Milnacipran (Savella) - Uses, Dose, MOA, Brands, Side effects

A norepinephrine and serotonin reuptake inhibitor called milnacipran (Savella) is used to treat fibromyalgia patients.

  • Fibromyalgia:
    • It is recommended for treating fibromyalgia.

Milnacipran (Savella) Dose in the treatment of Fibromyalgia:

  • By mouth, take 50 milligrams two times a day.
  • Start with 5 mg on the first day, then take 12.5 mg two times a day for the next three days.
  • After that, take 25 mg two times a day for the next four days.
  • Finally, take 50 mg two times a day for the rest of the days.
  • If your body reacts well, the doctor might increase the dose to 100 mg two times a day.
  • They haven't studied doses higher than 200 mg a day.

  • Discontinuation of therapy:

    • Stopping antidepressants suddenly after using them for more than three weeks can lead to withdrawal symptoms and the return of the original symptoms.

    • To reduce these effects, it's recommended to gradually decrease the dose over 2-4 weeks.

    • If someone is taking a medication with a short half-life (like paroxetine or venlafaxine), has a history of withdrawal symptoms, or is on a high dose, they should slowly adjust the dose, perhaps over four weeks.

    • If withdrawal symptoms become too difficult, going back to the previous dose or decreasing the dose more slowly are the best choices.

    • There's not a lot of evidence to guide the ideal speed for tapering off antidepressants.

  • Switching antidepressants:

    • There isn't much evidence on the best ways to switch antidepressants, but there are a couple of strategies:

    • Cross-titration: This involves gradually stopping the first antidepressant while, at the same time, slowly increasing the new antidepressant.

    • This is the usual approach for most switches, except for MAOIs (Monoamine oxidase inhibitors).

    • Straight switch: This means abruptly stopping the first antidepressant and then starting the new one at an equivalent dose or lower, gradually increasing it.

    • However, this method is not recommended for MAOIs.

    • In certain situations, a direct switch is preferable. For example:

    • When transitioning between two SSRIs (Selective Serotonin Reuptake Inhibitors), especially if the antidepressant being stopped has been taken for less than a week.

    • When deciding on a switch strategy, consider factors like the likelihood of withdrawal symptoms, potential medication interactions, features of each antidepressant (such as half-life, side effects, and how they work), and the level of symptom control needed.

  • Switching to or from an MAOI:

    • Wait at least 14 days after you stop taking MAOI before you start using milnacipran.
    •  Also, wait for 5 days after stopping milnacipran before starting MAOI.

Use in Children:

Not indicated. 

Pregnancy Risk Factor C

    • Research on animal reproduction indicates potential risks.

    • If a newborn is exposed to SSRI/SNRI in the last three months of the third trimester, it might not cause birth defects, but adverse events can occur.

    • These may include respiratory symptoms like crying, respiratory distress, and apnea.

    • Seizures, abnormal muscle tone (hyper or hypotonia), hyperreflexia, and jitteriness are also possible.

    • Other symptoms such as vomiting, feeding difficulties, hypoglycemia, constant crying, and irritability may arise.

    • These symptoms could be linked to toxicity, discontinuation syndrome, or serotonin disorder associated with SSRI treatment.

    • The long-term effects of these changes on the newborn are not well understood.

    Milnacipran can be used during breastfeeding

    • It comes out in breast milk, so it's advised that breastfeeding mothers avoid using it.

Dose in Kidney Disease:

  • For mild kidney issues, no change in dosage is needed.
  • If there's moderate impairment, be cautious.
  • In severe cases (when kidney function is significantly reduced), decrease the dose to 25-50 mg twice a day based on individual tolerance.
  • However, it's not recommended for use in end-stage renal disease (ESRD).

Dose in Liver Disease:

  • For mild-to-moderate liver issues, there's no need to adjust the dosage.
  • In cases of severe liver impairment, no dosage adjustment is required, but it's advisable to use the medication cautiously.

