Savella (Page 6 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Dietary administration of milnacipran to rats at doses of 50 mg/kg/day (2 times the MRHD on a mg/m2 basis) for 2 years caused a statistically significant increase in the incidence of thyroid C-cell adenomas and combined adenomas and carcinomas in males. A carcinogenicity study was conducted in Tg.rasH2 mice for 6 months at oral gavage doses of up to 125 mg/kg/day.

Milnacipran did not induce tumors in Tg.rasH2 mice at any dose tested.

Mutagenesis

Milnacipran was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test) or in the L5178Y TK +/- mouse lymphoma forward mutation assay. Milnacipran was also not clastogenic in an in vitro chromosomal aberration test in human lymphocytes or in the in vivo mouse micronucleus assay.

Impairment of Fertility

Although administration of milnacipran to male and female rats had no statistically significant effect on mating or fertility at doses up to 80 mg/kg/day (4 times the MRHD on an mg/m2 basis), there was an apparent dose-related decrease in the fertility index at clinically relevant doses based on body surface area.

13.2 Animal Toxicology and/or Pharmacology

Hepatic Effects

Chronic administration (2 years) of milnacipran to rats at 15 mg/kg (0.6 times the MRHD on an mg/m2 basis) and higher doses showed increased incidences of centrilobular vacuolation of the liver in male rats and eosinophilic foci in male and female rats in the absence of any change in hepatic enzymes. The clinical significance of the finding is not known. Chronic (1 year) administration in the primate at doses up to 25 mg/kg (2 times the MRHD on a mg/m2 basis) did not demonstrate similar evidence of hepatic changes.

Ocular Effects

Chronic (2 years) administration of milnacipran to rats at 15 mg/kg (0.6 times the MRHD on a mg/m2 basis) and higher doses showed increased incidence of keratitis of the eye. One-year studies in the rat and primate did not show this response.

14 CLINICAL STUDIES

Management of Fibromyalgia

The efficacy of Savella for the management of fibromyalgia was established in two double-blind, placebo-controlled, multicenter studies in adult patients (18-74 years of age). Enrolled patients met the American College of Rheumatology (ACR) criteria for fibromyalgia (a history of widespread pain for 3 months and pain present at 11 or more of the 18 specific tender point sites). Approximately 35% of patients had a history of depression. Study 1 was six months in duration and Study 2 was three months in duration.

A larger proportion of patients treated with Savella than with placebo experienced a simultaneous reduction in pain from baseline of at least 30% (VAS) and also rated themselves as much improved or very much improved based on the patient global assessment (PGIC). In addition, a larger proportion of patients treated with Savella met the criteria for treatment response, as measured by the composite endpoint that concurrently evaluated improvement in pain (VAS), physical function (SF-36 PCS), and patient global assessment (PGIC), in fibromyalgia as compared to placebo.

Study 1: This 6-month study compared total daily doses of Savella 100 mg and 200 mg to placebo. Patients were enrolled with a minimum mean baseline pain score of ≥ 50 mm on a 100 mm visual analog scale (VAS) ranging from 0 (“no pain”) to 100 (“worst possible pain”). The mean baseline pain score in this trial was 69. The efficacy results for Study 1 are summarized in Figure 1.

Figure 1 shows the proportion of patients achieving various degrees of improvement in pain from baseline to the 3-month time point and who concurrently rated themselves globally improved (PGIC score of 1 or 2). Patients who did not complete the 3-month assessment were assigned 0% improvement. More patients in the Savella treatment arms experienced at least a 30% reduction in pain from baseline (VAS) and considered themselves globally improved (PGIC) than did patients in the placebo arm. Treatment with Savella 200 mg/day did not confer greater benefit than treatment with Savella 100 mg/day.

Figure 1: Patients Achieving Various Levels of Pain Relief with Concurrent Ratings of Being Much or Very Much Improved on the PGIC — Study 1

Figure 1
(click image for full-size original)

Study 2: This 3-month study compared total daily doses of Savella 100 mg and 200 mg to placebo. Patients were enrolled with a minimum mean baseline pain score of ≥ 40 mm on a 100-mm VAS ranging from 0 (“no pain”) to 100 (“worst possible pain”). The mean baseline pain score in this trial was 65. The efficacy results for Study 2 are summarized in Figure 2.

