 days, fever and jaundice. Laboratory results showed ALT 23.6 times the upper limit of normal (ULN), AST 8.6 times the ULN, alkaline phosphatase 4.3 times the ULN, GGT 19.6 times the ULN, total bilirubin 22 micromol/L and conjugated bilirubin 17 micromol/L. Treatment with milnacipran was stopped upon admission, while alprazolam and buprenorphine were continued. Both the patient's symptoms and the liver enzyme abnormalities resolved quickly (deWiderspach-Thor et al, 2004).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) HOT SWEATS
    1) WITH THERAPEUTIC USE
    a) During controlled clinical trials, hot flush was reported in 12% of fibromyalgia patients who received milnacipran (n=1557) compared with 2% of patients who received placebo (n=652) and was one of the most commonly-reported adverse reactions (Prod Info SAVELLA(R) oral tablets, 2009).
    B) STEVENS-JOHNSON SYNDROME
    1) WITH THERAPEUTIC USE
    a) During postmarketing surveillance, Stevens-Johnson syndrome has been reported in patients who received milnacipran (Prod Info SAVELLA(R) oral tablets, 2009).
    C) SKIN FINDING
    1) WITH THERAPEUTIC USE
    a) PILOERECTION
    1) CASE REPORT: A 40-year-old woman began therapy with milnacipran 25 mg twice daily after having discontinued fluvoxamine due to drug-drug interactions resulting in drowsiness. Although her drowsiness subsided with milnacipran, she complained of piloerection throughout her body soon after starting milnacipran. The piloerection lasted about 5 days, and completely subsided within one month. When her dose was increased to 50 mg twice daily at 2 months, the piloerection did not reoccur.
    a) The authors postulated the cause to be milnacipran's ability to induce alpha-1-adrenoceptor-agonist side effects through norepinephrine reuptake inhibition. They found the alpha-1-adrenoceptor occupancy by endogenous norepinephrine to be increased in a dose-dependent manner by milnacipran (Hori et al, 2007).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPONATREMIA
    1) WITH THERAPEUTIC USE
    a) Treatment with selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), including milnacipran, may result in hyponatremia. Serum sodium levels lower than 110 mmol/L have been reported in patients receiving SSRI or SNRI therapy. In many cases hyponatremia has been the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) (Prod Info SAVELLA(R) oral tablets, 2009).

Reproductive

    3.20.1) SUMMARY
    A) Milnacipran is classified as FDA pregnancy category C. Skeletal variations were seen in rabbits exposed to milnacipran during organogenesis, and an increased incidence of fetal death was seen in rat studies.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) No embryotoxicity or teratogenicity was reported in mice administered milnacipran during organogenesis at doses up to 3 times the maximum recommended human dose (MRHD) of 200 mg/day on a mg/m(2) basis), respectively. Following doses of 1.5 the MRHD during the period of organogenesis in rabbits, there was an increased incidence of skeletal variation of extra single ribs (Prod Info SAVELLA(R) oral tablets, 2012).
    2) The no-effect dose (2.5 mg/kg per day) for maternal and offspring toxicity in mice was 0.1 times the MRHD (Prod Info SAVELLA(R) oral tablets, 2012).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified milnacipran as FDA pregnancy category C. A pregnancy registry has been established for pregnant patients who receive milnacipran, and patients may be enrolled by calling 1-877-643-3010 or by visiting www.savellapregnancyregistry.com (Prod Info SAVELLA(R) oral tablets, 2012).
    2) Exposure to serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs) during the third trimester of pregnancy has resulted in a variety of neonatal complications that can manifest immediately after delivery and necessitate extended hospitalizations, respiratory support, and tube feeding. These complications may include respiratory distress, cyanosis, apnea, seizures, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These complications appear to be consistent with either a direct toxic effect of the SSRI or SNRI or as a result of a drug discontinuation syndrome. In some cases, clinical findings have been consistent with serotonin syndrome (Prod Info SAVELLA(R) oral tablets, 2012).
    B) ANIMAL STUDIES
    1) Pregnant rats treated with milnacipran 5 mg/kg/day (0.25 times the maximum recommended human dose (MRHD) of 200 mg/day on a mg/m(2) basis) had an increased incidence of dead fetuses. Milnacipran, at 0.25 times the MRHD, administered to rats during late gestation showed a decrease in pup body weight and viability on postpartum day 4 (Prod Info SAVELLA(R) oral tablets, 2012).
    2) The no-effect dose (2.5 mg/kg per day) for maternal and offspring toxicity in mice was 0.1 times the MRHD (Prod Info SAVELLA(R) oral tablets, 2012).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) In a pharmacokinetic study, milnacipran was found in the milk of lactating women (n=8) who were at least 12 weeks postpartum and were administered a single oral dose of milnacipran hydrochloride 50 mg. The maximum estimated daily infant dose via breast milk was 5% of the maternal dose, based on peak plasma concentrations (usually occurring within 4 hours of maternal dosing) and an estimated milk consumption of 150 mL/kg/day (Prod Info SAVELLA(R) oral tablets, 2012).
    B) ANIMAL STUDIES
    1) Animal studies have shown that milnacipran or its metabolites are excreted in breast milk (Prod Info SAVELLA(R) oral tablets, 2010).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) A dose-related decrease in the fertility index was reported at doses that were clinically relevant based on body surface area; however, there was no evidence of impaired mating or fertility when male and female rats were given milnacipran doses up to 80 mg/kg/day (4 times the maximum recommended human dose on a mg/m(2) basis) (Prod Info SAVELLA(R) oral tablets, 2010).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS92623-85-3 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.4) ANIMAL STUDIES
    A) CARCINOMA
    1) In rat studies, doses of milnacipran 50 mg/kg/day (2 times the MRHD) administered for 2 years resulted in a statistically significant increase in the incidence of thyroid C-cell adenomas and combined adenomas and carcinomas in males (Prod Info SAVELLA(R) oral tablets, 2009).

