Consumer medicine information

Joncia

Milnacipran hydrochloride

BRAND INFORMATION

Brand name

Joncia

Active ingredient

Milnacipran hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Joncia.

What is in this leaflet

This leaflet answers some common questions about Joncia®.

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of you taking Joncia® against the benefits this medicine is expected to have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Joncia® is used for

Joncia® is used to manage fibromyalgia.

Fibromyalgia is a health problem involving muscle and joint pain, tenderness, tiredness, sleep problems and a number of symptoms such as morning stiffness, mood disturbances and cognition problems.

Joncia® is a kind of medicine called a serotonin-noradrenaline reuptake inhibitor which has the ability to increase the levels of the biochemicals, serotonin and noradrenaline thereby improving the problems experienced with fibromyalgia syndrome.

Your doctor may have prescribed Joncia® for another purpose.

Ask your doctor if you have any questions about why Joncia® has been prescribed for you.

This medicine is available only on a doctor’s prescription.

Before you take Joncia®

When you must not take it

You must not take Joncia® if you are taking medicine to treat depression. Joncia® is not used to treat depression, but it acts like medicines that are used to treat depression (antidepressants) and other psychiatric disorders. If you are taking medicine to treat another psychiatric disorder you should discuss this with your doctor before you take Joncia®.

If you take Joncia® with medicines to treat depression, the potentially life-threatening condition of serotonin syndrome may occur. Serotonin syndrome may include agitation, hallucinations, coma, changes in blood pressure, fast heart rate, increased body temperature, incoordination, nausea and vomiting.

Do not take Joncia® if you have an allergy to Joncia® or any of the ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not take Joncia® if you have severe problems with your heart, a high risk of serious arrhythmia (changes in the rate or rhythm of your heart beat), uncontrolled high blood pressure or severe or unstable heart disease. Joncia® can increase blood pressure and heart rate which may make your condition worse.

Do not take Joncia® if you have glaucoma.

Do not take Joncia® if you are having injections of adrenaline (epinephrine) or noradrenaline (noradrenaline). Taking milnacipran with this kind of medicine may cause high blood pressure and possibly change the rhythm or rate of your heart beat.

Ask your doctor or pharmacist if you are not sure if you have been taking or have been given one of these medicines.

Do not take Joncia® if you are breastfeeding. Small amounts of the active ingredient in Joncia® may pass into breast milk and therefore there is a possibility that the breast-fed baby may be affected.

Do not take Joncia® after the expiry date printed on the pack. The expiry date refers to the last day of that month. If you take this medicine after the expiry date has passed, it may not work as well.

Do not take Joncia® if the packaging is torn or shows signs of tampering. If your medicine has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking Joncia®, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any medical conditions, especially the following:

  • kidney disease;
  • liver disease;
  • glaucoma or high pressure of the fluids inside your eye;
  • an enlarged prostate or difficulty urinating;
  • epilepsy (fits or convulsions) or a history of epilepsy;
  • high blood pressure or heart disease;
  • bleeding problems;

Tell your doctor if you suffer from depression or have or have had suicidal thoughts. Symptoms of depression may include thoughts of harming yourself or committing suicide. It is the experience with depression that these suicidal thoughts or actions may increase in the early stages of recovering from your depression. Joncia® has anti-depressant effects, although it is not used to treat depression. Therefore, during the first few weeks or more of treatment with Joncia®, thoughts of suicide may get worse.

You should tell your doctor if you suffer from depression or have or have had suicidal thoughts so that you will receive careful monitoring during your treatment with Joncia®.

Tell your doctor if you are pregnant or intend to become pregnant. It is not recommended to take Joncia® if you are a woman of childbearing potential not using contraception and during pregnancy. If you discover that you are pregnant during treatment, tell your doctor. Your doctor will discuss the risks and benefits of using Joncia® when pregnant and decide whether or not treatment should be continued.

Tell your doctor if you drink a lot of alcohol.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and Joncia® may interfere with each other. These include:

  • MAO inhibitors, medicines used to treat depression;
  • serotonin reuptake inhibitors, medicines used to treat depression;
  • St John’s wort (Hypericum perforatum), a herbal product used to treat depression;
  • Strong pain killers such as tramadol or pethidine;
  • injections of adrenaline (epinephrine) or noradrenaline (norepinephrine);
  • digoxin, a medicine used to treat heart failure;
  • clonidine, a medicine used to treat high blood pressure;
  • medicines used to treat migraine belonging to a group known as triptans eg. sumatriptan;
  • medicines which have an effect on blood clotting such as NSAIDS and aspirin, or other medicines that may increase the risk of bleeding;
  • some medicines used to treat Parkinson’s disease.
  • medicines which affect the central nervous system.
  • diuretics, medicines used to treat swelling of the ankles, feet or legs or high blood pressure.
  • lithium, a medicine used to treat mood swings and some types of depression.
  • antipsychotic medicines, used to treat certain mental and emotional conditions.
  • dopamine agonists, medicines typically used for treating Parkinson’s disease.
  • tryptophan, an amino acid found in protein-based foods which can increase the levels of serotonin in the brain.

These medicines may be affected by Joncia®, or may affect how well it works. You may need to take different amounts of your medicine, or you may need to take different medicines. Your doctor or pharmacist will advise you.

Your doctor and pharmacist have more information on medicines to be careful with or to avoid while taking Joncia®.

Avoid drinking alcohol or taking medicines which contain alcohol while taking Joncia®. Alcohol may interfere with the way Joncia® works or how well it works.

