SAVELLA (Page 4 of 8)

6.4 Weight Changes

In placebo-controlled fibromyalgia clinical trials, patients treated with Savella for up to 3 months experienced a mean weight loss of approximately 0.8 kg in both the Savella 100 mg/day and the Savella 200 mg/day treatment groups, compared with a mean weight loss of approximately 0.2 kg in placebo-treated patients.

6.5 Genitourinary Adverse Reactions in Males

In the placebo-controlled fibromyalgia studies, the following treatment-emergent adverse reactions related to the genitourinary system were observed in at least 2% of male patients treated with Savella, and occurred at a rate greater than in placebo-treated male patients: dysuria, ejaculation disorder, erectile dysfunction, ejaculation failure, libido decreased, prostatitis, scrotal pain, testicular pain, testicular swelling, urinary hesitation, urinary retention, urethral pain, and urine flow decreased.

6.6 Other Adverse Reactions Observed During Clinical Trials of Savella in Fibromyalgia

Following is a list of frequent (those occurring on one or more occasions in at least 1/100 patients) treatment-emergent adverse reactions reported from 1824 fibromyalgia patients treated with Savella for periods up to 68 weeks. The listing does not include those events already listed in Table 1, those events for which a drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life threatening.

Adverse reactions are categorized by body system and listed in order of decreasing frequency. Adverse reactions of major clinical importance are described in the Warnings and Precautions section (5).

Gastrointestinal Disorders — diarrhea, dyspepsia, gastroesophageal reflux disease, flatulence, abdominal distension

General Disorders — fatigue, peripheral edema, irritability, pyrexia

Infections — urinary tract infection, cystitis

Injury, Poisoning, and Procedural Complications — contusion, fall

Investigations — weight decreased or increased

Metabolism and Nutrition Disorders — hypercholesterolemia

Nervous System Disorders — somnolence, dysgeusia

Psychiatric Disorders — depression, stress

Skin Disorders — night sweats

6.7 Postmarketing Spontaneous Reports

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

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, neuroleptic malignant syndrome, Parkinsonism, serotonin syndrome

Psychiatric Disorders — delirium, hallucination

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 (12.4)].

7.1 Monoamine Oxidase Inhibitors

[See Contraindications (4.1)]

7.2 Serotonergic Drugs

Due to the mechanism of action of SNRIs and SSRIs, including Savella, and the potential for serotonin syndrome or Neuroleptic Malignant Syndrome (NMS) – like reactions, caution is advised when Savella is co-administered with other drugs that may affect the serotonergic neurotransmitter systems. This includes drugs such as triptans, lithium, tryptophan, antipsychotics and dopamine antagonists.

Co-administration of Savella with other inhibitors of serotonin re-uptake may result in hypertension and coronary artery vasoconstriction, through additive serotonergic effects. Concomitant use of Savella with other SSRIs, SNRIs, or tryptophan is not recommended [see 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 – Effects on Blood Pressure (5.3) and Effects on Heart Rate (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

Milnacipran increased the incidence of dead fetuses in utero in rats at doses of 5 mg/kg/day (0.25 times the MRHD on a mg/m2 basis). Administration of milnacipran to mice and rabbits during the period of organogenesis did not result in embryotoxicity or teratogenicity at doses up to 125 mg/kg/day in mice (3 times the maximum recommended human dose [MRHD] of 200 mg/day on a mg/m2 basis) and up to 60 mg/kg/day in rabbits (6 times the MRHD of 200 mg/day on a mg m2 basis). In rabbits, the incidence of the skeletal variation, extra single rib, was increased following administration of milnacipran at 15 mg/kg/day during the period of organogenesis.

There are no adequate and well-controlled studies in pregnant women. Savella should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

To provide information regarding the exposure to Savella during pregnancy, 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 registries@kendle.com . Data forms may also be downloaded from the registry website at www.savellapregnancyregistry.com .

Nonteratogenic Effects

Neonates exposed to dual reuptake inhibitors of serotonin and norepinephrine, or selective serotonin reuptake inhibitors late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included 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) ].

In rats, a decrease in pup body weight and viability on postpartum day 4 were observed when milnacipran, at a dose of 5 mg/kg/day (approximately 0.2 times the MRHD on a mg/m2 basis), was administered orally to rats during late gestation. 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).

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2024. All Rights Reserved.