Genotoxicity

    A) Milnacipran was not mutagenic in the in vitro Ames test or L5178Y TK +/- mouse lymphoma forward mutation assay. No clastogenic effects were found in the in vitro chromosomal aberration test in human lymphocytes or in an in vivo mouse micronucleus assay.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Serum milnacipran concentrations are not clinically useful in guiding therapy after overdose.
    B) Monitor vital signs, serum electrolytes, and liver enzyme levels in symptomatic patients.
    C) Obtain an ECG and institute continuous cardiac monitoring in symptomatic patients.
    D) Monitor neurologic exam for evidence of mental status depression and serotonin syndrome.

Methods

    A) CHROMATOGRAPHY
    1) High-performance liquid chromatography-mass spectrometry (LC-MS) with sonic spray ionization has been used to successfully extract milnacipran from plasma. The recovery and limit of detection for milnacipran was 85.2% and 0.08 mcg/L, respectively (Shinozuka et al, 2006).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with a deliberate ingestions demonstrating cardiotoxicity, seizure activity, or other persistent neurotoxicity should be admitted.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions who are symptomatic should be observed in a healthcare facility.

Monitoring

    A) Serum milnacipran concentrations are not clinically useful in guiding therapy after overdose.
    B) Monitor vital signs, serum electrolytes, and liver enzyme levels in symptomatic patients.
    C) Obtain an ECG and institute continuous cardiac monitoring in symptomatic patients.
    D) Monitor neurologic exam for evidence of mental status depression and serotonin syndrome.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital activated charcoal is not recommended because of the potential for somnolence and rarely, seizures.
    6.5.2) PREVENTION OF ABSORPTION
    A) Consider activated charcoal in a patient with a potentially toxic ingestion who is able to maintain airway or if airway is protected.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Serum milnacipran concentrations are not clinically useful in guiding therapy after overdose.
    2) Monitor vital signs, serum electrolytes, and liver enzyme levels in symptomatic patients.
    3) Obtain an ECG and institute continuous cardiac monitoring in symptomatic patients.
    4) Monitor neurologic exam for evidence of mental status depression or serotonin syndrome.
    B) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    C) HYPERTENSIVE EPISODE
    1) Monitor vital signs regularly. For mild/moderate hypertension without evidence of end organ damage, pharmacologic intervention is generally not necessary. Sedative agents such as benzodiazepines may be helpful in treating hypertension and tachycardia in agitated patients, especially if a sympathomimetic agent is involved in the poisoning.
    2) For hypertensive emergencies (severe hypertension with evidence of end organ injury (CNS, cardiac, renal), or emergent need to lower mean arterial pressure 20% to 25% within one hour), sodium nitroprusside is preferred. Nitroglycerin and phentolamine are possible alternatives.
    3) SODIUM NITROPRUSSIDE/INDICATIONS
    a) Useful for emergent treatment of severe hypertension secondary to poisonings. Sodium nitroprusside has a rapid onset of action, a short duration of action and a half-life of about 2 minutes (Prod Info NITROPRESS(R) injection for IV infusion, 2007) that can allow accurate titration of blood pressure, as the hypertensive effects of drug overdoses are often short lived.
    4) SODIUM NITROPRUSSIDE/DOSE
    a) ADULT: Begin intravenous infusion at 0.1 microgram/kilogram/minute and titrate to desired effect; up to 10 micrograms/kilogram/minute may be required (American Heart Association, 2005). Frequent hemodynamic monitoring and administration by an infusion pump that ensures a precise flow rate is mandatory (Prod Info NITROPRESS(R) injection for IV infusion, 2007). PEDIATRIC: Initial: 0.5 to 1 microgram/kilogram/minute; titrate to effect up to 8 micrograms/kilogram/minute (Kleinman et al, 2010).
    5) SODIUM NITROPRUSSIDE/SOLUTION PREPARATION
    a) The reconstituted 50 mg solution must be further diluted in 250 to 1000 mL D5W to desired concentration (recommended 50 to 200 mcg/mL) (Prod Info NITROPRESS(R) injection, 2004). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    6) SODIUM NITROPRUSSIDE/MAJOR ADVERSE REACTIONS
