Consumer medicine information

DESVENLAFAXINE ACTAVIS

Desvenlafaxine

BRAND INFORMATION

Brand name

Desvenlafaxine Amneal

Active ingredient

Desvenlafaxine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using DESVENLAFAXINE ACTAVIS.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Desvenlafaxine Actavis.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist or asking questions.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Desvenlafaxine Actavis against the expected benefits it will have for you.

If you have any questions about Desvenlafaxine Actavis, ask your doctor or pharmacist.

Keep this leaflet with your Desvenlafaxine Actavis tablets. You may need to read it again.

What Desvenlafaxine Actavis is used for

What it does

Desvenlafaxine is used in the treatment and prevention of relapse of depression. Depression can affect your whole body and may cause emotional and physical symptoms such as feeling low in spirit, being unable to enjoy life, poor appetite or overeating, disturbed sleep, loss of sex drive, lack of energy and feeling guilty over nothing.

Ask your doctor if you have any questions about why Desvenlafaxine Actavis has been prescribed for you. Your doctor may have prescribed it for another reason.

How it works

Desvenlafaxine Actavis contains the active ingredient called desvenlafaxine. It belongs to a class of medications called Serotonin-Noradrenaline Reuptake Inhibitors (SNRIs).

Serotonin and noradrenaline are chemical messengers that allow certain nerves in the brain to work. Desvenlafaxine Actavis tablets increase the level of these two messengers. Experts think this is how it helps to restore your feeling of wellness.

Desvenlafaxine Actavis is not addictive. It is available only with a doctor's prescription.

Before you take Desvenlafaxine Actavis

When you must not take it

Do not take Desvenlafaxine Actavis if you are taking other medications for depression known as monoamine oxidase inhibitors, even if you have stopped taking them, but have taken them within the last 14 days.

Do not take Desvenlafaxine Actavis if you are allergic to desvenlafaxine, venlafaxine or to any of the ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction include:

  • Skin rash
  • Itching or hives on the skin
  • Swelling of the face, lips, tongue, throat or other parts of the body
  • Shortness of breath, wheezing, troubled breathing or difficulty swallowing.

Do not give Desvenlafaxine Actavis to children or adolescents under 18 years of age. The safety and effectiveness of desvenlafaxine in this age group have not been established.

Do not take this medicine after the expiry date (EXP) printed on the pack, or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

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

Tell your doctor or pharmacist if you are pregnant or intend to become pregnant. Desvenlafaxine Actavis is not recommended for use during pregnancy. Your doctor will discuss the risks and benefits of taking desvenlafaxine if you are pregnant. One of these risks is that newborn babies whose mothers have been taking desvenlafaxine may have several problems including breathing difficulties, seizures and lack of oxygen in their blood.

Tell your doctor or pharmacist if you are breast-feeding or plan to breast-feed. Desvenlafaxine passes into breast milk and there is a possibility that the breast-fed baby may be affected. For this reason, the use of desvenlafaxine is not recommended in breast-feeding women.

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

  • a history of fits (seizures or convulsions)
  • a personal history or family history of bipolar disorder
  • blood pressure problems
  • glaucoma (increased pressure in the eye)
  • a tendency to bleed more than normal or you are taking a blood thinning medication
  • raised cholesterol or lipid levels
  • problems with your kidneys or liver
  • problems with your heart
  • low sodium levels in your blood
  • any other medical conditions.

Tell your doctor if you plan to have surgery. If you have not told your doctor about any of the above, tell them before you start to take Desvenlafaxine Actavis.

Taking other medicines

Tell your doctor or pharmacist if you take any other medicines, including:

  • all prescription medicines
  • all medicines, vitamins, herbal supplements or natural therapies you buy without a prescription from a pharmacy, supermarket, naturopath or health food shop, such as St John's Wort or tryptophan supplements.

Do not start to take any other medicine while you are taking Desvenlafaxine Actavis, unless it is prescribed or approved by your doctor.

Some medicines may interfere with desvenlafaxine or desvenlafaxine may interfere with these medicines. These include:

  • medications for depression known as monoamine oxidase inhibitors (MAOIs) (such as moclobemide, phenelzine and tranylcypromine). Tell your doctor if you are taking or have stopped taking them within the last 14 days. Ask your doctor or pharmacist if you are unsure if you are taking any of these medicines. It is important that you do not take Desvenlafaxine Actavis or medicines similar to Desvenlafaxine Actavis with MAOIs or within 14 days of taking an MAOI as this may result in a serious life-threatening condition. Your doctor or pharmacist can tell you what to do if you are taking any of these medicines.
  • any other medications for bipolar disorder, depression, anxiety, obsessive-compulsive disorder or pre-menstrual dysphoric disorder, including St John's Wort
  • drugs that affect serotonin levels e.g. tramadol, dextromethorphan, fentanyl, methadone and pentazocine
  • medicines for weight loss, including sibutramine
  • triptans (used to treat migraine)
  • linezolid (used to treat infections)
  • drugs that affect your tendency to bleed e.g. aspirin, NSAIDS, warfarin.

You may need to take different amounts of your medicine, or you may need to take different medicines. Your doctor will advise you.

Your doctor or pharmacist has more information on medicines to be careful with or to avoid while taking Desvenlafaxine Actavis.

Switching to Desvenlafaxine Actavis from other antidepressants

Side effects from discontinuing antidepressant medication may occur if you are switched from other antidepressants, including venlafaxine, to Desvenlafaxine Actavis. Your doctor may gradually reduce the dose of your initial antidepressant medication to help reduce these side effects.

How to take Desvenlafaxine Actavis

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

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

How to take it

Swallow the tablets whole with a glass of water or other non-alcoholic liquid.

Do not divide, crush, chew or place the tablets in water.

Do not be concerned if you see a tablet 'shell' in your faeces after taking Desvenlafaxine Actavis. As the tablet travels the length of your gastrointestinal tract, the active ingredient desvenlafaxine is slowly released. The tablet 'shell' remains undissolved and is eliminated in your faeces. Therefore, even though, you may see a tablet 'shell' in your faeces, your dose of desvenlafaxine has been absorbed.

How much to take

The usual dose is 50 mg taken once daily with or without food.

Do not change your dose unless your doctor tells you to. Your doctor will gradually increase your dose if needed. If you have kidney problems, you may need a lower dose of Desvenlafaxine Actavis.

When to take it

Desvenlafaxine Actavis should be taken once daily and can be taken with or without food.

Take Desvenlafaxine Actavis at approximately the same time each day. This could be either in the morning or in the evening. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

How long to take it

Continue taking your medicine for as long as your doctor tells you. Although you may begin to feel better after two weeks, it may take several weeks before you feel much better. It is important to give Desvenlafaxine Actavis time to work.