If you are 65 years or older, you should be especially careful while taking Joncia®. Report any side effects promptly to your doctor. As people grow older, they are more likely to get side effects from medicines.

The safety and effectiveness of Joncia® in children and adolescents under the age of 18 years have not been established. Use in children and adolescents aged under 18 years is not recommended.

If you have not told your doctor or pharmacist about any of the above, tell them before you start taking Joncia®.

How to take Joncia®

Take Joncia® exactly as your doctor has prescribed.

How much to take

Your doctor will decide what dose you will receive.

Your treatment with Joncia® has to be started gradually. Your doctor will prescribe a dosage schedule for the start of your treatment.

After this initiation period, the usual dose is one 50 mg capsule in the morning and one 50 mg capsule in the evening, preferably during meals.

Your doctor may prescribe a different dosing schedule and/or dose if you have problems with your kidneys.

If you feel that Joncia® is not having enough of an effect or is having too strong an effect, talk to your doctor or pharmacist.

Follow all directions given to you by your doctor and pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box or bottle, ask your doctor or pharmacist for help.

How to take it

Swallow Joncia® with a glass of water preferably during meals.

How long to take it

Continue taking your medicine for as long as your doctor tells you. Treatment will usually last for several months.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to. Otherwise, take it as soon as you remember, then go back to taking it as you would normally.

Do not double a dose to make up for the dose you have missed.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints

If you take too much (overdose)

Immediately contact your doctor or the Poisons Information Centre (In Australia telephone 131 126. In New Zealand telephone 0800 764 766) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Joncia®. You may need urgent medical attention.

If you stop taking it

Do not stop taking Joncia® without the advice of your doctor even if you feel better. If your doctor decides that you no longer need to take Joncia®, your doctor will reduce your dose gradually over a period of no less than two weeks before stopping treatment altogether. Suddenly stopping Joncia® may lead to headache, dizziness, sleepiness, diarrhoea, vomiting, anxiety disorders and pain (withdrawal symptoms).

While you are taking Joncia®

Things you must do

You must tell your doctor if you are experiencing any distressing thoughts or feelings at any time while you are taking Joncia®.

If you are suffering from depression, you must tell your doctor immediately if you feel that your depression is getting worse or if you are having suicidal feelings or thoughts of harming yourself while you are taking Joncia®.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Joncia®.

Tell any other doctors, dentists and pharmacists who treat you that you are taking Joncia®.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking Joncia®.

If you become pregnant while taking Joncia®, tell your doctor immediately.

Things you must not do

Do not stop taking Joncia® without the advice of your doctor. Suddenly stopping Joncia® may cause withdrawal symptoms.

Do not give this medicine to anyone else, even if their symptoms seem similar to yours or if they have the same condition as you.

Do not take Joncia® to treat any other complaints unless your doctor tells you to.

Things to be careful of

Be careful driving or operating machinery until you know how Joncia® affects you. Joncia® may reduce physical ability and alertness in some people.

Side effects

Tell your doctor as soon as possible if you do not feel well while you are taking Joncia®.

Like other medicines, Joncia® can cause some side effects. If they occur, most are likely to be minor and temporary. However, some may be serious and need medical attention.

Do not be alarmed by the following list of possible side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

  • headache
  • nausea
  • constipation
  • excessive sweating
  • hot flushes
  • loss of appetite
  • weight loss
  • agitation
  • anxiety
  • depression
  • problems sleeping
  • dizziness
  • migraine
  • shaking or tremor
  • change in taste
  • increase in skin sensitivity
  • stomach pain or discomfort
  • diarrhoea
  • dry mouth
  • indigestion
  • vomiting
  • itching, rash
  • muscle ache, pain or tenderness
  • pain passing urine
  • problems with erection, ejaculation or pain in the testicles
  • fatigue
  • memory problems
  • palpitations (fast or irregular heart beat)
  • fast heart rate
  • high blood pressure
  • chest pain
  • swelling

These are the more common side effects of Joncia®.

Tell your doctor immediately if you have any suicidal thoughts or other mental/mood changes.

Contact your doctor or mental health professional immediately or go to the nearest hospital for treatment if you or someone you know is showing any of the following warning signs of suicide:

  • worsening of your anxiety or depression;
  • thoughts or talk of death or suicide;
  • thoughts or talk of self-harm or harm to others;
  • any recent attempts of self-harm or suicide;
  • an extreme increase in activity and talking (mania);
  • increase in agitation or restlessness;
  • panic attacks;
  • increase in aggressive behavior, irritability or any other unusual changes in behavior or mood.

All mentions of suicide or violence must be taken seriously.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • difficulty breathing
  • chest pain
  • palpitations, fast or irregular heart beat
  • rash, itching or hives on the skin
  • swelling of the feet and ankles, face, lips, tongue or other parts of the body.
  • severe agitation, confusion, hallucinations, inability to walk, fainting or seizure.

These are very serious side effects. You may need urgent medical attention or hospitalisation. Serious side effects are rare.

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice anything else that is making you feel unwell.

After using Joncia®

Storage

Your Joncia® capsules both in the blister pack or in the bottle, should be stored in a dry place where the temperature stays below 30°C.

Keep your capsules in their original pack/container until it is time to take them.

Do not store Joncia® or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car Heat and dampness can destroy some medicines.

Keep this medicine where young children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking Joncia®, or the capsules have passed their expiry date, ask your pharmacist what to do with any capsules left over.

Product description

What it looks like

The 25 mg capsules are yellow and white with “PFM 25” imprinted in black.