    a) Severe hypotension; headaches, nausea, vomiting, abdominal cramps; thiocyanate or cyanide toxicity (generally from prolonged, high dose infusion); methemoglobinemia; lactic acidosis; chest pain or dysrhythmias (high doses) (Prod Info NITROPRESS(R) injection for IV infusion, 2007). The addition of 1 gram of sodium thiosulfate to each 100 milligrams of sodium nitroprusside for infusion may help to prevent cyanide toxicity in patients receiving prolonged or high dose infusions (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    7) SODIUM NITROPRUSSIDE/MONITORING PARAMETERS
    a) Monitor blood pressure every 30 to 60 seconds at onset of infusion; once stabilized, monitor every 5 minutes. Continuous blood pressure monitoring with an intra-arterial catheter is advised (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    8) NITROGLYCERIN/INDICATIONS
    a) May be used to control hypertension, and is particularly useful in patients with acute coronary syndromes or acute pulmonary edema (Rhoney & Peacock, 2009).
    9) NITROGLYCERIN/ADULT DOSE
    a) Begin infusion at 10 to 20 mcg/min and increase by 5 or 10 mcg/min every 5 to 10 minutes until the desired hemodynamic response is achieved (American Heart Association, 2005). Maximum rate 200 mcg/min (Rhoney & Peacock, 2009).
    10) NITROGLYCERIN/PEDIATRIC DOSE
    a) Usual Dose: 29 days or Older: 1 to 5 mcg/kg/min continuous IV infusion. Maximum 60 mcg/kg/min (Laitinen et al, 1997; Nam et al, 1989; Rasch & Lancaster, 1987; Ilbawi et al, 1985; Friedman & George, 1985).
    11) PHENTOLAMINE/INDICATIONS
    a) Useful for severe hypertension, particularly if caused by agents with alpha adrenergic agonist effects usually induced by catecholamine excess (Rhoney & Peacock, 2009).
    12) PHENTOLAMINE/ADULT DOSE
    a) BOLUS DOSE: 5 to 15 mg IV bolus repeated as needed (U.S. Departement of Health and Human Services, National Institutes of Health, and National Heart, Lung, and Blood Institute, 2004). Onset of action is 1 to 2 minutes with a duration of 10 to 30 minutes (Rhoney & Peacock, 2009).
    b) CONTINUOUS INFUSION: 1 mg/hr, adjusted hourly to stabilize blood pressure. Prepared by adding 60 mg of phentolamine mesylate to 100 mL of 0.9% sodium chloride injection; continuous infusion ranging from 12 to 52 mg/hr over 4 days has been used in case reports (McMillian et al, 2011).
    13) PHENTOLAMINE/PEDIATRIC DOSE
    a) 0.05 to 0.1 mg/kg/dose (maximum of 5 mg per dose) intravenously every 5 minutes until hypertension is controlled, then every 2 to 4 hours as needed (Singh et al, 2012; Koch-Weser, 1974).
    14) PHENTOLAMINE/ADVERSE EFFECTS
    a) Adverse events can include orthostatic or prolonged hypotension, tachycardia, dysrhythmias, angina, flushing, headache, nasal congestion, nausea, vomiting, abdominal pain and diarrhea (Rhoney & Peacock, 2009; Prod Info Phentolamine Mesylate IM, IV injection Sandoz Standard, 2005).
    15) CAUTION
    a) Phentolamine should be used with caution in patients with coronary artery disease because it may induce angina or myocardial infarction (Rhoney & Peacock, 2009).
    D) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    E) SEROTONIN SYNDROME
    1) SUMMARY
    a) Benzodiazepines are the mainstay of therapy. Cyproheptadine, a 5-HT antagonist, is also commonly used. Severe cases have been managed with benzodiazepine sedation and neuromuscular paralysis with non-depolarizing agents(Claassen & Gelissen, 2005).
    2) HYPERTHERMIA
    a) Control agitation and muscle activity. Undress patient and enhance evaporative heat loss by keeping skin damp and using cooling fans.
    b) MUSCLE ACTIVITY: Benzodiazepines are the drug of choice to control agitation and muscle activity. DIAZEPAM: ADULT: 5 to 10 mg IV every 5 to 10 minutes as needed, monitor for respiratory depression and need for intubation. CHILD: 0.25 mg/kg IV every 5 to 10 minutes; monitor for respiratory depression and need for intubation.
    c) Non-depolarizing paralytics may be used in severe cases.
    3) CYPROHEPTADINE
    a) Cyproheptadine is a non-specific 5-HT antagonist that has been shown to block development of serotonin syndrome in animals (Sternbach, 1991). Cyproheptadine has been used in the treatment of serotonin syndrome (Mills, 1997; Goldberg & Huk, 1992). There are no controlled human trials substantiating its efficacy.
    b) ADULT: 12 mg initially followed by 2 mg every 2 hours if symptoms persist, up to a maximum of 32 mg in 24 hours. Maintenance dose 8 mg orally repeated every 6 hours (Boyer & Shannon, 2005).
    c) CHILD: 0.25 mg/kg/day divided every 6 hours, maximum dose 12 mg/day (Mills, 1997).
    4) HYPERTENSION
    a) Monitor vital signs regularly. For mild/moderate asymptomatic hypertension, pharmacologic intervention is usually not necessary.
    5) HYPOTENSION