Figure 2 shows the proportion of patients achieving various degrees of improvement in pain from baseline to the 3-month time point and who concurrently rated themselves globally improved (PGIC score of 1 or 2). Patients who did not complete the 3-month assessment were assigned 0% improvement. More patients in the Savella treatment arms experienced at least a 30% reduction in pain from baseline (VAS) and considered themselves globally improved (PGIC) than did patients in the placebo arm. Treatment with Savella 200 mg/day did not confer greater benefit than treatment with Savella 100 mg/day.

Figure 2: Patients Achieving Various Levels of Pain Relief with Concurrent Ratings of Being Much or Very Much Improved on the PGIC — Study 2

Figure 2
(click image for full-size original)

In both studies, some patients who rated themselves as globally “much” or “very much” improved experienced a decrease in pain as early as week 1 of treatment with a stable dose of Savella that persisted throughout these studies.

16 HOW SUPPLIED/STORAGE AND HANDLING

Product: 50436-9993

NDC: 50436-9993-2 60 TABLET, FILM COATED in a BOTTLE

17 PATIENT COUNSELING INFORMATION

See Medication Guide

Information for Patients

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Savella and should counsel them in its appropriate use. A patient Medication Guide is available for Savella. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Savella:

Clinical Worsening and Suicide Risk

Patients and their families and caregivers should be advised that Savella is a selective norepinephrine and serotonin reuptake inhibitor and therefore belongs to the same class of drugs as antidepressants. Patients, their families, and their caregivers should be advised that patients with depression may be at increased risk for clinical worsening and/or suicidal ideation if they stop taking anti-depressant medication, change the dose, or start a new medication.

Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, or other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during treatment with Savella or other drugs that inhibit the reuptake of norepinephrine and/or serotonin, and when the dose is adjusted up or down. Families and caregivers of patients should be advised to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms [see Boxed Warning and Warnings and Precautions (5.1)].

Serotonin Syndrome

Patients should be cautioned about the risk of serotonin syndrome with concomitant use of Savella with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines and St. John’s Wort, and with drugs that impair metabolism of serotonin (in particular MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid) [see Warnings and Precautions (5.2)].

Patients should be advised of the signs and symptoms associated with serotonin syndrome that may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be cautioned to seek medical care immediately if they experience these symptoms.

Elevated Blood Pressure and Heart Rate

Patients should be advised that Savella may increase their blood pressure and heart rate and that they should have their blood pressure and heart rate monitored at regular intervals when receiving treatment with Savella [see Warnings and Precautions (5.3, 5.4)].

Abnormal Bleeding

Patients should be cautioned about the concomitant use of Savella and NSAIDs, aspirin, or other drugs that affect coagulation, since the combined use of agents that interfere with serotonin reuptake and these agents has been associated with an increased risk of abnormal bleeding [see Warnings and Precautions (5.9)].

Angle Closure Glaucoma

Patients should be advised that taking Savella can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible [see Warnings and Precautions (5.12)].

Ability to Drive and Use Machinery

Savella might diminish mental and physical capacities necessary to perform certain tasks such as operating machinery, including motor vehicles. Patients should be cautioned about operating machinery or driving motor vehicles until they are reasonably certain that Savella treatment does not affect their ability to engage in such activities.

Alcohol

Patients should talk to their healthcare provider about their alcohol intake prior to initiating treatment with Savella [see Warnings and Precautions (5.6, 5.13)].

Discontinuation

Patients should be advised that withdrawal symptoms can occur when discontinuing treatment with Savella, particularly when discontinuation is abrupt [see Warnings and Precautions (5.7)].

Missing a Dose

Patients should be advised that if they miss a dose, they should skip the missed dose and take the next dose at their regular time.

Pregnancy

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during Savella therapy [see Use in Specific Populations (8.1)].

Patients should be encouraged to enroll in the Savella Pregnancy Registry if they become pregnant, preferably before any prenatal testing is done. This registry is collecting information about the safety of milnacipran during pregnancy. To enroll, patients or their healthcare providers may call the toll-free number 1-877-643-3010 [see Use In Specific Populations (8.1)] , download data forms from our website, www.savellapregnancyregistry.com, or email the registry for further information at pregnancyregistries@incresearch.com.