The 50 mg capsules are orange and white with “PFM 50” imprinted in black.

The 100 mg capsules are orange and yellow with “PFM 100” imprinted in black.

The 25, 50 and 100 mg capsules are supplied in blister packs of 14, 28, or 56 capsules.

Ingredients

Active ingredient:

  • milnacipran hydrochloride

Other ingredients:

  • calcium hydrogen phosphate dihydrate
  • carmellose calcium
  • povidone K30
  • Hydrophobic colloidal silica anhydrous
  • magnesium stearate
  • purified talc

The capsule shell for the 25 mg and 100 mg strengths contain:

  • titanium dioxide (E171)
  • quinoline yellow (E104)
  • sunset yellow FCF (E110)
  • gelatin

The capsule shell for the 50 mg strength contains:

  • titanium dioxide (E171)
  • sunset yellow FCF (E110)
  • gelatin

The capsules are marked with the food grade inks

  • OPACODE monogramming ink S-1-27794 BLACK
  • Opacode monogramming ink S-1-27797 Black
  • TekPrint SW-9008 Black Ink

Distributor

Joncia® is supplied in Australia by:

Pierre Fabre Australia Pty Limited
Suite 901, 1 Elizabeth
Plaza, North Sydney,
NSW 2060

Australian Registration Number:

25 mg: AUST R 176508
50 mg: AUST R 176513
100 mg: AUST R 176515

This leaflet was prepared in November 2011 and updated in January 2020

Published by MIMS April 2020

BRAND INFORMATION

Brand name

Joncia

Active ingredient

Milnacipran hydrochloride

Schedule

S4

 

1 Name of Medicine

Milnacipran hydrochloride.

2 Qualitative and Quantitative Composition

The milnacipran hydrochloride drug product is presented in an immediate-release hard capsule containing 25, 50 and 100 mg of milnacipran hydrochloride.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

25 mg hard capsule.

Yellow cap with "PFM" imprinted in black, white body with "25" imprinted in black.

50 mg hard capsule.

Orange cap with "PFM" imprinted in black, white body with "50" imprinted in black.

100 mg hard capsule.

Orange cap with "PFM" imprinted in black, yellow body with "100" imprinted in black.

4 Clinical Particulars

4.1 Therapeutic Indications

Management of fibromyalgia.

4.2 Dose and Method of Administration

Joncia capsules are for oral use.
The recommended dose is 100 mg per day in two divided doses (morning and evening, preferably during meals).
Based on efficacy and tolerability dosing may be titrated according to the following schedule.
Day 1 - Day 2: 25 mg once daily (in the evening).
Day 3 - Day 7: 50 mg daily in two divided doses (25 mg morning and 25 mg evening).
After Day 7: 100 mg daily in two divided doses (50 mg morning and 50 mg evening).
Based on individual patient response, the dose may be increased to 200 mg/day (100 mg twice daily). Doses above 200 mg/day have not been studied.
After an initial 12 week period patients should be assessed and those with little or no benefit should discontinue treatment. In patients with apparent benefit, consideration should be given to periodically reassessing the need for ongoing treatment.
Joncia should be tapered and not abruptly discontinued after extended use (see Section 4.4 Special Warnings and Precautions for Use, Discontinuation of treatment).

Use in patients with renal insufficiency.

No dosage adjustment is necessary for patients with Chronic Kidney Disease (CKD) stage 2. Joncia should be used with caution in patients with CKD stage 3 (estimated GFR 30 - 59 mL/min/1.73 m2) and CKD stage 4 (estimated GFR 15 - 29 mL/min/1.73 m2) at a maximum dose of 50 mg/day.
Joncia should not be given to patients with CKD stage 5.

Use in patients with hepatic impairment.

No dosage adjustment is necessary for patients with hepatic impairment (see Section 5.2 Pharmacokinetic Properties, Special populations).
Joncia should ordinarily not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease (see Section 4.4 Special Warnings and Precautions for Use).

Use in the elderly (over 65 years of age).

Dosage adjustment is not necessary in the elderly unless renal function is reduced to values for which a dose adjustment is recommended (see Section 5.2 Pharmacokinetic Properties, Special populations).

Use in children and adolescents (< 18 years).

The safety and effectiveness of milnacipran has not been established in patients below the age of 18 years.

Discontinuation of treatment.

Abrupt discontinuation of treatment with milnacipran should be avoided. When stopping treatment, the dose should be gradually reduced over a period of no less than two weeks in order to reduce the risk of withdrawal reactions (see Section 4.4 Special Warnings and Precautions for Use, Discontinuation of treatment; Section 4.8 Adverse Effects (Undesirable Effects)).

4.3 Contraindications

Joncia should never be given in the following cases:
Hypersensitivity to the active substance or to any of the excipients.
Patients with severe cardiac function impairment or identified very high risk of a serious cardiac arrhythmia (e.g. those with a significant left ventricular dysfunction, NYHA Class III/IV), uncontrolled hypertension, or severe or unstable coronary heart disease, as these underlying conditions may be compromised by increases in blood pressure and heart rate.
Patients with uncontrolled narrow angle glaucoma.
Co-administration with MAO inhibitors (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Co-administration with other serotonin reuptake inhibitors (selective serotonin reuptake inhibitors (SSRI), serotonin-noradrenaline reuptake inhibitors (SNRI), tramadol, pethidine and Hypericum perforatum (St. John's Wort), serotonin precursor (tryptophan), or tricyclics (such as clomipramine and amitriptyline) (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Co-administration with adrenaline (epinephrine) and noradrenaline (norepinephrine) (alpha and beta sympathomimetics) (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Breastfeeding.