Common Side Effects of Milnacipran (Savella):

  • Central nervous system:

    • Insomnia
    • Headache

  • Endocrine & metabolic:

    • Hot flash

  • Gastrointestinal:

    • Nausea
    • Constipation

Less Common Side Effects of Milnacipran (Savella):

  • Cardiovascular:

    • Palpitations
    • Increased Heart Rate
    • Hypertension
    • Flushing
    • Increased Blood Pressure
    • Tachycardia
    • Peripheral Edema

  • Central Nervous System:

    • Dizziness
    • Migraine
    • Chills
    • Depression
    • Drowsiness
    • Falling
    • Fatigue
    • Irritability

  • Dermatologic:

    • Hyperhidrosis
    • Skin Rash
    • Night Sweats

  • Endocrine & Metabolic:

    • Decreased Libido
    • Hypercholesterolemia
    • Weight Changes

  • Gastrointestinal:

    • Vomiting
    • Xerostomia
    • Flatulence
    • Decreased Appetite
    • Dysgeusia
    • Abdominal Distension
    • Dyspepsia
    • Gastroesophageal Reflux Disease
    • Diarrhea
    • Abdominal Pain

  • Genitourinary:

    • Cystitis
    • Dysuria
    • Urinary Hesitancy
    • Ejaculatory Disorder
    • Urethral Pain
    • Prostatitis
    • Testicular Pain
    • Erectile Dysfunction
    • Testicular Swelling
    • Scrotal Pain
    • Urinary Retention
    • Ejaculation Failure
    • Urinary Tract Infection
    • Decreased Urine Output

  • Neuromuscular & Skeletal:

    • Tremor

  • Ophthalmic:

    • Blurred Vision

  • Respiratory:

    • Dyspnea

  • Miscellaneous:

    • Fever

Contraindications to Milnacipran (Savella):

      • MAOIs are employed for treating psychiatric disorders.
      • However, be cautious not to use them at the same time as milnacipran or within five days of stopping milnacipran.
      • Also, avoid initiating milnacipran within two weeks after discontinuing MAOIs.
      • Additionally, if a patient has recently received intravenous linezolid or Methylene Blue, the initiation of milnacipran should be approached carefully.

Warnings and precautions

    • Bleeding Risk:

      • Due to its impact on platelet aggregation, there is a higher likelihood of bleeding.

      • This risk becomes more significant when combined with aspirin and NSAIDs.

      • While the evidence is inconclusive, there is a suggestion that SNRIs, when used with anticoagulants, may increase the risk of bleeding.

      • The use of SNRIs can lead to bleeding of varying severity, ranging from nosebleeds or minor bruising to potentially life-threatening hemorrhage.

    • Cardiovascular effects

      • The treatment may raise blood pressure and heart rate.

      • It's crucial to evaluate these factors before starting the therapy and monitor them regularly.

      • If there's a condition of rapid heart rate (tachycardia) or sustained high blood pressure, it's important to either decrease the dosage or gradually stop using the treatment.

      • Before initiating any therapy, it's essential to address any existing heart disease.

      • Patients with preexisting heart conditions should receive treatment with caution.

    • Fractures

      • Antidepressants have been associated with an increased risk of bone fractures.
      • If someone using antidepressants or similar medications experiences unexplained bone pain, it's essential to seek medical attention.
      • This pain might be accompanied by specific signs like point tenderness, swelling, or bruising.

    • Hepatotoxicity

      • The use of this medication may lead to liver injury, including severe conditions like fulminant liver disease and an elevation in liver enzymes.

      • If a patient is experiencing high levels of alcohol intake, chronic liver disease (CLD), or other liver problems, it's advisable to avoid using this medication.

      • If any signs of liver dysfunction are observed, it's crucial to stop the therapy immediately.

      • Restarting the medication should only be considered after identifying and addressing any other potential causes or sources of the hepatic issues.

    • Ocular effects

      • Using this medication could lead to a slight dilation of the pupils, and in rare instances, it may cause narrow-angle glaucoma.