This medicine helps to control your condition, so it is important to keep taking your medicine even if you feel well.

If you forget to take it

If it is less than 12 hours until your next dose, skip the dose you missed and then take your next dose when you are meant to. Otherwise, take it as soon as you remember, and then go back to taking as you would normally.

Do not take a double dose to make up for the dose you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist. If you have trouble remembering when to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (tel: 13 11 26) for advice, or go to Accident and Emergency at your nearest hospital if you think that you or anyone else may have taken too much Desvenlafaxine Actavis.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Keep the telephone number for these places handy whilst taking any medications.

While you are taking Desvenlafaxine Actavis

Things you must do

Visit your doctor regularly for a check up so that your progress can be checked. Always discuss any questions you have about Desvenlafaxine Actavis with your doctor.

Take Desvenlafaxine Actavis tablets as your doctor has prescribed. Tell any other doctors, dentists and pharmacists who treat you that you are taking this medicine.

Keep enough Desvenlafaxine Actavis tablets to last weekends and holidays. This medicine helps to control your condition, but does not cure it. It is important to keep taking your medicine even if you feel well.

Watch carefully for signs that your depression is getting worse, especially in the first few weeks of treatment or if your dose has changed. Sometimes people with depression can experience a worsening of their depressive symptoms. This can happen even when taking an antidepressant.

Tell your doctor there is the potential for a false positive urinary drug screen while on Desvenlafaxine Actavis.

Tell your doctor immediately if you experience any of the following symptoms, especially if they are severe, you have not had these symptoms before or they happen very suddenly.

  • anxiety or agitation
  • panic attacks
  • difficulty sleeping
  • irritability
  • aggressiveness
  • hostility or impulsiveness
  • restlessness
  • overactivity or uninhibited behaviour
  • other unusual changes in behaviour
  • thoughts of suicide.

Tell your doctor immediately if you have any thoughts about suicide or doing harm to yourself.

Warning signs of suicide

If you or someone you know is showing the following warning signs, contact your doctor or a mental health advisor right away or go to the nearest hospital for treatment.

All thoughts or talk about suicide or violence are serious.

  • thoughts or talk about death or suicide
  • thoughts or talk about self-harm or doing harm to others
  • any recent attempts of self-harm
  • an increase in aggressive behaviour, irritability or agitation.

Things to be careful of

Be careful driving or operating dangerous machinery until you know how Desvenlafaxine Actavis affects you. Desvenlafaxine Actavis tablets may make you feel drowsy.

Things you must not do

Do not stop taking Desvenlafaxine Actavis or change the dose without the advice of your doctor, even if you feel better. Your doctor may want to slowly decrease your dose of Desvenlafaxine Actavis to help avoid side effects. Side effects are known to occur when people stop taking Desvenlafaxine Actavis, especially when they suddenly stop therapy.

Some of these side effects include:

  • headache
  • nausea
  • dizziness
  • tiredness
  • irritability
  • anxiety
  • abnormal dreams
  • diarrhoea
  • excessive sweating.

Slowly reducing the amount of Desvenlafaxine Actavis being taken reduces the possibility of these effects occurring.

Some of these symptoms may impair driving, or the operation of dangerous machinery. Avoid these activities if you experience any of these symptoms.

Avoid drinking alcohol while you are taking Desvenlafaxine Actavis. Do not give this medicine to anyone else even if they have the same condition as you.

SIDE EFFECTS

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Desvenlafaxine Actavis. All medicines can have side effects. Sometimes they are serious; often they are not. You may need medical attention if you get some of the side effects.

It can be difficult to tell whether side effects are the result of taking this medicine, symptoms of your condition, or side effects of other medicines you may be taking. For this reason it is important to tell your doctor of any change in your condition.

Do not be alarmed by the list of 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...

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

  • stomach, bowel or urinary tract problems:
    - nausea or vomiting
    - loss of appetite
    - diarrhoea
    - constipation
    - difficulty passing urine
  • changes in your behaviour:
    - difficulty sleeping, abnormal sleepiness or abnormal dreams
    - sexual function problems such as decreased sex drive, delayed ejaculation, problems achieving erection or difficulties achieving orgasm
    - nervousness or anxiety
    - feeling jittery or irritable
  • difficulty thinking or working because of:
    - yawning
    - disturbances in concentration
    - fainting or dizziness after standing up
    - fatigue -Rapid heart beat
    - chills
    - headache
  • changes in your appearance:
    - excessive sweating
    - hot flushes
    - rash
    - weight loss or weight gain
  • blurred vision
  • ringing in the ears
  • altered taste, dry mouth.

Tell your doctor as soon as possible if...

Tell your doctor as soon as possible if you notice any of the following:

  • muscle stiffness, weakness or movement disorders
  • abnormal facial movements such as tongue thrusting, repetitive chewing, jaw swinging, or grimacing
  • a feeling of apathy or not caring about things
  • feeling detached from yourself
  • hallucinations, confusion
  • bleeding or bruising more easily than normal
  • numbness or pins and needles.

Go to hospital if...

Tell your doctor immediately, or go to Accident and Emergency at your nearest hospital if you notice any of the following:

  • swelling of the face, lips, tongue, throat or other parts of the body
  • seizures or fits
  • symptoms of sudden fever with sweating, rapid heartbeat and muscle stiffness, which may lead to loss of consciousness.

Tell your doctor or pharmacist if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some people. Some of these side effects (for example, increase in blood pressure, increase in blood cholesterol, changes to liver function, protein in the urine) can only be found when your doctor does tests from time to time to check your progress.

This is not a complete list of all possible side effects. Others may occur in some people and there may be some side effects not yet known.

Tell your doctor if you notice anything that is making you feel unwell.

After taking Desvenlafaxine Actavis

Storage

Keep your Desvenlafaxine Actavis tablets in their blister pack until it is time to take them. The tablets may not last as well if you take them out of the blister pack.

Keep Desvenlafaxine Actavis tablets in a cool dry place where the temperature stays below 25°C.

Do not store Desvenlafaxine Actavis tablets or any other medicine in the bathroom or near a sink. Do not leave Desvenlafaxine Actavis tablets in the car or on windowsills. Heat and dampness can destroy some medicines.

Keep Desvenlafaxine Actavis tablets and all medication 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 this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

PRODUCT DESCRIPTION

What Desvenlafaxine Actavis looks like

There are two strengths of Desvenlafaxine Actavis tablets:

  • 50 mg, light pink coloured, diamond shaped, biconvex tablets, debossed with ‘L189’ on one side and plain on other side. Blister packs and bottles containing 7, 14 or 28 tablets*.
  • 100 mg, dark brown to red coloured, diamond shaped, biconvex tablets, debossed with ‘L190’ on one side and plain on other side. Blister packs and bottles containing 7, 14 or 28 tablets*.