4.4 Special Warnings and Precautions for Use

Joncia should be prescribed with caution in the following cases:
in patients with severe renal impairment: dosage may have to be reduced because of prolongation of elimination half-life;
in patients with high intra-ocular pressure or at risk of narrow-angle glaucoma;
in patients with prostatic hypertrophy or other lower urinary tract obstructive disorders;
in patients with epilepsy or with a history of epilepsy, Joncia should be used with caution and should be discontinued in any patient developing a seizure. Seizures have been reported in patients taking milnacipran;
in patients treated with other CNS acting drugs.

Blood pressure and heart rate.

In the placebo-controlled trials, among fibromyalgia patients who were non-hypertensive at baseline, approximately twice as many patients in the Joncia treatment arms became hypertensive at the end of the study (SBP ≥ 140 mmHg or DBP ≥ 90 mmHg) compared with the placebo patients: 7.2% of patients in the placebo arm versus 19.5% of patients treated with Joncia 100 mg/day and 16.6% of patients treated with Joncia 200 mg/day. Among patients who met systolic criteria for pre-hypertension at baseline (SBP 120 - 139 mmHg), more patients became hypertensive at the end of the study in the Joncia treatment arms than placebo: 9% of patients in the placebo arm versus 14% in both the Joncia 100 mg/day and the Joncia 200 mg/day treatment arms.
Blood pressure and heart rate monitoring is recommended at treatment initiation, following dosage increases and periodically throughout the treatment with Joncia for all patients and more closely in patients with known cardiovascular risk.
For patients who experience a clinically significant sustained increase in blood pressure or heart rate while receiving Joncia gradual discontinuation should be considered.
Safety of Joncia has not been studied in fibromyalgia patients with a recent history of myocardial infarction or unstable heart disease.

Use with alcohol.

Although there is no evidence of an interaction with alcohol, as with any CNS medication, it is recommended that the use of alcohol while taking Joncia should be avoided.

Hyponatraemia.

Hyponatraemia may occur as a result of treatment with SSRIs and SNRIs, including Joncia. In many cases, this hyponatraemia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 100 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatraemia with SNRIs, SSRIs, or Joncia. Also, patients taking diuretics or other treatments known to induce hyponatraemia, patients who are otherwise volume-depleted, or patients with cirrhosis or malnutrition may be at greater risk. Discontinuation of Joncia should be considered in patients with symptomatic hyponatraemia.
Signs and symptoms of hyponatraemia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest and death.

Bleeding.

Cases of haemorrhages, sometimes serious, have been reported with the use of serotonin re-uptake inhibitors. Caution should be exercised in patients concomitantly treated with oral anticoagulants, drugs which have an effect on platelet function, e.g. NSAIDs and aspirin, or other drugs that may increase the risk of bleeding. Caution is also required in patients with previous bleeding abnormalities.

Depression, suicidal ideation and behaviour.

Milnacipran is a selective serotonin and noradrenaline reuptake inhibitor (SNRI), similar to some medicines used for the treatment of depression and other psychiatric disorders. Antidepressants increased the risk compared to placebo of suicidal thinking and behaviour (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. The risk of suicide attempt is inherent in depression and may persist until significant remission occurs. This risk must be considered in all depressed patients.
Patients with depression may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviours (suicidality) whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored for clinical worsening and suicidality, especially at the beginning of a course of treatment, or at a time of dose changes, either increases or decreases.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the milnacipran, in patients whose depression is persistently worse or whose emergent suicidality is severe, abrupt in onset, or was not part of the patient's presenting symptoms. Patients (and caregivers of patients) should be alerted about the need to monitor for any worsening of their condition and/or the emergence of suicidal ideation/behaviour or thoughts of harming themselves and to seek medical advice immediately if these symptoms present. Patients with co-morbid depression associated with other psychiatric disorders being treated with antidepressants should be similarly observed for clinical worsening and suicidality.
Pooled analyses of 24 short-term (4 to 16 weeks), placebo-controlled trials of nine antidepressant medicines (SSRIs and others) in 4400 children and adolescents with major depressive disorder (16 trials), obsessive compulsive disorder (4 trials) or other psychiatric disorders (4 trials) have revealed a greater risk of adverse events representing suicidal behaviour or thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients treated with an antidepressant was 4% compared with 2% of patients given placebo. There was considerable variation in risk among the antidepressants, but there was a tendency towards an increase for almost all antidepressants studied. The risk of suicidality was most consistently observed in the major depressive disorder trials, but there were signals of risk arising from trials in other psychiatric indications (obsessive compulsive disorder and social anxiety disorder) as well. No suicides occurred in these trials.
It is unknown whether the suicidality risk in children and adolescent patients extends to use beyond several months. The nine antidepressant medications in the pooled analyses included five SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) and four non-SSRIs (bupropion, mirtazapine, nefazodone, venlafaxine).
Symptoms of anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia (psychomotor restlessness), hypomania and mania have been reported in adults, adolescents and children being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either worsening of depression and/or emergence of suicidal impulses has not been established, there is concern that such symptoms may be precursors of emerging suicidality.
Families and caregivers of children and adolescents being treated with antidepressants for major depressive disorder or for any other condition (psychiatric or non-psychiatric) should be informed about the need to monitor these patients for the emergence of agitation, irritability, unusual changes in behaviour and other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. It is particularly important that monitoring be undertaken during the initial few months of antidepressant treatment or at times of dose increase or decrease.
Milnacipran has not been studied in patients under the age of 18 and is not intended for use in this age group. Although a causal role for milnacipran in inducing such events has not been established, some analyses from pooled studies of antidepressants in psychiatric disorders found an increased risk for suicidal ideation and/or suicidal behaviours in paediatric and young adult (< 25 years of age) patients compared to placebo. Physicians should encourage patients to report any distressing thoughts or feelings at any time.