      • It's important to assess for risk factors associated with narrow-angle glaucoma before starting the treatment.

    • Serotonin syndrome

      • Serotonin syndrome can occur with drugs that affect serotonin levels (like SSRIs, SNRIs).

      • This risk increases when these drugs are used with other serotonergic medications (such as triptans, TCAs, fentanyls, lithium, tramadols, buspirones, St John's wort, and tryptophan), as well as substances that affect serotonin metabolism (like linezolid or IV methylene blue).

      • Watch out for signs of serotonin syndrome, including mental status changes (agitation, hallucinations, delirium, coma), autonomic instability (rapid heart rate, unstable blood pressure, dizziness, sweating, flushing, high body temperature, and incoordination), neuromuscular changes (tremor, rigidity, myoclonus, hyperreflexia, and coordination issues), GI symptoms (nausea, vomiting, diarrhea), and seizures.

      • If any of these signs or symptoms appear, it's crucial to stop the treatment immediately.

    • SIADH and Hyponatremia

      • Both SSRIs and SNRIs can potentially cause SIADH (syndrome of inappropriate antidiuretic hormone secretion).

      • In rare cases, there have been reports of severe hyponatremia, with levels as low as 110 mg/L.

      • This risk is particularly prevalent in older patients.

      • The likelihood of this condition increases if there is volume depletion or concurrent use of diuretics.

      • It's important to be cautious in such situations to minimize the risk of severe hyponatremia.

    • Urinary hesitancy

      • The medication may lead to increased resistance in urine flow.
      • It's important to advise the patient to inform you if they notice any symptoms of urgency or difficulty in urination.
      • If the patient is already experiencing symptoms related to prostatism or any other lower urinary tract disorder, caution should be exercised in the use of this medication.

    • Hypomania/mania:

      • Individuals with mood disorders or those taking similar medications may experience episodes of mania.

      • The use of this medication might worsen psychosis in some patients or trigger mania and hypomania in individuals with bipolar disorder.

      • It's crucial to note that bipolar disorder should not be treated with this medication alone.

      • Testing for bipolar disorder should be conducted on patients exhibiting symptoms of depression.

      • It's important to emphasize that milnacipran has not been approved by the FDA for the treatment of bipolar disorder.

    • Seizure disorders

      • Exercise caution if there is a history or condition that could potentially lead to seizures, such as a history of brain damage or addiction.

Milnacipran: Drug Interaction

Risk Factor C (Monitor therapy)

Acalabrutinib

Agents with antiplatelet properties may have an enhanced antiplatelet impact.

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.)

Other agents with antiplatelet properties may have an enhanced antiplatelet impact.

Almotriptan

Makes serotonergic agents more effective (High Risk). Serotonin syndrome might  occur from this. When these medications are taken together, it is important to watch  out for  any signs and symptoms of serotonin syndrome or serotonin poisoning,  such as hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic  instability,  and changes in mental status.

Alosetron

Makes serotonergic agents more effective (High Risk). Serotonin syndrome might  occur from this. When these medications are taken together, it is important to watch  out for  any signs and symptoms of serotonin syndrome or serotonin poisoning,  such as hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic  instability,  and changes in mental status.

Alpha2-Agonists

The antihypertensive action of Alpha2-Agonists may be diminished by  Serotonin/Norepinephrine Reuptake Inhibitors.Exceptions: Apraclonidine.

Amphetamines

Makes serotonergic agents more effective (High Risk). Serotonin syndrome might  occur from this. When these medications are taken together, it is important to watch  out for  any signs and symptoms of serotonin syndrome or serotonin poisoning,  such as hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic  instability,  and changes in mental status.

Anticoagulants

The anticoagulant impact of anticoagulants may be strengthened by agents with antiplatelet  properties.Exceptions: Bemiparin; Enoxaparin; Heparin.

Antiemetics (5HT3 Antagonists)

Makes serotonergic agents more effective (High Risk). Serotonin syndrome might  occur from this. When these medications are taken together, it is important to watch  out for  any signs and symptoms of serotonin syndrome or serotonin poisoning,  such as hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic  instability,  and changes in mental status.Exceptions: Alosetron; Ondansetron; Ramosetron.

Antipsychotic Agents

Serotonergic Agents (High Risk) may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonergic agents may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome.

Apixaban

Antiplatelet agents may intensify the toxic/unfavorable effects of apixaban. In particular, there  may  be an elevated risk of bleeding. Management: Carefully weigh the advantages and  disadvantages of this pairing,  and keep a tight eye on things.

Aspirin

Serotonin/Norepinephrine Reuptake Inhibitors may improve aspirin's ability to reduce  blood clots.

Brexanolone

Serotonin/Norepinephrine Reuptake Inhibitors may increase Brexanolone's ability to depress  the  central nervous system.

BusPIRone

Makes serotonergic agents more effective (High Risk). Serotonin syndrome might  occur from this. When these medications are taken together, it is important to watch  out for  any signs and symptoms of serotonin syndrome or serotonin poisoning,  such as hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic  instability,  and changes in mental status.

Cephalothin

Agents having antiplatelet properties may intensify cephalothin's harmful or hazardous effects.  In particular, there may be an elevated risk of bleeding.

Collagenase (Systemic)

Collagenase's harmful or toxic effects may be enhanced by substances with antiplatelet  properties (Systemic). In particular, there may be an increased risk of bruising and/or  bleeding  at the injection site.

Cyclobenzaprine

Makes serotonergic agents more effective (High Risk). Serotonin syndrome might  occur from this. When these medications are taken together, it is important to watch  out for  any signs and symptoms of serotonin syndrome or serotonin poisoning,  such as hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic  instability,  and changes in mental status.

Dabigatran Etexilate

Dabigatran Etexilate's anticoagulant activity may be strengthened by substances with antiplatelet  properties. Dabigatran Etexilate's serum levels may rise in response to substances with antiplatelet  properties. The drug clopidogrel is especially covered by this mechanism. Management: Carefully  weigh the advantages and disadvantages of this combination, and keep a tight eye on things;  Canadian labelling advises against using prasugrel or ticagrelor.

Dasatinib

Agents having antiplatelet properties may strengthen their anticoagulant effects.  Management: Separate drug interaction monographs go into further detail about  the medications indicated as exceptions to this book.

Deoxycholic Acid

Deoxycholic Acid's harmful or toxic effects may be increased by substances with antiplatelet  properties. In particular, there may be a higher chance of bleeding or bruising in the treatment  region.

Dexmethylphenidate-Methylphenidate

Makes serotonergic agents more effective (High Risk). Serotonin syndrome might  occur from this. When these medications are taken together, it is important to watch  out for  any signs and symptoms of serotonin syndrome or serotonin poisoning,  such as hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic  instability,  and changes in mental status.

Dextromethorphan

Makes serotonergic agents more effective (High Risk). Serotonin syndrome might  occur from this. When these medications are taken together, it is important to watch  out for  any signs and symptoms of serotonin syndrome or serotonin poisoning,  such as hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic  instability,  and changes in mental status.

Edoxaban

Antiplatelet agents may intensify the toxic/unfavorable effects of edoxaban. In particular, there  may be an elevated risk of bleeding.

Eletriptan

Makes serotonergic agents more effective (High Risk). Serotonin syndrome might  occur from this. When these medications are taken together, it is important to watch  out for  any signs and symptoms of serotonin syndrome or serotonin poisoning,  such as hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic  instability,  and changes in mental status.

Ergot Derivatives

Makes serotonergic agents more effective (High Risk). Serotonin syndrome might  occur from this. When these medications are taken together, it is important to watch  out for  any signs and symptoms of serotonin syndrome or serotonin poisoning,  such as hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic  instability,  and changes in mental status. Exceptions: Nicergoline.

Fat Emulsion (Fish Oil Based)

Agents with poisonous or harmful effects may intensify their negative or hazardous effects.

FentaNYL

Makes serotonergic agents more effective (High Risk). Serotonin syndrome might  occur from this. When these medications are taken together, it is important to watch  out for  any signs and symptoms of serotonin syndrome or serotonin poisoning,  such as hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic  instability,  and changes in mental status.

Glucosamine

Agents with antiplatelet properties may have an enhanced antiplatelet impact.

Ibritumomab Tiuxetan

Antiplatelet agents may intensify the toxic/unfavorable effects of ibritumomab tiuxetan. Both  substances may raise the risk of bleeding and compromise platelet function.

Ibrutinib

Agents with poisonous or harmful effects may intensify their negative or hazardous effects.

Inotersen

Agents with antiplatelet properties may have an enhanced antiplatelet impact.

Ioflupane I 123

Ioflupane I 123's ability to serve as a diagnostic tool may be diminished by serotonin/norepinephrine  reuptake inhibitors.

Lasmiditan

Makes serotonergic agents more effective (High Risk). Serotonin syndrome might  occur from this. When these medications are taken together, it is important to watch  out for  any signs and symptoms of serotonin syndrome or serotonin poisoning,  such as hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic  instability,  and changes in mental status.

Limaprost

Agents with antiplatelet properties may have an enhanced antiplatelet impact.

Lorcaserin

Makes serotonergic agents more effective (High Risk). Serotonin syndrome might  occur from this. When these medications are taken together, it is important to watch  out for  any signs and symptoms of serotonin syndrome or serotonin poisoning,  such as hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic  instability,  and changes in mental status.

Meperidine

Makes serotonergic agents more effective (High Risk). Serotonin syndrome might  occur from this. When these medications are taken together, it is important to watch  out for  any signs and symptoms of serotonin syndrome or serotonin poisoning,  such as hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic  instability,  and changes in mental status.

Metaxalone

Makes serotonergic agents more effective (High Risk). Serotonin syndrome might  occur from this. When these medications are taken together, it is important to watch  out for  any signs and symptoms of serotonin syndrome or serotonin poisoning,  such as hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic  instability,  and changes in mental status.

Mirtazapine

Makes serotonergic agents more effective (High Risk). Serotonin syndrome might  occur from this. When these medications are taken together, it is important to watch  out for  any signs and symptoms of serotonin syndrome or serotonin poisoning,  such as hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic  instability,  and changes in mental status.

Multivitamins/Fluoride (with ADE)

Agents with antiplatelet properties may have an enhanced antiplatelet impact.

Multivitamins/Minerals (with ADEK, Folate, Iron)

Agents with antiplatelet properties may have an enhanced antiplatelet impact.

Multivitamins/Minerals (with AE, No Iron)

Agents with antiplatelet properties may have an enhanced antiplatelet impact.

Nefazodone

Makes serotonergic agents more effective (High Risk). Serotonin syndrome might  occur from this. When these medications are taken together, it is important to watch  out for  any signs and symptoms of serotonin syndrome or serotonin poisoning,  such as hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic  instability,  and changes in mental status..

Nonsteroidal Anti-Inflammatory Agents (Nonselective)

Nonsteroidal Anti-Inflammatory Drugs may have a stronger antiplatelet impact when  used  with Serotonin/Norepinephrine  Reuptake Inhibitors (Nonselective).

Obinutuzumab

Agents with antiplatelet properties may intensify Obinutuzumab's toxic/unfavorable effects. In particular,  there may be an increased risk of life-threatening bleeding-related incidents.

Omega-3 Fatty Acids

Agents with antiplatelet properties may have an enhanced antiplatelet impact.

Ondansetron

Makes serotonergic agents more effective (High Risk). Serotonin syndrome might  occur from this. When these medications are taken together, it is important to watch  out for  any signs and symptoms of serotonin syndrome or serotonin poisoning,  such as hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic  instability,  and changes in mental status.

