Savella (Page 4 of 7)

6.2 Postmarketing Experience

The following additional adverse reactions have been identified from spontaneous reports of Savella received worldwide. These adverse reactions have been chosen for inclusion because of a combination of seriousness, frequency of reporting, or potential causal connection to Savella. However, because these adverse reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events include:

Blood and Lymphatic System Disorders — leukopenia, neutropenia, thrombocytopenia

Cardiac Disorders — supraventricular tachycardia

Eye Disorders — accommodation disorder

Endocrine Disorders — hyperprolactinemia

Gastrointestinal Disorders — acute pancreatitis

Hepatobiliary Disorders — hepatitis

Metabolism and Nutrition Disorders — anorexia, hyponatremia

Musculoskeletal and Connective Tissue Disorders — rhabdomyolysis

Nervous System Disorders — convulsions (including grand mal), loss of consciousness, Parkinsonism

Psychiatric Disorders — aggression, anger, delirium, hallucination, homicidal ideation

Renal and Urinary Disorders — acute renal failure

Reproductive System and Breast Disorders — galactorrhea

Skin Disorders — erythema multiforme, Stevens Johnson syndrome

Vascular Disorders — hypertensive crisis

7 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 (12.3)].

7.1 Monoamine Oxidase Inhibitors (MAOIs)

[See Dosage and Administration (2.5 and 2.6), Contraindications (4.1), Warnings and Precautions (5.2)].

7.2 Serotonergic Drugs

[See Dosage and Administration (2.5 and 2.6), Contraindications (4.1), Warnings and Precautions (5.2)].

7.3 Triptans

There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Savella with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Warnings and Precautions (5.2)].

7.4 Catecholamines

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 (5.3, 5.4)].

7.5 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.

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

7.6 Clinically Important Interactions with Select Cardiovascular Agents

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.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

Risk Summary

There are no adequate or well-controlled studies in pregnant women. Neonates exposed to dual reuptake inhibitors of serotonin and norepinephrine (such as Savella), or selective serotonin reuptake inhibitors late in the third trimester have developed complications that can arise immediately upon delivery. Reproduction studies have been performed in rats, rabbits and mice. Milnacipran was shown to increase embryo fetal and perinatal lethality in rats and the incidence of a minor skeletal variation in rabbits at doses below (rat) or approximately equal to (rabbit) the maximum recommended human dose (MRHD) of 200 mg/day on a mg/m2 basis. No effects were seen in mice when treated with milnacipran during the period of organogenesis at doses up to 3 times the MHRD on a mg/m2 basis. Because animal reproduction studies are not always predictive of human response, Savella should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pregnancy Registry

Physicians are advised to recommend that pregnant patients taking Savella enroll in the Savella Pregnancy Registry. Enrollment is voluntary and may be initiated by pregnant patients or their healthcare providers by contacting the registry at 1-877-643-3010 or by email at pregnancyregistries@incresearch.com. Data forms may also be downloaded from the registry website at www.savellapregnancyregistry.com.

Clinical Consideration

Neonates exposed to dual reuptake inhibitors of serotonin and norepinephrine, or selective serotonin reuptake inhibitors late in the third trimester have developed complications that can arise immediately upon delivery and require prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Monitor neonates for reported clinical findings such as respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of these classes of drugs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions (5.2)].

Animal Data

Studies were conducted in rats, rabbits and mice with dosing of milnacipran during the period of organogenesis. In rats, milnacipran was shown to increase embryo fetal lethality at doses of 5 mg/kg/day (0.25 times the MRHD on a mg/m2 basis). In rabbits, dose-dependent increases in the incidence of the skeletal variation of an extra single rib were observed in several pups from multiple litters in the absence of maternal toxicity at 15 mg/kg/day (1.5 times the MRHD on a mg/m2 basis). The clinical significance of this finding is unknown. In mice, no embryotoxic or teratogenic effects were seen at doses up to 125 mg/kg/day (3 times the MHRD on a mg/m2 basis).

With peri- and postnatal exposure to oral milnacipran in rats, decreases in viability and body weight were observed on Postpartum Day 4 at a dose of 5 mg/kg/day (approximately 0.25 times the MRHD on a mg/m2 basis). The no-effect dose for maternal and offspring toxicity was 2.5 mg/kg/day (approximately 0.1 times the MRHD on a mg/m2 basis).

8.3 Nursing Mothers

Milnacipran is present in the milk of lactating women treated with Savella. In a pharmacokinetic study, a single, oral dose of 50 mg milnacipran HCl tablet was administered to 8 lactating women who were at least 12 weeks postpartum and weaning their infants. The maximum estimated daily infant dose for milnacipran from breast milk (assuming mean milk consumption of 150 mL/kg/day) was 5% of the maternal dose based on peak plasma concentrations. In most patients, peak concentrations of milnacipran in breast milk were seen within 4 hours after the maternal dose. Because of the limited data regarding infant exposure to Savella, caution should be exercised when Savella is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of Savella in a fibromyalgia pediatric population below the age of 18 have not been established [see Boxed Warning, Indications and Usage (1), and Warnings and Precautions (5.1)]. The use of Savella is not recommended in pediatric patients.

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