Activation of mania/hypomania.

As with all antidepressants, switches to mania/hypomania have occurred. Close supervision of patients with bipolar disorders is recommended.

Seizure disorders.

In clinical trials evaluating Joncia in patients with fibromyalgia, seizures/convulsions have not been reported. However, seizures have been reported infrequently in patients treated with Joncia for disorders other than fibromyalgia. Joncia should be prescribed with care in patients with a history of a seizure disorder.

Hepatic disorders.

In the placebo-controlled fibromyalgia trials, increases in the number of patients treated with milnacipran with mild elevations of ALT or AST (1-3 times the upper limit of normal, ULN) were observed. Increases in ALT were more frequently observed in the patients treated with milnacipran 100 mg/day (6%) and milnacipran 200 mg/day (7%), compared to the patients treated with placebo (3%). One patient receiving milnacipran 100 mg/day (0.2%) had an increase in ALT greater than 5 times the upper limit of normal but did not exceed 10 times the upper limit of normal. Increases in AST were more frequently observed in the patients treated with milnacipran 100 mg/day (3%) and milnacipran, 200 mg/day (5%) compared to the patients treated with placebo (2%).
The increases of bilirubin observed in the fibromyalgia clinical trials were not clinically significant.
No case met the criteria of elevated ALT > 3x ULN and associated with an increase in bilirubin ≥ 2x ULN.
There have been cases of increased liver enzymes and reports of severe liver injury, including fulminant hepatitis with milnacipran from postmarketing experience. In the cases of severe liver injury there were significant underlying clinical conditions and/or the use of multiple concomitant medications. Because of underreporting, it is impossible to provide an accurate estimate of the true incidence of these reactions. Milnacipran should be discontinued in patients who develop jaundice or other evidence of liver dysfunction. Treatment with milnacipran should not be resumed unless another cause can be established.
Milnacipran should ordinarily not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.

Genitourinary effects.

Because of their noradrenergic effect, SNRIs including Joncia, can affect urethral resistance and micturition. In the controlled fibromyalgia trials, dysuria occurred more frequently in patients treated with Joncia (1%) than in placebo-treated patients (0.5%). Caution is advised in use of Joncia in patients with a history of dysuria, notably in male patients with prostatic hypertrophy, prostatitis, and other lower urinary tract obstructive disorders. Male patients are more prone to genitourinary adverse effects, such as dysuria or urinary retention and may experience testicular pain or ejaculation disorders.

Sexual dysfunction.

Selective serotonin reuptake inhibitors (SSRIs)/serotonin norepinephrine reuptake inhibitors (SNRIs) may cause symptoms of sexual dysfunction (see Section 4.8 Adverse Effects (Undesirable Effects)). There have been reports of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation of SSRIs/SNRI.

Discontinuation of treatment.

The risk of withdrawal reactions when treatment with selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs) is discontinued may be dependent on several factors including the duration and dose of therapy and the rate of dose reduction.
Adverse events seen in clinical trials upon discontinuation of treatment with milnacipran (post-tapering), including potential withdrawal reactions were reported in 20% of patients treated with milnacipran and 17.5% of patients on placebo. The most commonly reported reactions are listed, see Section 4.8 Adverse Effects (Undesirable Effects). Generally the symptoms are mild to moderate, however, in some patients they may be severe in intensity. They usually occur within the first few days of discontinuing treatment, but there have been very rare reports of such symptoms in patients who have inadvertently missed a dose. Generally these symptoms are self-limiting and resolve within two weeks. It is therefore advised that the dose of milnacipran should be gradually tapered when discontinuing treatment over a period of no less than two weeks according to the patient's needs (see Section 4.2 Dose and Method of Administration).

Use in renal impairment.

See Section 4.2 Dose and Method of Administration, Use in patients with renal insufficiency.

Use in the elderly.

See Section 4.2 Dose and Method of Administration, Use in the elderly (over 65 years of age).

Paediatric use.

Safety and effectiveness have not been established. Use in children and adolescents aged < 18 years is not recommended.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Interaction studies have only been performed in adults.

MAO inhibitors.

Milnacipran is contraindicated in combination with MAO inhibitors (see Section 4.3 Contraindications): with non-selective MAO inhibitors and A selective MAO inhibitors there is a risk of a serotoninergic syndrome (*see below); with B selective MAO inhibitors there is a risk of paroxysmal hypertension.
There should be an interval of two weeks between the end of treatment with a MAO inhibitor and the beginning of treatment with milnacipran, and at least one week between the end of treatment with milnacipran and the beginning of treatment with a MAO inhibitor.
* Serotoninergic syndrome: the development of a potentially life-threatening serotonin syndrome may occur with agents that inhibit serotonin reuptake, including milnacipran, particularly with concomitant use of serotoninergic (including triptans) and with drugs which impair metabolism of serotonin (including MAO inhibitors). Serotonin syndrome may include mental changes (such as agitation, hallucinations, coma), autonomic instability (such as tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (such as hyperreflexia, incoordination), and/or gastrointestinal symptoms (such as nausea, vomiting, diarrhoea).