    a) Administer 10 to 20 mL/kg 0.9% saline bolus and place patient supine. Further fluid therapy should be guided by central venous pressure or right heart catheterization to avoid volume overload.
    b) Pressor agents with dopaminergic effects may theoretically worsen serotonin syndrome and should be used with caution. Direct acting agents (norepinephrine, epinephrine, phentolamine) are theoretically preferred.
    c) NOREPINEPHRINE
    1) PREPARATION: Add 4 mL of 0.1% solution to 1000 mL of dextrose 5% in water to produce 4 mcg/mL.
    2) INITIAL DOSE
    a) ADULT: 2 to 3 mL (8 to 12 mcg)/minute.
    b) ADULT or CHILD: 0.1 to 0.2 mcg/kg/min. Titrate to maintain adequate blood pressure.
    3) MAINTENANCE DOSE
    a) 0.5 to 1 mL (2 to 4 mcg)/minute.
    6) SEIZURES
    a) DIAZEPAM
    1) MAXIMUM RATE: Administer diazepam IV over 2 to 3 minutes (maximum rate: 5 mg/min).
    2) ADULT DIAZEPAM DOSE: 5 to 10 mg initially, repeat every 5 to 10 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 30 milligrams.
    3) PEDIATRIC DIAZEPAM DOSE: 0.2 to 0.5 mg/kg, repeat every 5 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 10 milligrams in children over 5 years or 5 milligrams in children under 5 years of age.
    4) RECTAL USE: If an intravenous line cannot be established, diazepam may be given per rectum (not FDA approved), or lorazepam may be given intramuscularly.
    b) LORAZEPAM
    1) MAXIMUM RATE: The rate of IV administration of lorazepam should not exceed 2 mg/min (Prod Info Ativan(R), 1991).
    2) ADULT LORAZEPAM DOSE: 2 to 4 mg IV. Initial doses may be repeated in 10 to 15 minutes, if seizures persist (Prod Info ATIVAN(R) injection, 2003).
    3) PEDIATRIC LORAZEPAM DOSE: 0.1 mg/kg IV push (range: 0.05 to 0.1 mg/kg; maximum dose 4 mg); may repeat dose in 5 to 10 minutes if seizures continue. It has also been given rectally at the same dose in children with no IV access (Sreenath et al, 2010; Chin et al, 2008; Wheless, 2004; Qureshi et al, 2002; De Negri & Baglietto, 2001; Mitchell, 1996; Appleton, 1995; Giang & McBride, 1988).
    c) RECURRING SEIZURES
    1) If seizures cannot be controlled with diazepam or recur, give phenobarbital or propofol.
    d) PHENOBARBITAL
    1) SERUM LEVEL MONITORING: Monitor serum levels over next 12 to 24 hours for maintenance of therapeutic levels (15 to 25 mcg/mL).
    2) ADULT PHENOBARBITAL LOADING DOSE: 600 to 1200 mg of phenobarbital IV initially (10 to 20 mg/kg) diluted in 60 mL of 0.9% saline given at 25 to 50 mg/minute.
    3) ADULT PHENOBARBITAL MAINTENANCE DOSE: Additional doses of 120 to 240 mg may be given every 20 minutes.
    4) MAXIMUM SAFE ADULT PHENOBARBITAL DOSE: No maximum safe dose has been established. Patients in status epilepticus have received as much as 100 mg/min until seizure control was achieved or a total dose of 10 mg/kg.
    5) PEDIATRIC PHENOBARBITAL LOADING DOSE: 15 to 20 mg/kg of phenobarbital intravenously at a rate of 25 to 50 mg/min.
    6) PEDIATRIC PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 5 to 10 mg/kg may be given every 20 minutes.
    7) MAXIMUM SAFE PEDIATRIC PHENOBARBITAL DOSE: No maximum safe dose has been established. Children in status epilepticus have received doses of 30 to 120 mg/kg within 24 hours. Vasopressors and mechanical ventilation were needed in some patients receiving these doses.
    8) NEONATAL PHENOBARBITAL LOADING DOSE: 20 to 30 mg/kg IV at a rate of no more than 1 mg/kg/min in patients with no preexisting phenobarbital serum levels.
    9) NEONATAL PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 2.5 mg/kg every 12 hours may be given; adjust dosage to maintain serum levels of 20 to 40 mcg/mL.
    10) MAXIMUM SAFE NEONATAL PHENOBARBITAL DOSE: Doses of up to 20 mg/kg/min up to a total of 30 mg/kg have been tolerated in neonates.
    11) CAUTION: Adequacy of ventilation must be continuously monitored in children and adults. Intubation may be necessary with increased doses.
    7) CHLORPROMAZINE
    a) Chlorpromazine is a 5-HT2 receptor antagonist that has been used to treat cases of serotonin syndrome (Graham, 1997; Gillman, 1996). Controlled human trial documenting its efficacy are lacking.
    b) ADULT: 25 to 100 mg intramuscularly repeated in 1 hour if necessary.
    c) CHILD: 0.5 to 1 mg/kg repeated as needed every 6 to 12 hours not to exceed 2 mg/kg/day.
    8) NOT RECOMMENDED
    a) BROMOCRIPTINE: It has been used in the treatment of neuroleptic malignant syndrome but is NOT RECOMMENDED in the treatment of serotonin syndrome as it has serotonergic effects (Gillman, 1997). In one case the use of bromocriptine was associated with a fatal outcome (Kline et al, 1989).