*Not all pack sizes are available in Australia.

Ingredients

Desvenlafaxine Actavis tablets contain 50 mg or 100 mg desvenlafaxine as the active ingredient.

It also contains the following inactive ingredients:

  • alginic acid
  • citric acid monohydrate
  • microcrystalline cellulose
  • povidone
  • talc
  • magnesium stearate
  • hypromellose.

The 50 mg tablets are film coated with OPADRY film coating system 03F84770 PINK (ARTG No. 109228) and the 100 mg tablets are coated with OPADRY film coating system 03F86990 BROWN (ARTG No. 109232).

Supplier

Desvenlafaxine Actavis tablets are supplied by:
Actavis Pty Ltd
117 Harrington Street
THE ROCKS
NSW 2000

Australian Registration Numbers

Bottles*

  • Desvenlafaxine Actavis 50 mg modified release tablets:
    AUST R 218070
  • Desvenlafaxine Actavis 100 mg modified release tablets:
    AUST R 218078

Blister packs

  • Desvenlafaxine Actavis 50 mg modified release tablets:
    AUST R 218064
  • Desvenlafaxine Actavis 100 mg modified release tablets:
    AUST R 218071

* Not marketed in Australia.

Date of Preparation

This leaflet was last revised in February 2015.

Published by MIMS July 2015

BRAND INFORMATION

Brand name

Desvenlafaxine Amneal

Active ingredient

Desvenlafaxine

Schedule

S4

 

1 Name of Medicine

Desvenlafaxine.

6.7 Physicochemical Properties

Desvenlafaxine is a white to off-white crystalline powder that is practically insoluble in water and slightly soluble in ethanol and acetone. The solubility of desvenlafaxine is pH dependent.
Chemical name: 4-[2-(dimethylamino)-1RS-(1-hydroxycyclohexyl)ethyl]phenol.
Molecular formula: C16H25NO2.
Molecular weight: 263.38.

Chemical structure.

The structural formula is shown below:

CAS number.

93413-62-8.

2 Qualitative and Quantitative Composition

Two strengths of Desvenlafaxine Amneal tablets are available, containing 50 mg and 100 mg of desvenlafaxine.
Inactive ingredients are alginic acid, citric acid monohydrate, microcrystalline cellulose, povidone, purified talc, magnesium stearate and hypromellose. The 50 mg tablets are film coated with Opadry film coating system 03F84770 pink (ARTG No. 109228) and the 100 mg tablets are coated with Opadry film coating system 03F86990 brown (ARTG No. 109232).

3 Pharmaceutical Form

Desvenlafaxine Amneal is formulated as a modified release tablet for once-a-day oral administration.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Nonclinical studies have shown that desvenlafaxine is a selective serotonin and noradrenaline reuptake inhibitor (SNRI).
Desvenlafaxine lacked significant affinity for numerous receptors, including muscarinic cholinergic, H1-histaminergic, or α1-adrenergic receptors in vitro. Pharmacological activity at these receptors has been hypothesised to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. In the same comprehensive binding profile assay, desvenlafaxine, also lacked significant affinity for various ion channels, including calcium, chloride, potassium and sodium ion channels and also lacked monoamine oxidase (MAO) inhibitory activity. Desvenlafaxine lacked significant activity in the in vitro cardiac potassium channel (hERG) assay.
In preclinical rodent models, desvenlafaxine demonstrated activity predictive of antidepressant, anxiolytic and thermoregulatory actions, and pain inhibitory properties.

Clinical trials.

Major depressive disorder.

The efficacy of desvenlafaxine as a treatment for depression was established in four, 8 week, randomised, double blind, placebo controlled, fixed dose trials in adult outpatients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for major depressive disorder (MDD). In the first study, patients received 100 mg (n = 114), 200 mg (n = 116), or 400 mg (n = 113) of desvenlafaxine once daily, or placebo (n = 118). In a second study, patients received either 200 mg (n = 121) or 400 mg (n = 124) of desvenlafaxine once daily, or placebo (n = 124). In two additional trials, patients received 50 mg (n = 150 and n = 164) or 100 mg (n = 147 and n = 158) of desvenlafaxine once daily, or placebo (n = 150 and n = 161).
Desvenlafaxine showed superiority over placebo as measured by improvement in the 17 item Hamilton Rating Scale for Depression (HAM-D17) total score in four trials and, as measured by the Clinical Global Impressions Scale - Improvement (CGI-I), in three of the four trials. There was no clear evidence that doses greater than 50 mg/day conferred any additional benefit. Two other studies that treated patients with doses of 200 mg to 400 mg also showed superiority to placebo when appropriately analysed to take early dropouts for adverse effects into account.
In a long-term study, adult outpatients meeting DSM-IV criteria for major depressive disorder and who responded to 12 weeks of acute treatment with desvenlafaxine were assigned randomly to the same dose (200 or 400 mg/day) they had received during acute treatment or to placebo for up to 26 weeks of observation for relapse. Response during the open label phase was defined as a HAM-D17 total score of ≤ 11 at the day 84 evaluation. Relapse during the double blind phase was defined as follows: (1) a HAM-D17 total score of ≥ 16 at any office visit, (2) a CGI-I score of ≥ 6 (versus day 84) at any office visit, or (3) discontinuation from the study due to unsatisfactory response. Patients receiving continued desvenlafaxine treatment experienced significantly lower relapse rates over the subsequent 26 weeks compared with those receiving placebo.
Analyses of the relationships between treatment outcome and age and treatment outcome and gender did not suggest any differential responsiveness on the basis of these patient characteristics.

5.2 Pharmacokinetic Properties

The single dose pharmacokinetics of desvenlafaxine are linear and dose proportional in a dose range of 100 to 600 mg/day. The mean terminal half-life, t1/2, is approximately 11 hours. With once daily dosing, steady-state plasma concentrations are achieved within approximately 4-5 days. At steady state, multiple dose accumulation of desvenlafaxine is linear and predictable from the single dose pharmacokinetic profile.
The pharmacokinetics of desvenlafaxine have been thoroughly evaluated in women and men. There are minimal differences based on gender; data from all subjects are presented below.

Absorption and distribution.

Desvenlafaxine is well absorbed, with an absolute oral bioavailability of 80%. Mean time to peak plasma concentrations (Tmax) is about 7.5 hours after oral administration. AUC and Cmax of 6,747 nanogram.hr/mL and 376 nanogram/mL, respectively, are predicted after a single dose of 100 mg.
Administration with food has minimal impact on drug absorption. Following administration with low, medium, and high fat meals, increases in Cmax of approximately 16% (observed confidence interval: 107.8-125.1%; required confidence interval for bioequivalence 80-125%) were observed only following a high fat meal. There was no statistically significant change in AUC values for any of the meals; therefore, desvenlafaxine can be taken without regard to meals.
The plasma protein binding of desvenlafaxine in vitro is low (approximately 30%) and is independent of drug concentration over the range 100-500 nanogram/mL. Desvenlafaxine's volume of distribution at steady-state following intravenous administration is 3.4 L/kg, indicating distribution into nonvascular compartments.

Metabolism and excretion.

Approximately 45% of desvenlafaxine is excreted unchanged in urine. Desvenlafaxine is primarily metabolised by conjugation (shown to be mediated by UGT isoforms UGT1A1, UGT1A3, UGT2B4, UGT2B15, and UGT2B17 in vitro) and to a minor extent through oxidative metabolism. Approximately 19% of the administered dose is excreted as the glucuronide metabolite and < 5% as the oxidative metabolite (N,O-didesmethylvenlafaxine) in urine. In vitro studies showed that CYP3A4 is the predominant cytochrome P450 isozyme mediating the oxidative metabolism (N-demethylation) of desvenlafaxine.

Special populations.

Elderly (> 65 years).

In a trial of healthy subjects administered doses up to 300 mg, there was an age dependent decrease in desvenlafaxine clearance, resulting in a 32% increase in Cmax and a 55% increase in AUC values in subjects greater than 75 years of age as compared with subjects 18-45 years of age. No dosage adjustment is required solely on the basis of age; however, possible reduced renal clearance of desvenlafaxine should be considered when determining dose.

Children and adolescents.

Safety and effectiveness in the paediatric population have not been established.

Renal impairment.

The pharmacokinetics of desvenlafaxine succinate 100 mg were studied in subjects with mild (n = 9), moderate (n = 8), severe (n = 7) and endstage renal disease (ESRD) requiring dialysis (n = 9) and in healthy, age matched control subjects (n = 8). Elimination was significantly correlated with creatinine clearance. Total body clearance was reduced by 29% in mild, 39% in moderate, 51% in severe renal impairment, and 58% in ESRD compared to healthy subjects. This reduced clearance resulted in increases in AUCs of 42% in mild (24 hr CrCl = 50-80 mL/min), 56% in moderate (24 hr CrCl = 30-50 mL/min), 108% in severe (24 hr < CrCl, 30 ml/min) renal impairment, and 116% in ESRD subjects.
The mean terminal half-life (t1/2) was prolonged from 11.1 hours in the control subjects to 13.5, 15.5, 17.6, and 22.8 hours in mild, moderate, severe renal impairment and ESRD subjects, respectively.
Less than 5% of the drug in the body was cleared during a standard 4 hour haemodialysis procedure. Therefore, supplemental doses should not be given to patients after dialysis. Dosage adjustment is recommended in patients with significant impairment of renal function (see Section 4.2 Dose and Method of Administration).

Hepatic impairment.

The pharmacokinetics of desvenlafaxine succinate 100 mg were studied in subjects with mild (Child-Pugh A, n = 8), moderate (Child-Pugh B, n = 8), and severe (Child-Pugh C, n = 8) hepatic impairment and in healthy subjects (n = 12).
Average AUC was increased by approximately 31% and 35% in patients with moderate and severe hepatic impairment, respectively, as compared to healthy subjects. Average AUC values were comparable in subjects with mild hepatic impairment and healthy subjects (< 5% difference).
Systemic clearance (CL/F) was decreased by approximately 20% and 36% in patients with moderate and severe hepatic impairment, respectively, as compared to healthy subjects. CL/F values were comparable in mild hepatic impairment and healthy subjects (< 5% difference).
The mean t1/2 changed from approximately 10 hours in healthy subjects and subjects with mild hepatic impairment to 13 and 14 hours in moderate and severe hepatic impairment, respectively.

Thorough QTc trial.

In a thorough QTc trial with prospectively determined criteria, in healthy women, desvenlafaxine did not cause QT prolongation. Additionally, no effect on QRS interval was observed.

5.3 Preclinical Safety Data

Genotoxicity.

Desvenlafaxine was not genotoxic in in vitro assays for bacterial gene mutation, mammalian gene mutation, chromosomal aberrations and cell transformation, or in in vivo tests for clastogenic activity in mice and rats.

Carcinogenicity.

Desvenlafaxine did not increase the incidence of tumours in long-term mouse and rat carcinogenicity studies at oral doses up to 7 (mice), 14 (male rats) and 23 (female rats) times the maximal recommended human dose of 200 mg/day, on a mg/m2 basis.

Teratogenicity.

Desvenlafaxine was not teratogenic in rats at an oral dose resulting in a drug exposure (plasma AUC) that was 7 times that in humans treated with 200 mg/day. There were tendencies for reduced numbers and bodyweights of foetuses with this dose in some studies. No teratogenicity was observed in a rabbit embryo-foetal development study, but the oral doses resulted in drug exposures (AUC) that were below the value in humans treated with 200 mg/day. Potential effects on embryo-foetal development may therefore not have been fully defined due to excessive maternal toxicity at higher dosages in rabbits.
Oral administration of desvenlafaxine to pregnant rats from early gestation to weaning was associated with increased post-partum pup mortality and reduced birth weight persisting to maturity, but no effect on developmental indices, at maternal exposure (plasma AUC) 7 times that in humans treated with 200 mg/day. Maternal toxicity was observed at this dose; at the no-effect dose maternal exposure was 2 times that in humans treated with 200 mg/day.

4 Clinical Particulars

4.1 Therapeutic Indications

Desvenlafaxine Amneal is indicated for the treatment of major depressive disorder, including the prevention of relapse.
Desvenlafaxine Amneal is not indicated for paediatric use.

4.3 Contraindications

Hypersensitivity to desvenlafaxine, venlafaxine hydrochloride or to any excipients in the Desvenlafaxine Amneal formulation.

Monoamine oxidase inhibitors (MAOIs).

Desvenlafaxine Amneal must not be used in combination with monoamine oxidase inhibitors (MAOIs) or reversible MAOIs (RIMA) (e.g. moclobemide, linezolid and intravenous methylene blue), or within 14 days of discontinuing treatment with a MAOI. Similarly, Desvenlafaxine Amneal must be discontinued for at least 7 days before starting treatment with a MAOI. Cases of serious reactions, such as potentially life threatening serotonin syndrome (characterised by neuromuscular excitation, altered mental status and autonomic dysfunction) have been reported in patients receiving an SNRI in combination with MAOIs and RIMA, and in patients who have recently discontinued an SNRI and have been started on a MAOI (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Clinical worsening and suicide risk.

Patients with major depression, both adult and paediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behaviour (suicidality) or unusual changes in behaviour, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. Antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. As improvement may not occur during the first few weeks or more of treatment, patients should be monitored appropriately and observed closely for clinical worsening and suicidality, especially at the beginning of a course of treatment or at the time of dose changes, either increases or decreases.
Pooled analyses of short-term placebo controlled trials of antidepressant medicines (SSRIs and others) showed that these medicines increase the risk of suicidality in children, adolescents, and young adults (ages 18-24 years) with major depression and other psychiatric disorders, generally during initial treatment (1-2 months). Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond the age of 24 years; there was a reduction in the risk of suicidality with antidepressants compared to placebo in adults age 65 years and older.
The pooled analysis of placebo controlled trials in children and adolescents with major depression, obsessive compulsive disorder, or other psychiatric disorders included a total of 24 short-term trials of nine antidepressant medicines in over 4400 patients. The pooled analyses of placebo controlled trials in adults with major depression or other psychiatric disorders included a total of 295 short-term trials (medium duration 2 months) of 11 antidepressant medicines in over 77,000 patients. There was considerable variation in risk of suicidality among medicines, but a tendency toward an increase in the younger patients for almost all medicines studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence with major depression.
No suicides occurred in any of the paediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about the medicine effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e. beyond several months. However, there is substantial evidence from placebo controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, 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 (see Discontinuation effects below).
It is particularly important that monitoring be undertaken during the initial course of antidepressant treatment or at times of dose increase or decrease.
Patients with comorbid depression associated with other psychiatric or nonpsychiatric disorders being treated with antidepressants should be similarly observed for clinical worsening and suicidality.
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 depression 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.
Prescriptions for Desvenlafaxine Amneal should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the possibility of overdosage. This is particularly so at the times of treatment initiation or dosage change.

Information for patients and caregivers.

Patients and their caregivers should be alerted about the need to monitor for the emergence of anxiety, agitation, panic attacks, insomnia, hostility, impulsivity, akathisia, hypomania, mania, worsening of depression, and suicidal ideation, especially early during antidepressant treatment. Such symptoms should be reported to the patient's doctor, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

Mania/ hypomania.

In clinical trials, mania was reported for approximately 0.1% of patients treated with desvenlafaxine. Activation of mania/ hypomania has also been reported in a small proportion of patients with mood disorders who were treated with other marketed antidepressants. A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/ manic episode in patients at risk for bipolar disorder. Whether any of the symptoms represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Desvenlafaxine Amneal is not approved for use in treating bipolar depression.
As with all antidepressants, desvenlafaxine should be used cautiously in patients with a history or family history of mania or hypomania.

Serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions.

The development of a potentially life threatening serotonin or neuroleptic malignant syndrome (NMS)-like reactions syndrome may occur with desvenlafaxine treatment, particularly with concomitant use of other serotonergic drugs (including SSRIs, SNRIs and triptans) and with drugs that impair metabolism of serotonin (e.g. MAOIs, including reversible MAOIs such as moclobemide, linezolid and intravenous methylene blue), or with antipsychotics or other dopamine antagonists (see Section 4.3 Contraindications).
Serotonin syndrome symptoms may include mental status changes (e.g. agitation, confusion, hallucinations, and coma), autonomic instability (e.g. diaphoresis, tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g. hyperreflexia, incoordination, myoclonus, tremor) and/or gastrointestinal symptoms (e.g. nausea, vomiting, and diarrhoea).
Serotonin syndrome, in its most severe form can resemble NMS, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs and mental status changes (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
If concomitant treatment with desvenlafaxine and other agents that may affect the serotonergic and/or dopaminergic neurotransmitter system (such as an SSRI, another SNRI or a 5-hydroxytryptamine receptor agonist (triptan)) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.
The concomitant use of desvenlafaxine with serotonin precursors (such as tryptophan supplements) is not recommended.
Treatment with desvenlafaxine should be discontinued if serotonin syndrome or NMS-like reactions occur and supportive symptomatic treatment initiated.

Narrow-angle glaucoma.

Patients with raised intraocular pressure (IOP) or narrow angle glaucoma were excluded from all desvenlafaxine studies. Mydriasis has been reported in association with desvenlafaxine. It is recommended that patients with raised intraocular pressure or patients at risk for acute narrow angle glaucoma (angle closure glaucoma) should be closely monitored.

Coadministration of drugs containing venlafaxine and/or desvenlafaxine.

Desvenlafaxine is the major active metabolite of venlafaxine, a medication used to treat major depressive, generalised anxiety, social anxiety and panic disorders. Products containing desvenlafaxine should not be used concomitantly with products containing venlafaxine hydrochloride or other products containing desvenlafaxine.

Effects on blood pressure.

Increases in blood pressure were observed in some patients in clinical trials, particularly with higher doses. Pre-existing hypertension should be controlled before treatment with desvenlafaxine. Patients receiving desvenlafaxine should have regular monitoring of blood pressure. Cases of elevated blood pressure requiring immediate treatment have been reported with desvenlafaxine. Sustained blood pressure increases could have adverse consequences. For patients who experience a sustained increase in blood pressure while receiving desvenlafaxine, either dose reduction or discontinuation should be considered. Caution should be exercised in treating patients with underlying conditions that might be compromised by increases in blood pressure.

Cardiovascular/ cerebrovascular disease.

Caution is advised in administering desvenlafaxine to patients with cardiovascular, cerebrovascular, or lipid metabolism disorders (see Section 4.8 Adverse Effects (Undesirable Effects)). Increases in blood pressure and heart rate were observed in clinical trials with desvenlafaxine. Desvenlafaxine has not been evaluated systematically in patients with a recent history of myocardial infarction, unstable heart disease, uncontrolled hypertension, or cerebrovascular disease. Patients with these diagnoses, except for cerebrovascular disease, were excluded from clinical trials.

Serum lipids.

In the short-term, placebo controlled, premarketing trials for MDD, desvenlafaxine treatment was associated with mean increases of 5.7, 1.4, 3.6 and 5.5 mg/dL in total cholesterol, HDL, LDL cholesterol and triglycerides, respectively (0.11, 0.03, 0.07 and 0.04 mmol/L, respectively). The changes in fasting serum total cholesterol, LDL, and triglycerides were dose related. Measurement of serum lipids should be considered during treatment with desvenlafaxine.

Seizures.

Cases of seizures have been reported in clinical trials with desvenlafaxine. Desvenlafaxine has not been systematically evaluated in patients with a seizure disorder. Patients with a history of seizures were excluded from clinical trials. Desvenlafaxine should be prescribed with caution in patients with a seizure disorder.

Discontinuation effects.

During marketing of SNRIs (serotonin and noradrenaline reuptake inhibitors), and SSRIs (selective serotonin reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g. paraesthesias, such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events are generally self limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored when discontinuing treatment with desvenlafaxine. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered (see Section 4.8 Adverse Effects (Undesirable Effects); Section 4.2 Dose and Method of Administration).

Abnormal bleeding.

Selective serotonin reuptake inhibitors (SSRIs) and serotonin noradrenaline reuptake inhibitors (SNRIs), including desvenlafaxine, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anticoagulants may add to this risk. Bleeding events related to SSRIs and SNRIs have ranged from ecchymosis, haematoma, epistaxis, and petechiae to life threatening haemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of desvenlafaxine and NSAIDs, aspirin, or other drugs that affect coagulation or bleeding.

Hyponatraemia.

Cases of hyponatraemia and/or the syndrome of inappropriate antidiuretic hormone (SIADH) secretion have been described with SNRIs (including desvenlafaxine) and SSRIs, usually in volume depleted or dehydrated patients, including elderly patients and patients taking diuretics (see Section 4.8 Adverse Effects (Undesirable Effects)).

Physical and psychological dependence.

Although desvenlafaxine has not been systematically studied in preclinical or clinical trials for its potential for abuse, no indication of drug seeking behaviour was seen in the clinical trials. However, it is not possible to predict on the basis of premarketing experience, the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of desvenlafaxine (e.g. development of tolerance, incrementation of dose, drug seeking behaviour).

Electroconvulsive therapy.

There are no clinical data establishing the risks and/or benefits of electroconvulsive therapy combined with desvenlafaxine treatment for MDD.

Paediatric use.

Safety and effectiveness in patients less than 18 years of age have not been established.

Use in the elderly.

No dosage adjustment is required solely on the basis of age; however, possible reduced renal clearance of desvenlafaxine should be considered when determining dose (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).
Greater sensitivity to desvenlafaxine in some older patients cannot be ruled out.
Of the 3,292 patients in premarketing clinical trials of desvenlafaxine for major depressive disorder, 5% were 65 years of age or older. No overall differences in safety or efficacy were observed between these subjects and younger subjects; however, in the short-term placebo controlled trials, there was a higher incidence of systolic orthostatic hypotension in patients ≥ 65 years of age compared to patients < 65 years of age treated with desvenlafaxine.

Effects on laboratory tests.

False positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients taking desvenlafaxine. This is due to lack of specificity of the screening tests. False positive test results may be expected for several days following discontinuation of desvenlafaxine therapy. Confirmatory tests, such as gas chromatography/ mass spectrometry, will distinguish desvenlafaxine from PCP and amphetamine.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Monoamine oxidase inhibitors.

Adverse reactions, some of which were serious, have been reported in patients who have recently been discontinued from a monoamine oxidase inhibitor (including reversible MAOIs such as moclobemide, linezolid and intravenous methylene blue) and started on antidepressants with pharmacological properties similar to desvenlafaxine (SNRIs or SSRIs), or who have recently has SNRI or SSRI therapy discontinued prior to initiation of an MAOI (see Section 4.4 Special Warnings and Precautions for Use). Concomitant use of desvenlafaxine in patients taking monoamine oxidase inhibitors is contraindicated (see Section 4.3 Contraindications).

Central nervous system (CNS) active agents.

The risk of using desvenlafaxine in combination with other CNS active drugs has not been systematically evaluated. Consequently, caution is advised when desvenlafaxine is taken in combination with other CNS active drugs.

Serotonin syndrome.

As with other serotonergic agents, serotonin syndrome, a potentially life threatening condition, may occur with desvenlafaxine treatment, particularly with concomitant use of other agents that may affect the serotonergic neurotransmitter system (including triptans, SSRIs, other SNRIs, lithium, sibutramine, fentanyl and its analogues, tramadol, dextromethorphan, tapentadol, pethidine, methadone, pentazocine or St. John's wort [Hypericum perforatum]), with drugs which impair metabolism of serotonin (such as MAOIs including moclobemide, linezolid [an antibiotic which is a reversible nonselective MAOI] and intravenous methylene blue), or with serotonin precursors (such as tryptophan supplements). Serotonin syndrome symptoms may include mental status changes, autonomic instability, neuromuscular aberrations and/or gastrointestinal symptoms (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).
If concomitant treatment with desvenlafaxine and other agents that may affect the serotonergic neurotransmitter system (such as an SSRI, another SNRI or a 5-hydroxytryptamine receptor agonist (triptan)) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of desvenlafaxine with serotonin precursors (such as tryptophan supplements) is not recommended (see Section 4.4 Special Warnings and Precautions for Use).

Ethanol.

A clinical study has shown that desvenlafaxine does not increase the impairment of mental and motor skills caused by ethanol. However, as with all CNS active drugs, patients should be advised to avoid alcohol consumption while taking desvenlafaxine.

Potential for other drugs to affect desvenlafaxine.

Inhibitors of CYP3A4.

CYP3A4 is minimally involved in desvenlafaxine elimination. In a clinical study, ketoconazole (200 mg BID) increased the AUC of desvenlafaxine (400 mg single dose) by approximately 43%, a weak interaction. Concomitant use of desvenlafaxine with potent inhibitors of CYP3A4 may result in higher exposure to desvenlafaxine.

Inhibitors of other CYP enzymes.

Based on in vitro data, drugs that inhibit CYP isozymes 1A1, 1A2, 2A6, 2D6, 2C8, 2C9, 2C19, and 2E1 are not expected to have significant impact on the pharmacokinetic profile of desvenlafaxine.

Potential for desvenlafaxine to affect other drugs.

Drugs metabolised by CYP2D6.

When desvenlafaxine was administered at a dose of 400 mg daily in conjunction with a single 50 mg dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased approximately 90%. Concomitant use of desvenlafaxine with a drug metabolised by CYP2D6 may result in higher concentrations of that drug.

Drugs metabolised by CYP3A4.

In vitro desvenlafaxine does not inhibit, or induce the CYP3A4 isozyme.
In a clinical study, desvenlafaxine (400 mg daily) decreased the AUC of midazolam (a single 4 mg dose), by approximately 31%. Concomitant use of desvenlafaxine with a drug metabolised by CYP3A4 may result in lower exposures to that drug.

Drugs metabolised by CYP1A2, 2A6, 2C8, 2C9 and 2C19.

In vitro desvenlafaxine does not inhibit CYP1A2, 2A6, 2C8, 2C9, and 2C19 isozymes and would not be expected to affect the pharmacokinetics of drugs that are metabolised by these CYP isozymes.

P-glycoprotein transporter.