Serotonin reuptake inhibitors.

Milnacipran is contraindicated in combination with other serotonin reuptake inhibitors and any other medicines with the same mechanism of action (see Section 4.3 Contraindications).

Adrenaline (epinephrine) and noradrenaline (norepinephrine).

Milnacipran is contraindicated in combination with adrenaline (epinephrine) and noradrenaline (norepinephrine) (alpha and beta sympathomimetics) (see Section 4.3 Contraindications). There is the risk of paroxysmal hypertension with possible arrhythmia due to inhibition of entry of adrenaline or noradrenaline into the sympathetic nerve fibre.
When haemostatic action by subcutaneous or gingival injection is sought, limit intake, for example, to less than 0.1 mg adrenaline (epinephrine) in 10 minutes or 0.3 mg in an hour in adults.
Milnacipran should be used with caution in combination with the following:
Oral anticoagulants, drugs which have an effect on platelet function, e.g. NSAIDs and aspirin, or other drugs that may increase the risk of bleeding.
Digoxin by the parenteral route due to the risk of potentiation of haemodynamic effects.
Clonidine and related compounds (reported with desipramine and imipramine) due to the risk of inhibition of clonidine's antihypertensive effect due to antagonism of adrenergic receptors.
5-HT1D agonists (triptans) due to the risk of hypertension and coronary artery vasoconstriction by additive serotoninergic effects. There should be an interval of one week between the end of treatment with milnacipran, and the beginning of treatment with 5-HT1D agonists.
Lithium, antipsychotic medications, dopamine agonists and tryptophan. These medicines may increase the incidence of serotonin syndrome or neuroleptic malignant syndrome.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There were no adverse effects on the fertility of rats treated orally with milnacipran at dose levels up to 80 mg/kg/day (about 4-fold the MRHD, based on mg/m2).
(Category B3)
Joncia has not been studied in pregnant women. There was no evidence of teratogenicity in mice or rabbits treated with milnacipran during the period of organogenesis at respective oral doses up to 125 and 60 mg/kg/day (respective exposures 7 and 2 times the clinical exposure at the MRHD, based on AUC).
Neonatal risk after pregnancy exposure with serotonin re-uptake inhibitors have been reported and may be related to either withdrawal syndrome or serotonin toxicity: tachypnea, feeding difficulties, tremors, hypertonicity or hypotonia, sleeping disorders, hyper-excitability or more rarely long lasting crying have been reported. All these signs appear in the first days of life and are generally of short duration.
Consequently, as a precautionary measure, Joncia should not be administered during pregnancy or in women of childbearing potential not using contraception.
 Breast-feeding is contraindicated. Milnacipran and/or its metabolites are excreted in milk in lactating rats. Oral administration of milnacipran to rats from late gestation to weaning was associated with decreased pup survival and development delays at a dose similar to the MRHD (based on mg/m2) or greater. These effects may be due to maternal toxicity observed at these and lower doses.

4.7 Effects on Ability to Drive and Use Machines

Although no alterations in cognitive or psychomotor functions have been observed in healthy volunteers, this medication can reduce mental and physical capacities necessary to perform certain dangerous tasks, such as operating machinery or driving motor vehicles.

4.8 Adverse Effects (Undesirable Effects)

The adverse drug reactions observed in the phase II and III placebo-controlled clinical trials comprising a total of 4203 patients: 2550 on milnacipran (50 mg BID and 100 mg BID) and 1653 on placebo, for a treatment duration of at least 12 weeks are presented in Table 1.
The most commonly reported adverse drug reactions were nausea, headache, constipation, hyperhidrosis and hot flushes.
The majority of the most frequent adverse reactions occurred mainly in the first four weeks of therapy and were mild to moderate in severity. A few adverse reactions which appeared to be dose-related: hyperhidrosis, increased heart rate, insomnia, headache, nausea, vomiting and constipation, were the most frequent adverse reactions leading to discontinuation of therapy. Milnacipran hydrochloride dose reduction can be attempted before treatment discontinuation.
Table 1 presents the most frequent adverse events, whether or not a causal relationship has been suspected.
The following additional adverse drug reactions were reported less frequently during clinical trials in fibromyalgia with a suspected relationship. Common events are defined as those occurring in =1% and < 10% of patients (but only those occurring in =1% and < 2% of patients are listed here), uncommon events are defined as those occurring in =0.1% and < 1% of patients, and rare events are defined as those occurring in < 0.1% of patients and not known (cannot be estimated from the available data).

Immune system disorders.

Uncommon: hypersensitivity.

Metabolism and nutrition disorders.

Uncommon: weight loss.

Psychiatric disorders.

Common: agitation. Uncommon: suicidal ideation, panic attack, confusion, hallucination, nightmares, decreased libido. Not known: aggression.

Nervous system disorders.

Common: memory impairment, tremor, dysaesthesia, dysgeusia, somnolence. Uncommon: syncope. Rare: balance disorder, cerebrovascular accident.

Eye disorders.

Uncommon: dry eye, mydriasis, blurred vision, reduced visual acuity.

Ear and labyrinth disorders.

Uncommon: tinnitus, vertigo.

Cardiac disorders.

Uncommon: arrhythmia, extrasystoles. Rare: acute coronary syndrome, angina pectoris. Not known: Takotsubo cardiomyopathy.

Vascular disorders.

Uncommon: Raynaud's phenomenon, hypotension, orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders.

Uncommon: dyspnoea. Rare: epistaxis.