Enhanced Elimination

    A) HEMODIALYSIS/HEMOPERFUSION
    1) Due to the fairly large volume of distribution of milnacipran, hemodialysis, hemoperfusion, and exchange transfusion are NOT likely to be beneficial.

Range Of Toxicity

Summary

    A) TOXICITY: Ingestions up to 2800 mg milnacipran, alone or in combination with other drugs, have resulted in CNS depression. A 59-year-old woman developed coma, respiratory failure, autonomic instability, fever, tremor, and acute cardiac dysfunction after ingesting 3000 mg of milnacipran. Following supportive care, she recovered gradually. Fatalities have been reported rarely, but the ingested dose was unknown.
    B) THERAPEUTIC DOSE: The recommended dose of milnacipran for the management of fibromyalgia is 50 mg orally twice daily. Depending on the patient's clinical response, dose maybe increased up to 200 mg/day (100 mg twice daily).

Therapeutic Dose

    7.2.1) ADULT
    A) INITIAL: 12.5 mg orally once on day 1; 12.5 mg twice daily on days 2 and 3; 25 mg twice daily on days 4 to 7 (Prod Info Savella(R) oral tablets, 2013a).
    B) MAINTENANCE: 50 mg orally twice daily; maximum dose is 100 mg twice daily (Prod Info Savella(R) oral tablets, 2013a).
    7.2.2) PEDIATRIC
    A) Milnacipran is not approved for use in the pediatric population (Prod Info Savella(R) oral tablets, 2013a).

Minimum Lethal Exposure

    A) CASE REPORT: A 42-year-old woman was found dead in her car surrounded by empty medication containers (anetholtrithione, bromazepam, chlorazepate, heptaminol, prazepam and venlafaxine). A bottle with residual of a white suspension was also found, and it's contents were identified to be milnacipran and sertraline. Toxicologic analysis revealed eight psychotropic molecules in the victim's blood; all were within therapeutic concentrations except for milnacipran. Femoral and cardiac serum concentrations of milnacipran were 21.5 and 21 mg/L, respectively (approximately 40 times the usual maximum prescribed concentration). Autopsy found slight mitral prolapse, polyvisceral congestion and approximately 20 grams of whitish substance in the victim's stomach. The authors speculate the victim ingested about 4 grams of milnacipran, and suspect milnacipran's pharmacokinetics played a part in this fatal intoxication (Fanton et al, 2008).

Maximum Tolerated Exposure

    A) Acute intoxications have been reported with ingestions up to 2.8 grams of milnacipran; however few clinical details are available. The most common symptoms associated with acute intoxications are nausea, vomiting and somnolence (Prod Info SAVELLA(R) oral tablets, 2009).
    B) CASE SERIES: Fanton et al (2008) details three cases of intentional milnacipran overdose with favorable outcomes (Fanton et al, 2008):
    1) The first case involved an ingestion of 950 mg milnacipran (9 times the recommended dose) resulting in sleepiness and a complication of amenorrhea-galactorrhea three days postingestion. The patient was treated with activated charcoal and diuresis.
    2) The second case reported serum milnacipran levels of 0.334 g/L, along with alcohol (1.33 g/L), resulting in somnolence that resolved under simple surveillance.
    3) The third case was a multi-drug ingestion with an estimated milnacipran intake of 1.4 grams. The milnacipran serum concentration was 3 mg/L, and toxic concentration of meprobamate was also reported. Isolated impairment of consciousness (GCS of 5) occurred; however a favorable recovery was made.
    C) CASE REPORT: A 59-year-old woman developed coma, respiratory failure, autonomic instability, fever, tremor, and acute cardiac dysfunction after ingesting 3000 mg of milnacipran. Following supportive care, she recovered gradually. It is suggested that the combination of paroxetine taken therapeutically and milnacipran overdose could have caused serotonin syndrome in this patient (Levine et al, 2011).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CASE REPORT: A 59-year-old woman developed coma, respiratory failure, autonomic instability, fever, tremor, and acute cardiac dysfunction after ingesting 3000 mg of milnacipran. Plasma milnacipran concentration 5 hours postingestion was 8400 ng/mL. Following supportive care, she recovered gradually (Levine et al, 2011).

Workplace Standards

    A) ACGIH TLV Values for CAS92623-85-3 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS92623-85-3 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS92623-85-3 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS92623-85-3 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Pharmacology Toxicology

Pharmacologic Mechanism

    A) The exact mechanism for milnacipran's central pain inhibition is unknown, but it is a strong inhibitor of neuronal norepinephrine and serotonin reuptake; thus potentiating the serotonergic and noradrenergic activity in the CNS. In vitro studies demonstrate a three fold greater potency for norepinephrine uptake inhibition than that of serotonin. It has no significant affinity for adrenergic, dopaminergic, cholinergic, opioid, glutamate or histaminergic receptors in vitro and does not inhibit monoamine oxidase (Prod Info SAVELLA(R) oral tablets, 2009).

Toxicologic Mechanism

    A) Although not clinically reported at the time of this review, based on its mechanism of action, potentially life-threatening serotonin syndrome may occur with milnacipran (overdose or therapeutic use), especially with concomitant use of other serotonergic agents (Prod Info SAVELLA(R) oral tablets, 2009).

Physicochemical

Physical Characteristics

    A) Milnacipran hydrochloride is a white to off-white crystalline powder that is freely soluble in water, methanol, ethanol, chloroform, and methylene chloride, and sparingly soluble in diethyl ether. The melting point is 179 degrees C (Prod Info Savella(R) oral tablets, 2013).

Molecular Weight

    A) 282.8 g/mol (Prod Info Savella(R) oral tablets, 2013)

References

General Bibliography

    1) 40 CFR 372.28: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Lower thresholds for chemicals of special concern. National Archives and Records Administration (NARA) and the Government Printing Office (GPO). Washington, DC. Final rules current as of Apr 3, 2006.
    2) 40 CFR 372.65: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Chemicals and Chemical Categories to which this part applies. National Archives and Records Association (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Apr 3, 2006.
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