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SAVELLA (MILNACIPRAN): CLINICAL PHARMACOLOGY

Mechanism of Action

The exact mechanism of the central pain inhibitory action of milnacipran and its ability to improve the symptoms of fibromyalgia in humans are unknown. Preclinical studies have shown that Savella (Milnacipran HCl) is a potent inhibitor of neuronal norepinephrine and serotonin reuptake; milnacipran inhibits norepinephrine uptake with approximately 3-fold higher potency in vitro than serotonin without directly affecting the uptake of dopamine or other neurotransmitters. Milnacipran has no significant affinity for serotonergic (5-HT1-7), alpha- and beta-adrenergic, muscarinic (M1-5), histamine (H1-4), dopamine (D1-5), opiate, benzodiazepine, and -aminobutyric acid (GABA) receptors in vitro. Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Milnacipran has no significant affinity for Ca++, K+, Na+ and Cl. channels and does not inhibit the activity of human monoamine oxidases (MAO-A and MAO-B) or acetylcholinesterase.

Pharmacodynamics

Cardiovascular Electrophysiology

The effect of Savella (Milnacipran Hydrochloride) on the QTcF interval was measured in a double-blind placebo- and positive-controlled parallel study in 88 healthy subjects using 600 mg per day Savella (3 to 6 times the recommended therapeutic dose for fibromyalgia). After baseline and placebo adjustment, the maximum mean QTcF change was 8 ms (2-sided 90% CI, 3 - 12 ms). This increase is not considered to be clinically significant.

Pharmacokinetics

Milnacipran (Savella) is well absorbed after oral administration with an absolute bioavailability of approximately 85% to 90%. The exposure to milnacipran increased proportionally within the therapeutic dose range. It is excreted predominantly unchanged in urine (55%) and has a terminal elimination half-life of about 6 to 8 hours. Steady-state levels are reached within 36 to 48 hours and can be predicted from single-dose data. The active enantiomer, d-milnacipran, has a longer elimination half-life (8-10 hours) than the l-enantiomer (4-6 hours). There is no interconversion between the enantiomers.

Absorption and Distribution

Milnacipran HCl (Savella) is absorbed following oral administration with maximum concentrations (Cmax) reached within 2 to 4 hours post dose. Absorption of Savella is not affected by food. The absolute bioavailability is approximately 85% to 90%. The mean volume of distribution of milnacipran following a single intravenous dose to healthy subjects is approximately 400 L. Plasma protein binding is 13%.

Metabolism and Elimination

Milnacipran Hydrochloride (Savella) and its metabolites are eliminated primarily by renal excretion. Following oral administration of 14C-milnacipran hydrochloride, approximately 55% of the dose was excreted in urine as unchanged milnacipran (24% as L-Milnacipran and 31% as D-Milnacipran). The lmilnacipran carbamoyl-O-glucuronide was the major metabolite excreted in urine and accounted for approximately 17% of the dose; approximately 2% of the dose was excreted in urine as dmilnacipran carbamoyl-O-glucuronide. Approximately 8% of the dose was excreted in urine as the N-desethyl milnacipran metabolite.

Pharmacokinetics in Special Populations

Renal Impairment

Milnacipran pharmacokinetics were evaluated following single oral administration of 50 mg Savella to subjects with mild (creatinine clearance [CLcr] 50-80 ml / min), moderate (CLcr 30-49 ml / min), and severe (CLcr 5-29 ml / min) renal impairment and to healthy subjects (CLcr > 80 ml / min). The mean AUC0-∞ increased by 16%, 52%, and 199%, and terminal elimination half-life increased by 38%, 41%, and 122% in subjects with mild, moderate, and severe renal impairment, respectively, compared with healthy subjects.

No dosage adjustment is necessary for patients with mild renal impairment. Caution should be exercised in patients with moderate renal impairment. Dose adjustment is necessary in severe renal impairment patients.

Hepatic Impairment

Milnacipran pharmacokinetics were evaluated following single oral administration of 50 mg Savella to subjects with mild (Child-Pugh A), moderate (Child-Pugh B), and severe (Child-Pugh C) hepatic impairment and to healthy subjects. AUC0-∞ and T1/2 were similar in healthy subjects and subjects with mild and moderate hepatic impairment. However, subjects with severe hepatic impairment had a 31% higher AUC0-∞ and a 55% higher T1/2 than healthy subjects. Caution should be exercised in patients with severe hepatic impairment.

Elderly

Cmax and AUC parameters of milnacipran were about 30% higher in elderly (> 65 years) subjects compared with young subjects due to age-related decreases in renal function. No dosage adjustment is necessary based on age unless renal function is severely impaired.

Gender

Cmax and AUC parameters of milnacipran were about 20% higher in female subjects compared with male subjects. Dosage adjustment based on gender is not necessary.

Drug-Drug Interactions

In Vitro Studies

In general, milnacipran, at concentrations that were at least 25 times those attained in clinical trials, did not inhibit human CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 or induce human CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4/5 enzyme systems, indicating a low potential of interactions with drugs metabolized by these enzymes.

In vitro studies have shown that the biotransformation rate of milnacipran by human hepatic microsomes and hepatocytes was low. A low biotransformation was also observed following incubation of milnacipran with cDNA-expressed human CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 isozymes.

In Vivo Studies

The drug interaction studies described in this section were conducted in healthy adult subjects.

Carbamazepine: There were no clinically significant changes in the pharmacokinetics of milnacipran following coadministration of Savella (100 mg per day) and carbamazepine (200 mg twice a day). No changes were observed in the pharmacokinetics of carbamazepine or its epoxide metabolite due to coadministration with Savella (Milnacipran HCl).

Clomipramine: Switch from clomipramine (75 mg once a day) to milnacipran (100 mg per day) without a washout period did not lead to clinically significant changes in the pharmacokinetics of milnacipran. Because an increase in adverse events (eg, euphoria and postural hypotension) was observed after switching from clomipramine to milnacipran, monitoring of patients during treatment switch is recommended.

Digoxin: There was no pharmacokinetic interaction between Savella (200 mg per day) and digoxin (0.2 mg per day Lanoxicaps) following multiple-dose administration to healthy subjects.

Fluoxetine: Switch from fluoxetine (20 mg once a day), a strong inhibitor of CYP2D6 and a moderate inhibitor of CYP2C19, to milnacipran (100 mg per day) without a washout period did not affect the pharmacokinetics of milnacipran.

Lithium: Multiple doses of Savella (100 mg per day) did not affect the pharmacokinetics of lithium.

Lorazepam: There was no pharmacokinetic interaction between a single dose of Savella (50 mg) and lorazepam (1.5 mg).

Warfarin: Steady-state milnacipran (200 mg per day) did not affect the pharmacokinetics of R-warfarin and S-warfarin or the pharmacodynamics (as assessed by measurement of prothrombin INR) of a single dose of 25 mg warfarin. The pharmacokinetics of Savella (Milnacipran Hydrochloride) were not altered by warfarin.



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