Gastro-intestinal disorders.

Uncommon: gastritis, stomatitis, haemorrhoids.

Hepatobiliary disorders.

Uncommon: hepatic enzyme increase. Rare: hepatitis.

Skin and subcutaneous tissue disorders.

Uncommon: urticaria. Rare: photosensitivity reaction. Not known: Stevens-Johnson syndrome.

Renal and urinary disorders.

Common: dysuria. Uncommon: pollakiuria, urinary retention.

Reproductive system and breast disorders.

Uncommon: metrorrhagia. Rare: amenorrhoea.

General disorders and administration site conditions.

Uncommon: chills, pyrexia, feeling of body temperature change.
The urinary adverse reactions (e.g. dysuria) mainly occurred in male patients: dysuria was observed in 23.9% of male patients. A monitoring of the micturition disorders is necessary in patients with a history of difficult passage of urine (e.g. prostatic hypertrophy and other lower urinary tract obstructive disorders). However, dysuria and urinary retention were also reported in men without known prostatic disorders.
Other specific adverse drug reactions observed in male patients such as testicular pain, ejaculation disorders and erectile dysfunction were reported in 8.7%, 5.4% and 3.3% of male patients respectively.
As for all SSRI and SNRI active substances, it is advised that when milnacipran hydrochloride treatment is no longer required, gradual discontinuation by dose tapering over period of no less than two weeks should be carried out (see Section 4.4 Special Warnings and Precautions for Use, Discontinuation of treatment). In fibromyalgia clinical trials, the most frequently reported adverse reactions during the post-tapering follow-up phase were headache, dizziness, somnolence, diarrhoea, vomiting, anxiety disorders and pain. The frequency of these adverse reactions when no tapering is performed is unknown.

Post-marketing experience.

Post-marketing reports of adverse reactions from other countries where milnacipran hydrochloride is used for the treatment of major depressive episode are the following (frequency not known):

Metabolism and nutrition disorders.

Hyponatraemia.

Nervous system disorders.

Serotoninergic syndrome (especially when combined with other agents), convulsions (especially in patients with past history of epilepsy).

Vascular disorders.

Ecchymosis and other cutaneous or mucosal bleeding.

Hepatobiliary disorders.

Cytolytic hepatitis.
Other post-marketing adverse reactions reported in depressed patients were related to the depressive illness:
elimination of psychomotor inhibition, with suicidal risk;
mood switch, with episodes of mania;
reactivation of a delusion in psychotic patients;
paroxystic symptoms of anxiety (with psychostimulant antidepressants).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms of overdosage.

Cases of overdose with milnacipran have been observed in patients treated for other indications. With high doses the emetic effect can considerably limit the risk of overdose. With doses of 800 mg to 1 g in single-drug therapy, the main symptoms observed are vomiting, respiratory difficulties (apneic spells) and tachycardia. After a dose of 1.9 g to 2.8 g in combination with other drugs (in particular, benzodiazepines), the following additional symptoms occur: drowsiness, hypercapnia and alterations of consciousness. No cardiac toxicity has been reported. All fatal overdose cases occurred after ingestion of several medications.

Treatment of overdosage.

There is no specific antidote for milnacipran. For all overdoses, the mainstay of treatment is supportive and symptomatic care. Activated charcoal may reduce absorption of the drug if given within one or two hours after ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected. Medical monitoring should be continued for at least 24 hours.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Milnacipran is a balanced, specific, dual reuptake inhibitor of noradrenaline (NA) and serotonin (5-hydroxytryptamine [5-HT]), inhibiting noradrenaline uptake with greater potency than serotonin.
Milnacipran has no appreciable affinity for serotoninergic (5-HT1-7), α- or β-adrenergic, muscarinic (M1-5), histamine (H1-4), dopamine (D1-5), opiate, benzodiazepine and γ-aminobutyric acid-A (GABAA) receptors in vitro. Milnacipran has no significant activity for Ca++, K+, Na+, Cl- channels and does not inhibit the activity of human monoamine oxidases (MAO-A and MAO-B) or of acetylcholinesterase.
In vivo, milnacipran shows antinociceptive activity in some animal models of chronic pain (neuropathic or arthritic models), and demonstrates antidepressant-like effects in nonclinical models of mood disorders (anxiety, depression, cognition).

Clinical trials.

The efficacy of Joncia for the management of fibromyalgia was established in three double-blind, placebo-controlled, multicentre 3-month studies in adult patients (18 to 74 years of age). A total of 3097 patients were randomised in studies: MLN-MD-02, GE 302 and MLN-MD-03. 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 30% of patients had a history of depression. There were no statistically significant differences with respect to demographic or baseline characteristics between the placebo and Joncia treatment groups in the pivotal studies.
A larger proportion of patients treated with Joncia than with placebo experienced a simultaneous reduction in pain from baseline of at least 30% (visual analog scale (VAS)) and also rated themselves as much improved or very much improved based on the patient global assessment (PGIC). (See Table 2.)

Study MLN-MD-02.

More patients in the Joncia 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 Joncia 200 mg/day did not confer greater benefit than treatment with Joncia 100 mg/day.

Study GE 302.

More patients in the Joncia (200 mg/day) treatment arm experienced at least a 30% reduction in pain from baseline (VAS) and considered themselves globally improved (PGIC) than did patients in the placebo arm.

Study MLN-MD-03.