Opioid Agonists

Makes serotonergic agents more effective (High Risk). Serotonin syndrome might  occur from this. When these medications are taken together, it is important to watch  out for  any signs and symptoms of serotonin syndrome or serotonin poisoning,  such as hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic  instability,  and changes in mental status. Exceptions: FentaNYL; Meperidine; TraMADol.

Oxitriptan

Makes serotonergic agents more effective (High Risk). Serotonin syndrome might  occur from this. When these medications are taken together, it is important to watch  out for  any signs and symptoms of serotonin syndrome or serotonin poisoning,  such as hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic  instability,  and changes in mental status.

Pentosan Polysulfate Sodium

Agents with poisonous or harmful effects may intensify their negative or hazardous effects. In  particular,  the concurrent use of several drugs may raise the risk of bleeding.

Pentoxifylline

Agents with antiplatelet properties may have an enhanced antiplatelet impact.

Prostacyclin Analogues

Agents with antiplatelet properties may have an enhanced antiplatelet impact.

Ramosetron

Makes serotonergic agents more effective (High Risk). Serotonin syndrome might  occur from this. When these medications are taken together, it is important to watch  out for  any signs and symptoms of serotonin syndrome or serotonin poisoning,  such as hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic  instability,  and changes in mental status.

Rivaroxaban

Rivaroxaban's anticoagulant impact may be increased by substances with antiplatelet properties.  Management: Carefully weigh the advantages and disadvantages of this combination, and keep tight  eye on  things; Canadian labelling advises against using prasugrel or ticagrelor.

Salicylates

The harmful or toxic effect of salicylates may be increased by substances with antiplatelet properties.  Bleeding risk could rise as a result.

Selective Serotonin Reuptake Inhibitors

Makes serotonergic agents more effective (High Risk). Serotonin syndrome might  occur from this. When these medications are taken together, it is important to watch  out for  any signs and symptoms of serotonin syndrome or serotonin poisoning,  such as hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic  instability,  and changes in mental status. Exceptions: Dapoxetine.

Serotonergic Agents (High Risk, Miscellaneous)

Makes serotonergic agents more effective (High Risk). Serotonin syndrome might  occur from this. When these medications are taken together, it is important to watch  out for  any signs and symptoms of serotonin syndrome or serotonin poisoning,  such as hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic  instability,  and changes in mental status.

Serotonin 5-HT1D Receptor Agonists (Triptans)

Makes serotonergic agents more effective (High Risk). Serotonin syndrome might  occur from this. When these medications are taken together, it is important to watch  out for  any signs and symptoms of serotonin syndrome or serotonin poisoning,  such as hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic  instability,  and changes in mental status. Exceptions: Almotriptan; Eletriptan.

Serotonin/Norepinephrine Reuptake Inhibitors

Makes serotonergic agents more effective (High Risk). Serotonin syndrome might  occur from this. When these medications are taken together, it is important to watch  out for  any signs and symptoms of serotonin syndrome or serotonin poisoning,  such as hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic  instability,  and changes in mental status.In addition, monitor for signs and symptoms of bleeding.

St John's Wort

Makes serotonergic agents more effective (High Risk). Serotonin syndrome might  occur from this. When these medications are taken together, it is important to watch  out for  any signs and symptoms of serotonin syndrome or serotonin poisoning,  such as hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic  instability,  and changes in mental status.

Syrian Rue

Makes serotonergic agents more effective (High Risk). Serotonin syndrome might  occur from this. When these medications are taken together, it is important to watch  out for  any signs and symptoms of serotonin syndrome or serotonin poisoning,  such as hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic  instability,  and changes in mental status.

Thrombolytic Agents

The anticoagulant impact of thrombolytic agents may be strengthened by agents with  antiplatelet properties.

Tipranavir

Agents with antiplatelet properties may have an enhanced antiplatelet impact.

