Savella (Milnacipran Hydrochloride) - Drug Interactions, Contraindications, Overdosage, etc

DRUG INTERACTIONS

Milnacipran undergoes minimal CYP450 related metabolism, with the majority of the dose excreted unchanged in urine (55%), and has a low binding to plasma proteins (13%). In vitro and in vivo studies showed that Savella is unlikely to be involved in clinically significant pharmacokinetic drug interactions [see Pharmacokinetics in Special Populations ].

Clinically Important Interactions with Other Drugs

Lithium: Serotonin syndrome may occur when lithium is co-administered with Savella and with other drugs that impair metabolism of serotonin [ see Warnings and Precautions – Serotonin Syndrome (5.2) ].

Epinephrine and norepinephrine: Savella inhibits the reuptake of norepinephrine. Therefore concomitant use of Savella with epinephrine and norepinephrine may be associated with paroxysmal hypertension and possible arrhythmia [ see Warnings and Precautions – Effects on Blood Pressure (5.3) and Effects on Heart Rate (5.4) ]

Serotonergic Drugs: Co-administration of Savella with other inhibitors of serotonin re-uptake may result in hypertension and coronary artery vasoconstriction, through additive serotonergic effects [see Warnings and Precautions ].

Digoxin: Use of Savella concomitantly with digoxin may be associated with potentiation of adverse hemodynamic effects. Postural hypotension and tachycardia have been reported in combination therapy with intravenously administered digoxin (1 mg). Co-administration of Savella and intravenous digoxin should be avoided [ see Warnings and Precautions (5.3, 5.4) ]

Clonidine: Because Savella inhibits norepinephrine reuptake, co-administration with clonidine may inhibit clonidine's anti-hypertensive effect.

Clomipramine: In a drug-drug interaction study, an increase in euphoria and postural hypotension was observed in patients who switched from clomipramine to Savella.

CNS-active drugs: Given the primary CNS effects of Savella, caution should be used when it is taken in combination with other centrally acting drugs, including those with a similar mechanism of action.

Monoamine Oxidase Inhibitors (MAOIs): [ see Contraindications].

OVERDOSAGE

There is limited clinical experience with Savella overdose in humans. In clinical trials, cases of acute ingestions up to 1000 mg, alone or in combination with other drugs, were reported with none being fatal.

In postmarketing experience, fatal outcomes have been reported for acute overdoses primarily involving multiple drugs but also with Savella only. The most common signs and symptoms included increased blood pressure, cardio-respiratory arrest, changes in the level of consciousness (ranging from somnolence to coma), confusional state, dizziness, and increased hepatic enzymes.

Management of Overdose

There is no specific antidote to Savella, but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. In case of acute overdose, treatment should consist of those general measures employed in the management of overdose with any drug.

An adequate airway, oxygenation, and ventilation should be assured and cardiac rhythm and vital signs should be monitored. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Because there is no specific antidote for Savella, symptomatic care and treatment with gastric lavage and activated charcoal should be considered as soon as possible for patients who experience a Savella overdose.

Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be beneficial.

In managing overdose, the possibility of multiple drug involvement should be considered. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians' Desk Reference (PDR).

CONTRAINDICATIONS

Monoamine Oxidase Inhibitors

Concomitant use of Savella in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated. In patients receiving a serotonin reuptake inhibitor in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued serotonin reuptake inhibitors and have been started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. The effects of combined use of Savella and MAOIs have not been evaluated in humans. Therefore, it is recommended that Savella should not be used in combination with an MAOI, or within 14 days of discontinuing treatment with an MAOI. Similarly, at least 5 days should be allowed after stopping Savella before starting an MAOI [see Dosage and Administration (2.5), Warnings and Precautions (5.2)].

Uncontrolled Narrow-Angle Glaucoma

In clinical trials, Savella was associated with an increased risk of mydriasis. Mydriasis has been reported with other dual reuptake inhibitors of norepinephrine and serotonin; therefore, do not use Savella in patients with uncontrolled narrow-angle glaucoma.

DRUG ABUSE AND DEPENDENCE

Controlled Substance

Milnacipran is not a controlled substance.

Abuse

Milnacipran did not produce behavioral signs indicative of abuse potential in animal or human studies.

Dependence

Milnacipran produces physical dependence, as evidenced by the emergence of withdrawal symptoms following drug discontinuation, similar to other SNRIs and SSRIs. These withdrawal symptoms can be severe. Thus, Savella should be tapered and not abruptly discontinued after extended use. [see Section 5.7 Discontinuation of Treatment with Savella ].