Nursing

Advise patients to notify their physician if they are breast feeding [see Use in Specific Populations (8.3)].

FDA-Approved Medication Guide

MEDICATION GUIDE

Savella ® (Sa-vel-la)

(milnacipran HCl)

Tablets

Savella is not used to treat depression, but it acts like medicines that are used to treat depression (antidepressants) and other psychiatric disorders.

Read the Medication Guide that comes with Savella® before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. Talk with your healthcare provider if there is something you do not understand or want to learn more about.

What is the most important information I should know about Savella?

Savella and antidepressant medicines may cause serious side effects, including:

  1. Suicidal thoughts or actions:
    • Savella and antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment or when the dose is changed.
    • Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions. Watch for these changes and call your healthcare provider right away if you notice:
      • New or sudden changes, in mood, behavior, thoughts, or feelings, especially if severe.
      • Pay particular attention to such changes when Savella is started or when the dose is changed.
      • Keep all follow-up visits with your healthcare provider and call between visits if you are worried about symptoms.

      Call your healthcare provider right away or go to the nearest hospital emergency room if you have any of the following symptoms, especially if they are new, worse, or worry you:

    • attempts to commit suicide
    • acting on dangerous impulses
    • acting aggressive, being angry, or violent
    • thoughts about suicide or dying
    • new or worse depression
    • new or worse anxiety or panic attacks
    • feeling agitated, restless, angry or irritable
    • trouble sleeping (insomnia)
    • an increase in activity or talking more than what is normal for you
    • other unusual changes in behavior or mood

    Call your healthcare provider right away or go to the nearest hospital emergency room if you have any symptoms of the serious side effects listed below:

  2. Serotonin Syndrome. This condition can be life-threatening, symptoms may include:
    • agitation, hallucinations, coma or other changes in mental status
    • coordination problems or muscle twitching (overactive reflexes)
    • sweating or fever
    • diarrhea
    • muscle rigidity
    • dizziness
    • tremor

    Symptoms such as racing heartbeat, high or low blood pressure, nausea, vomiting, and flushing are common with Savella. Call your healthcare provider right away if you get these symptoms and they are severe or if they happen with any of the symptoms of serotonin syndrome listed above.

  3. Increase in blood pressure or heart rate: Savella may increase your blood pressure or heart rate. Your blood pressure and heart rate should be checked before you start and during treatment with Savella. Before taking Savella, tell your healthcare provider if you have high blood pressure or problems with your heart or blood vessels (cardiovascular disease).
  4. Seizures or convulsions.
  5. Liver problems. Symptoms of liver problems may include:
    • itching
    • right upper abdominal pain
    • dark urine
    • yellowing of your skin or eyes
    • enlarged liver
    • increased liver enzymes
  6. Low salt (sodium) levels in the blood. Elderly people may be at greater risk for this. Symptoms may include:
    • headache
    • weakness or feeling unsteady
    • confusion, problems concentrating or thinking or memory problems
  7. Abnormal bleeding: Savella and other similar medicines (antidepressants) may increase your risk of bleeding or bruising, especially if you take the blood thinner warfarin (Coumadin, Jantoven), a nonsteroidal anti-inflammatory drug (NSAID), or aspirin.
  8. Manic episodes
    • greatly increased energy
    • severe trouble sleeping
    • racing thoughts
    • reckless behavior
    • unusually grand ideas
    • excessive happiness or irritability
    • talking more or faster than usual
  9. Problems with urination
    • decreased urine flow
    • unable to pass any urine
      Men may be more likely to have these symptoms, and may develop pain in their testicles or have problems with ejaculation.
  10. Visual problems
    • eye pain
    • changes in vision
    • swelling or redness in or around eye

    Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are.

Do not stop Savella without first talking to your healthcare provider. Stopping Savella too quickly may cause symptoms, some serious, including:

  • anxiety, irritability, or confusion
  • feeling tired or problems sleeping
  • headache, dizziness, seizures
  • electric shock-like sensations, ringing in ears

What is Savella?

Savella is a prescription medicine used to manage fibromyalgia. It is important to talk with your healthcare provider about the risks of treating fibromyalgia and also the risks of not treating it. You should discuss all treatment choices with your healthcare provider.

It is not known if Savella is safe and effective in children.

Who should not take Savella?