In vitro desvenlafaxine is not a substrate or an inhibitor for the P-glycoprotein transporter.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Fertility in male rats was unaffected by oral administration of desvenlafaxine resulting in exposure (plasma AUC) up to 4 times that in humans treated with 200 mg/day. When treated male rats were mated with treated females, female fertility was variably reduced with oral doses resulting in exposures (plasma AUC) 2 to 7 times that in humans treated with 200 mg/day; there was some evidence that this was associated with disruption of oestrus cycles.
(Category B2)
The safety of desvenlafaxine in human pregnancy has not been established. Studies have demonstrated that desvenlafaxine crosses the human placenta. Only administer desvenlafaxine to pregnant women if the expected benefits outweigh any possible risk. If desvenlafaxine is used until, or shortly before birth, discontinuation effects in the newborn should be considered.
Neonates exposed to venlafaxine, other SNRIs (serotonin and noradrenaline reuptake inhibitors), or SSRIs (selective serotonin reuptake inhibitors), late in the third trimester have developed complications requiring prolonged hospitalisation, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnoea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycaemia, hypotonia, hypertonia, hyper-reflexia, tremor, jitteriness, irritability and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome.
Epidemiological data have suggested that the use of SSRIs in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the new born (PPHN). Although no studies have investigated an association of PPHN to SNRI treatment, this potential risk cannot be ruled out with desvenlafaxine taking into account the related mechanism of action (inhibition of the reuptake of serotonin).
A small prospective, observational study consisted of 56 mother-infant pairs: 18 controls and 38 SSRI/SNRI mother-infant pairs. Of these, 11 mother-infant pairs were exposed to venlafaxine. The median (interquartile range [IQR]) gestational age was higher in infants born to control mothers than those born to mothers treated with antidepressants (40 [39-40 weeks] versus 39 [38-40 weeks]; p < 0.05). Neonates born to control mothers also had a longer median (IQR) length at birth (51 [49-51.6] cm versus 49 [47-51] cm; p < 0.05) than infants born to mothers in the cases group. The infants also displayed mild behavioural anomalies, categorised as less optimal functioning for habituation and motor and autonomic clusters (using the Brazelton Neonatal Behavioural Assessment Scale [BNBAS]); however these events were selflimiting and usually resolved in 1 to 2 weeks.
In another study, 6 of the 7 neonates with in utero exposure to venlafaxine at near term had acceptable Apgar scores at birth; however an improvement in Apgar scores at 5 minutes was observed in all 7 neonates. No cases of intrauterine growth retardation were recorded. The adverse events observed in 5 neonates at birth, included respiratory distress, tachypnoea, irritability, tremors, excessive suckling, rigidity, increased tonus, vomiting, hyper-reflexia, disorganised movements of limbs, initial decreased reactivity, agitation, poor sleep and liquid/abundant stool. In 4 of the 5 neonates, the events resolved spontaneously without the need for any pharmacological treatment, while one neonate required resuscitation and continuous positive airway pressure (C-PAP) for 48 hours.
A prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy showed that women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication.
Exposure to SNRIs in mid to late pregnancy may increase the risk for preeclampsia, and exposure to SNRIs near delivery may increase the risk for postpartum haemorrhage.
 Desvenlafaxine is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from desvenlafaxine, a decision should be made whether or not to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Only administer desvenlafaxine to breastfeeding women if the expected benefits outweigh any possible risk.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials experience.

The safety of desvenlafaxine was established in a total of 4,724 patients, who were exposed to at least one dose of desvenlafaxine ranging from 50 to 400 mg/day in clinical trials. Long-term safety was evaluated in 1,576 patients, who were exposed to desvenlafaxine for at least 6 months and with 575 patients exposed for 1 year.
The following list of adverse reactions was reported by patients treated with desvenlafaxine throughout the dose range studied (50 to 400 mg) during both short and long-term trials. In general, the adverse reactions were most frequent in the first week of treatment.
Adverse reactions are listed below in CIOMS frequency categories. Very common: ≥ 10%; common: ≥ 1% and < 10%; uncommon: ≥ 0.1% and < 1%; rare: ≥ 0.01% and < 0.1%; very rare: < 0.01%; not known: cannot be estimated from the data available.

Cardiac disorders.

Common: palpitations, tachycardia.
Rare: Stress cardiomyopathy (Takitsubo cardiomyopathy)**.

Ear and labyrinth disorders.

Common: tinnitus, vertigo**.

Eye disorders.

Common: vision blurred, mydriasis.

Gastrointestinal disorders.

Very common: nausea, dry mouth, constipation.
Common: diarrhoea, vomiting.
Rare: pancreatitis acute**.

General disorders and administration site conditions.

Very common: fatigue.
Common: chills, asthenia, feeling jittery.

Immune system disorders.

Uncommon: hypersensitivity.

Investigations.

Common: liver function test abnormal, weight increased, weight decreased, blood cholesterol increased.
Uncommon: blood triglycerides increased, blood prolactin increased.

Metabolism and nutritional disorders.

Common: decreased appetite.
Rare: hyponatraemia.

Musculoskeletal, connective tissue and bone disorders.

Common: musculoskeletal stiffness.

Nervous system disorders.

Very common: dizziness, headache, somnolence.
Common: tremor, paraesthesia, dysgeusia, disturbance in attention.
Uncommon: syncope, extrapyramidal disorder, dyskinesia.
Rare: convulsion, Serotonin syndrome**, dystonia.

Psychiatric disorder.

Very common: insomnia.
Common: withdrawal syndrome anxiety, nervousness, abnormal dreams, irritability libido decreased, anorgasmia, orgasm abnormal.
Uncommon: depersonalisation, hypomania.
Rare: mania, hallucinations.

Renal and urinary disorders.

Common: urinary hesitation.
Uncommon: proteinuria, urinary retention**.

Reproductive system and breast disorders.

Common: erectile dysfunction*, ejaculation delayed*, ejaculation disorder*, ejaculation failure*.
Uncommon: sexual dysfunction.

Respiratory, thoracic and mediastinal disorders.

Common: yawning.
Uncommon: epistaxis.

Skin and subcutaneous tissue disorders.

Very common: hyperhidrosis.
Common: rash.
Uncommon: alopecia**.
Rare: angioedema**, photosensitivity reaction, Stevens-Johnson syndrome**.

Vascular disorders.

Common: hot flush, blood pressure increased.
Uncommon: orthostatic hypotension, peripheral coldness.
*Frequency is calculated based on men only.
**Adverse reaction identified during postapproval use.

Adverse reactions reported with other SNRIs.

Although the following are not considered adverse reactions for desvenlafaxine, they are adverse reactions for other SNRIs and may also occur with desvenlafaxine: gastrointestinal bleeding and severe cutaneous reactions (such as Stevens-Johnson syndrome, toxic epidermal necrolysis and/or erythema multiforme).

Ischaemic cardiac adverse events.

In clinical trials, there were uncommon reports of ischaemic cardiac adverse events including myocardial ischaemia, myocardial infarction, and coronary occlusion requiring revascularisation; these patients had multiple underlying cardiac risk factors. More patients experienced these events during desvenlafaxine treatment as compared to placebo (see Section 4.4 Special Warnings and Precautions for Use, Cardiovascular/ cerebrovascular disease).

Discontinuation symptoms.

Adverse drug reactions reported in association with abrupt discontinuation, dose reduction or tapering of treatment in MDD clinical trials at a rate of ≥ 5% include: dizziness, withdrawal syndrome, nausea, headache, irritability, diarrhoea, anxiety, abnormal dreams, fatigue, and hyperhidrosis. In general, discontinuation symptoms occurred more frequently with longer duration of therapy (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use, Discontinuation effects).

Orthostatic hypotension.

Of the 3,292 patients in clinical trials with Pristiq, 5% of patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients; however, in the short-term placebo controlled trials, there was a higher incidence of systolic orthostatic hypotension in patients ≥ 65 years of age compared to patients < 65 years of age treated with desvenlafaxine.

Adverse reactions leading to discontinuation of therapy.

The most common adverse reactions leading to discontinuation in at least 2% of the desvenlafaxine treated patients in the short-term trials, up to 8 weeks, were: nausea (4%); dizziness and vomiting (2% each); in the long-term trial, up to 9 months, the most common was vomiting (2%).

Reporting suspected effects.

Reporting suspected adverse reactions after registration of the medicinal products 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.

4.2 Dose and Method of Administration

Desvenlafaxine should be taken at approximately the same time each day. Tablets must be swallowed whole with fluid and not divided, crushed, chewed, or dissolved.

Initial treatment.

The recommended dose for desvenlafaxine is 50 mg once daily, with or without food. In clinical trials, no additional benefit was demonstrated at doses greater than 50 mg/day. Based on clinical judgment, if dose increases are indicated for individual patients, they should occur gradually and at intervals of not less than 7 days. The maximum dose should not exceed 200 mg/day.
When discontinuing therapy, gradual dose reduction is recommended whenever possible to minimise discontinuation symptoms (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).

Maintenance/ continuation/ extended treatment.

It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacological therapy. Patients should continue on the same dose at which they were stabilised. They should be periodically reassessed to determine the need for continued treatment.

Children and adolescents.

Safety and efficacy in patients less than 18 years of age have not been established.

Dosage adjustment in renal impairment.

The recommended starting dose in patients with severe renal impairment (24 hr CrCl < 30 mL/min) or endstage renal disease (ESRD) is 50 mg every other day. Because of individual variability in clearance in these patients, individualisation of dosage may be desirable. Supplemental doses should not be given to patients after dialysis (see Section 5 Pharmacological Properties).

Dosage adjustment in hepatic impairment.

No adjustment of dose is necessary in patients with mild, moderate, and severe hepatic impairment (see Section 5 Pharmacological Properties).

Dosage adjustment in the elderly.

No dosage adjustment is required solely on the basis of age; however, possible reduced renal clearance of desvenlafaxine should be considered when determining dose (see Section 5 Pharmacological Properties).

Discontinuing desvenlafaxine.

When discontinuing therapy gradual dose reduction should be considered to minimise discontinuation symptoms (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).
Symptoms associated with discontinuation of desvenlafaxine, as well as other SNRIs and SSRIs have been reported (see Section 4.4 Special Warnings and Precautions for Use). Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose, but at a more gradual rate (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).

Switching patients from other antidepressants to desvenlafaxine.

Discontinuation symptoms have been reported when switching patients from other antidepressants, including venlafaxine to desvenlafaxine. Tapering of the initial antidepressant followed by a washout period may be necessary to minimise discontinuation symptoms and the possibility of drug-drug interactions from a pharmacokinetic or pharmacodynamic perspective.

Residual inert tablet matrix.

Patients receiving desvenlafaxine may notice an inert matrix tablet passing in the stool or via colostomy.
Patients should be informed that the active medication has already been absorbed by the time the patient sees the inert matrix tablet.

4.7 Effects on Ability to Drive and Use Machines

The results of a clinical study that assessed the effects of desvenlafaxine on behavioural performance of healthy individuals revealed no clinically significant impairment of psychomotor, cognitive, or complex behaviour performance. However, since any CNS active drug may impair judgement, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that desvenlafaxine therapy does not adversely affect their ability to engage in such activities.

4.9 Overdose

There is limited clinical experience with desvenlafaxine overdosage in humans. In clinical trials, no cases of fatal acute overdose of desvenlafaxine were reported.
Among the patients included in the major depressive disorder trials of desvenlafaxine, there were four adults who ingested doses greater than 800 mg of desvenlafaxine (4000 mg [desvenlafaxine alone], 900, 1800 mg and 5200 mg [in combination with other drugs]); all patients recovered. In addition, a patient's 11 month old child accidentally ingested 600 mg of desvenlafaxine, was treated, and recovered.

Management of overdose.

In managing an overdose, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control centre for additional information on the treatment of any overdose. For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).
Treatment should consist of those general measures employed in the management of overdosage with any SSRI/ SNRI.
General supportive and symptomatic measures are recommended. Ensure an adequate airway, oxygenation and ventilation. Cardiac rhythm and vital signs must be monitored. Administration of activated charcoal may also limit drug absorption. Where there is a risk of aspiration, induction of emesis is not recommended. No specific antidotes for desvenlafaxine are known. Forced diuresis, dialysis, haemoperfusion and exchange transfusion are unlikely to be of benefit.

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

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

Store below 25°C.

6.5 Nature and Contents of Container

Desvenlafaxine Amneal (desvenlafaxine) modified release tablets are available as follows:
50 mg, light pink coloured, diamond shaped, biconvex tablets, debossed with 'L189' on one side and plain on other side. Blister packs (PVC/PVDC/Al) of 14 or 28 tablets and bottles (HDPE) of 7, 14, or 28 tablets*.
100 mg, dark brown to red coloured, diamond shaped, biconvex tablets, debossed with 'L190' on one side and plain on other side. Blister packs (PVC/PVDC/Al) of 14, or 28 tablets and bottles (HDPE) of 7, 14 or 28 tablets*.
The bottles of 7, 14 and 28 tablets are supplied with a child-resistant closure.
*Not all presentations and pack sizes are marketed in Australia.

6.6 Special Precautions for Disposal

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

Summary Table of Changes