TraMADol

Serotonin/Norepinephrine Reuptake Inhibitors may enhance the adverse/toxic effect of TraMADol. Makes serotonergic agents more effective (High Risk). Serotonin syndrome might  occur from this. When these medications are taken together, it is important to watch  out for  any signs and symptoms of serotonin syndrome or serotonin poisoning,  such as hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic  instability,  and changes in mental status.

TraZODone

Makes serotonergic agents more effective (High Risk). Serotonin syndrome might  occur from this. When these medications are taken together, it is important to watch  out for  any signs and symptoms of serotonin syndrome or serotonin poisoning,  such as hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic  instability,  and changes in mental status.

Tricyclic Antidepressants

Tricyclic Antidepressants' serotonergic effects may be strengthened by  serotonin/norepinephrine reuptake inhibitors. Serotonin syndrome might occur from this.  When using these drugs together, watch out for any changes in mental status  and indicators of serotonin syndrome,  such as hyperreflexia, clonus, hyperthermia,  diaphoresis, tremor, and autonomic instability.

Vitamin E (Systemic)

Agents with antiplatelet properties may have an enhanced antiplatelet impact.

Vitamin K Antagonists (eg, warfarin)

Milnacipran may make vitamin K antagonists more harmful or poisonous. In particular, there  may be an elevated risk of bleeding.

Zanubrutinib

Agents with antiplatelet properties may have an enhanced antiplatelet impact.

Risk Factor D (Consider therapy modification)

Alcohol (Ethyl)

Tricyclic Antidepressants' serotonergic effects may be strengthened by  serotonin/norepinephrine reuptake inhibitors. Serotonin syndrome might occur from this.  When using these drugs together, watch out for any changes in mental status  and indicators of serotonin syndrome,  such as hyperreflexia, clonus, hyperthermia,  diaphoresis, tremor, and autonomic instability.

Alpha-/Beta-Agonists

The tachycardic action of beta- and alpha-agonists may be enhanced by serotonin/norepinephrine  reuptake inhibitors. The vasopressor impact of alpha/beta agonists may be enhanced by  serotonin/norepinephrine reuptake inhibitors.

Bemiparin

Bemiparin's anticoagulant impact may be strengthened by substances with antiplatelet properties.  Management: Avoid taking bemiparin at the same time as antiplatelet medications. If concurrent use is unavoidable, keep a cautious eye out for bleeding signs and symptoms.

Digoxin

Milnacipran may intensify Digoxin's harmful or hazardous effects. Particularly when IV digoxin  is used, the risk of postural hypotension and tachycardia may increase. Avoid giving IV digoxin to  individuals  who are taking milnacipran at the same time. When using oral digoxin and milnacipran  together, proceed with caution and pay close  attention for any signs of postural hypotension  and tachycardia.

Enoxaparin

Enoxaparin's anticoagulant impact may be strengthened by substances with antiplatelet properties.  When feasible, stop using antiplatelet medications before starting enoxaparin. If simultaneous  administration must occur, keep a cautious eye out for any bleeding signs and symptoms.

Heparin

The anticoagulant effect of heparin may be strengthened by substances with antiplatelet properties.     If coadministration is necessary, reduce the dose of heparin or other medications with antiplatelet  characteristics.

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry)

Agents with poisonous or harmful effects may intensify their negative or hazardous effects. Bleeding  could happen. Management: When at all possible, avoid combining. If used, keep a closer eye out  for signs of bleeding. Two weeks before any type of surgery, dental work,  or invasive procedure,  stop using herbal  remedies that have anticoagulant or antiplatelet effects.

Metoclopramide

Tricyclic Antidepressants' serotonergic effects may be strengthened by  serotonin/norepinephrine reuptake inhibitors. Serotonin syndrome might occur from this.  When using these drugs together, watch out for any changes in mental status  and indicators of serotonin syndrome,  such as hyperreflexia, clonus, hyperthermia,  diaphoresis, tremor, and autonomic instability.

Risk Factor X (Avoid combination)

Bromopride

The negative or hazardous effects of serotonin/norepinephrine reuptake inhibitors may be increased.

Dapoxetine

Makes serotonergic agents more effective (High Risk). Serotonin syndrome might occur from this.  Treatment: Avoid using highrisk serotonergic medications with dapoxetine or within 7 days after  stopping them. Within 14 days of using a monoamine oxidase inhibitor, do not take dapoxetine.  This combination is listed on the labelling for dapoxetine as being harmful.

Iobenguane Radiopharmaceutical Products

Tricyclic Antidepressants' serotonergic effects may be strengthened by  serotonin/norepinephrine  reuptake inhibitors. Serotonin syndrome might occur from this.  When using these drugs together,  watch out for any changes in mental status  and indicators of serotonin syndrome,  such as  hyperreflexia, clonus, hyperthermia,  diaphoresis, tremor, and autonomic instability.

Linezolid

Serotonin/Norepinephrine Reuptake Inhibitors may improve their serotonergic effects. Serotonin  syndrome might occur from this.

Methylene Blue

Serotonin/Norepinephrine Reuptake Inhibitors may improve their serotonergic effects. Serotonin  syndrome might occur from this.

Monoamine Oxidase Inhibitors (Antidepressant)

Serotonin/Norepinephrine Reuptake Inhibitors may improve their serotonergic effects. Serotonin  syndrome might occur from this.

Rasagiline

Serotonin/Norepinephrine Reuptake Inhibitors may improve their serotonergic effects. Serotonin  syndrome might occur from this.

Safinamide

Serotonin/Norepinephrine Reuptake Inhibitors may improve their serotonergic effects. Serotonin  syndrome might occur from this.

Selegiline

Serotonin/Norepinephrine Reuptake Inhibitors may improve their serotonergic effects. Serotonin  syndrome might occur from this.

Urokinase

Urokinase's anticoagulant impact may be strengthened by substances with antiplatelet properties.

 

Monitoring Parameters:

  • Monitoring parameters for individuals on this therapy include:

  • Blood pressure and heart rate: Regularly check and monitor blood pressure and heart rate to ensure they are within the acceptable range.

  • Renal function: Monitor renal function to assess the health of the kidneys and ensure they are functioning properly.

  • Mental status: Keep a close eye on the patient's mental status, particularly for signs of suicidal ideation or tendencies. This is especially important at the beginning of therapy or with any changes in dosage.

  • Intraocular pressure: If the patient has a history of glaucoma, measure baseline intraocular pressure as it may already be elevated. Regular monitoring can help detect any changes.

  • Regular and thorough monitoring of these parameters is essential for the overall well-being of the patient during the course of the therapy.

How to administer Milnacipran (Savella)?

 

This medication can be taken orally, and it can be taken with or without food.

Mechanism of action of Milnacipran (Savella):

This medication is a strong inhibitor of norepinephrine reuptake and serotonin metabolism (in a ratio of 3:1).

Importantly, it does not possess properties that inhibit MAO (monoamine oxidase). Here are some details about its pharmacokinetics:

  • Absorption: It is well absorbed when taken orally.
  • Protein Binding: Approximately 13% of the drug binds to proteins.
  • Metabolism: The liver metabolizes it into inactive forms.
  • Bioavailability: The medication has a bioavailability of 85% to 90%.
  • Half-life Elimination: It has an elimination half-life of 6-8 hours.
  • Time to Peak in Plasma: When taken orally, it reaches peak plasma levels in 2-4 hours.
  • Excretion: The primary route of elimination is through urine, with 55% being excreted as the unchanged drug.

International Brand Names of Milnacipran:

  • Savella
  • Savella Titration Pack
  • Dalcipran
  • Ixel
  • Joncia
  • Milnacip
  • Milran
  • Misulvan
  • Mydonia
  • Neocipran
  • Tivanyl
  • Xian Wei Ning

Milnacipran Brand Names in Pakistan:

No Brands Available in Pakistan. 

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