Do not take Savella if you:

  • take a Monoamine Oxidase Inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid.
    • Do not take an MAOI within 5 days of stopping Savella unless your healthcare provider tells you to.
    • Do not start Savella if you stopped taking an MAOI in the last 14 days unless your healthcare provider tells you to.
    • People who take Savella close in time to an MAOI may have serious or even life-threatening side effects. Get medical help right away if you have any of these symptoms:
      • high fever
      • uncontrolled muscle spasms
      • stiff muscles
      • rapid changes in heart rate or blood pressure
      • confusion
      • loss of consciousness (pass out)

What should I tell my healthcare provider before taking Savella?

Before starting Savella, tell your healthcare provider if you:

  • have heart problems or high blood pressure
  • have liver problems
  • have kidney problems
  • have or had seizures or convulsions
  • have bipolar disorder or mania
  • have low sodium levels in your blood
  • have or had bleeding problems
  • drink alcohol. Talk to your healthcare provider about how often and how much alcohol you drink.
  • have any other medical conditions
  • are pregnant or plan to become pregnant. It is not known if Savella will harm your unborn baby.
    Pregnancy registry: There is a pregnancy registry for women who take Savella during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. You may talk to your healthcare provider about how you can take part in this registry, or you may call the Registry directly at 1-877-643-3010 or go to www.savellapregnancyregistry.com.
  • are breastfeeding or plan to breastfeed. Savella can pass into your breast milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby while taking Savella.

Tell your healthcare provider about all the medicines that you take, including prescription and over-the counter medicines, vitamins, and herbal supplements. Savella and some medicines may interact with each other, may not work as well, or may cause serious side effects when taken together.

Your healthcare provider or pharmacist can tell you if it is safe to take Savella with your other medicines. Do not start or stop any medicine while taking Savella without talking to your healthcare provider first.

How should I take Savella?

  • Take Savella exactly as your healthcare provider tells you.
  • Your healthcare provider will slowly increase your dose to find the dose that is right for you.
    • On the first day of treatment, you will take 1 dose of Savella as prescribed.
    • After your first dose, your healthcare provider will tell you how much Savella to take and when to take it, usually 2 times each day.
  • You may take Savella with or without food. Taking Savella with food may help you tolerate it better.
  • If you miss a dose, skip the missed dose and take the next dose at your regular time.
  • Tell your healthcare provider if you feel that your condition is not improving during treatment with Savella.
  • If you take too much Savella, call your healthcare provider or go to the nearest hospital emergency room right away.

What should I avoid while taking Savella?

  • Do not drive or operate machinery until you know how Savella affects you. Savella may make you less alert and affect your reaction time.

What are the possible side effects of Savella?

Savella may cause side effects, some serious, including:

The most common side effects of Savella include:

  • nausea
  • headache
  • constipation
  • dizziness
  • trouble sleeping
  • hot flush
  • increased sweating
  • vomiting
  • irregular heartbeat (palpitations)
  • heart rate increased
  • dry mouth
  • high blood pressure (hypertension)

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Savella. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Savella?

  • Store at room temperature between 68°F to 77°F (20°C to 25°C).

Keep Savella and all medicines out of the reach of children.

General information about the safe and effective use of Savella

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Savella for a condition for which it was not prescribed. Do not give Savella to other people, even if they have the same condition. It may harm them.

You may ask your healthcare provider or pharmacist for information about Savella that is written for health professionals.

For more information call 1-800-678-1605 or go to www.savella.com.

What are the ingredients in Savella?

Active ingredient: milnacipran hydrochloride

Inactive ingredients: dibasic calcium phosphate, povidone, carboxymethylcellulose calcium, colloidal silicon dioxide, magnesium stearate, and talc.

The film coat contains the inactive ingredients:

12.5 mg tablets: FD&C Blue #2 Aluminum Lake, polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide

25 mg tablets: Polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide

50 mg tablets: Polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide

100 mg tablets: FD&C Red #40 Aluminum Lake, polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Distributed by:
Allergan USA, Inc.
Irvine, CA 92612

Revised: August 2016

Licensed from Pierre Fabre Medicament

SAVELLA® is a registered trademark of Allergan Pharmaceuticals International Limited

© 2016 Allergan. All rights reserved.

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