More patients in the Joncia 100 mg/day treatment arm experienced at least a 30% reduction in pain from baseline (VAS) and considered themselves globally improved (PGIC) than did patients in the placebo arm.
The significant improvement in pain and PGIC was reinforced by the significant changes in fatigue and refreshing sleep in the Joncia treatment groups.
The results from uncontrolled studies supported maintenance of efficacy over 6 months of continuous dosing.
The small proportion of male patients in the milnacipran clinical studies is consistent with the epidemiology of the population with fibromyalgia, therefore the small number of male patients studied did not provide adequate power to show independent evidence of efficacy in this population. Efficacy and tolerability in fibromyalgia male patients should be specifically evaluated and monitored.

5.2 Pharmacokinetic Properties

Absorption.

After oral administration, milnacipran is well-absorbed. Its absolute bioavailability is about 85% and concomitant food intake does not affect the bioavailability. Peak plasma concentration (Cmax) is reached 2 to 4 hours after dosing. Plasma concentrations are dose-proportional up to 300 mg twice daily. After repeated administration, the steady-state is reached within 2 to 3 days. In these conditions, the Cmax is about 250 nanogram/mL after a 100 mg daily dose given in two divided doses. Pharmacokinetic within- and between-subject variability is low.

Distribution.

The binding to plasma proteins is limited (13%) and not saturable in a very large concentration range. The volume of distribution of milnacipran is around 5 L/kg.

Metabolism.

Limited evidence indicates that milnacipran is neither an inducer nor an inhibitor of human cytochrome P450 as demonstrated in vitro. The absence of inhibitory properties on the main cytochrome P450 isoenzymes (1A2, 2D6, 2C19 and 3A4) is confirmed in humans.

Excretion.

Milnacipran and its metabolites are eliminated primarily by renal excretion. Approximately 55% of the dose is excreted as unchanged drug. The remaining fraction is excreted as metabolites, mainly as glucuronide derivatives. Total plasma clearance is 40 L/h. Plasma elimination half-life is about 8 hours and drug elimination is completed 48 to 72 hours after termination of therapy.

Special populations.

Liver impaired patients.

Milnacipran pharmacokinetic parameters are not significantly affected by liver function impairment. No dosage adjustment is necessary for patients with impaired hepatic function.

Patients with renal insufficiency.

Reduction in milnacipran clearance leads to a higher plasma exposure, 16%, 52% and 200% in patients with Chronic Kidney Disease (CKD) stages 2, 3 and 4 respectively. Dose adjustment is recommended for patients with CKD stage 4. (See Section 4.2 Dose and Method of Administration.) Milnacipran is not recommended for patients with CKD stage 5.

Elderly patients.

Milnacipran pharmacokinetic parameters are not significantly modified with age. No age-related dose adjustment is necessary unless renal function is reduced to values for which dose adjustment is recommended (see Section 4.2 Dose and Method of Administration).

5.3 Preclinical Safety Data

Genotoxicity.

Milnacipran has not demonstrated genotoxic potential in standard in vitro and in vivo tests, including bacterial and mammalian mutation assays, chromosomal aberration assays in Chinese hamster lung cells and human lymphocytes, and the mouse micronucleus test.

Carcinogenicity.

Carcinogenicity studies were conducted via dietary administration in mice (up to 100 mg/kg/day) and in rats (up to 50 mg/kg/day). Although there was no evidence of a treatment-related increase in tumours in either study, the highest dose in the mouse study was not considered to be the maximum tolerated dose and a supplementary 26-week oral study in TG.rasH2 transgenic mice was undertaken (up to 125 mg/kg/day). This study also produced no evidence of an increase in treatment related tumours, with exposure (plasma AUC) up to 7.5 times the clinical exposure at the MRHD. Exposure was not measured in the rat study, but the high dose was twice the MRHD, based on mg/m2.

6 Pharmaceutical Particulars

6.1 List of Excipients

Milnacipran hydrochloride capsules also contain the excipients: calcium hydrogen phosphate dihydrate, carmellose calcium, povidone K30, hydrophobic colloidal silica anhydrous, magnesium stearate, purified talc.
The hard capsule shells for the 25 mg and 100 mg strengths contain: titanium dioxide (E171), quinoline yellow (E104), sunset yellow FCF (E110), gelatin.
The hard capsule shell for the 50 mg strength contains: titanium dioxide (E171), sunset yellow FCF (E110), gelatin.
The capsules are marked with the following food grade inks: Opacode monogramming ink S-1-27794 Black, Opacode monogramming ink S-1-27797 Black, TekPrint SW-9008 Black Ink.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Blister pack.

Store below 30°C.

Bottle.

Store below 30°C.

6.5 Nature and Contents of Container

Blister pack.

14's, 28's, 56's (25, 50 and 100 mg capsules).

Bottle*.

14's, 28's, 56's (25, 50 and 100 mg capsules).

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Milnacipran hydrochloride is a white to almost white crystalline powder with the molecular formula C15H23ClN2O and a molecular weight of 282.8. Milnacipran hydrochloride is freely soluble in water, methanol, ethanol, butanol, chloroform, dichloromethane and very slightly soluble in ethyl ether. It is non to slightly hygroscopic with a pKa value of 9.65. Milnacipran hydrochloride is a racemic mixture of the isomers 1R, 2S and 1S, 2R. The partition coefficient between octanol and an aqueous buffer (pH = 7.2), P=0.27 shows the highly hydrophilic character of milnacipran hydrochloride.

Chemical structure.

(1RS, 2SR)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropane-1-carboxamide hydrochloride (IUPAC name).

CAS number.

101152-94-7.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes