DESVENLAFAXINE

Main information

  • Trade name:
  • DESVENLAFAXINE AMNEAL desvenlafaxine 50 mg modified release tablets bottle
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • DESVENLAFAXINE AMNEAL desvenlafaxine 50 mg modified release tablets bottle
    Australia
  • Language:
  • English

Other information

Status

  • Source:
  • Dept. of Health,Therapeutic Goods Administration - Australia
  • Authorization number:
  • 218070
  • Last update:
  • 08-10-2017

Public Assessment Report

Public Summary

Summary for ARTG Entry:

218070

DESVENLAFAXINE AMNEAL desvenlafaxine 50 mg modified release tablets bottle

ARTG entry for

Medicine Registered

Sponsor

Medis Pharma Pty Ltd

Postal Address

PO Box 6127,North Sydney, NSW, 2059

Australia

ARTG Start Date

26/11/2014

Product category

Medicine

Status

Active

Approval area

Drug Safety Evaluation Branch

Conditions

Conditions applicable to all therapeutic goods as specified in the document "Standard Conditions Applying to Registered or Listed Therapeutic Goods

Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Conditions applicable to the relevant category and class of therapeutic goods as specified in the document "Standard Conditions Applying to Registered

or Listed Therapeutic Goods Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Products

1. DESVENLAFAXINE AMNEAL desvenlafaxine 50 mg modified release tablets bottle

Product Type

Single Medicine Product

Effective date

4/09/2017

Warnings

See Product Information and Consumer Medicine Information for this product

Standard Indications

Specific Indications

For the treatment of major depressive disorder, including the preventiton of relapse. Not indicated for paediatric use.

Additional Product information

Container information

Type

Material

Life Time

Temperature

Closure

Conditions

Bottle

HDPE

4 Years

Store below 25

degrees Celsius

Child resistant closure

Store in Original

Container

Pack Size/Poison information

Pack Size

Poison Schedule

(S4) Prescription Only Medicine

(S4) Prescription Only Medicine

(S4) Prescription Only Medicine

Components

1. DESVENLAFAXINE AMNEAL desvenlafaxine 50 mg modified release tablets bottle

Dosage Form

Tablet, modified release

Route of Administration

Oral

Visual Identification

Light pink colored, diamond shaped, biconvex tablets, debossed with 'Ll89'

on one side and plain on other side.

Active Ingredients

Desvenlafaxine

50 mg

© Commonwealth of Australia.This work is copyright.You are not permitted to re-transmit, distribute or commercialise the material without obtaining prior

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Public Summary

Page 1 of

Produced at 26.11.2017 at 05:34:13 AEDT

This is not an ARTG Certificate document.

The onus is on the reader to verify the current accuracy of the information on the document subsequent to the date shown.

Visit www.tga.gov.au for contact information

Summary of Product characteristics

Desvenlafaxine Actavis PI 070415 Version 1

PRODUCT INFORMATION

DESVENLAFAXINE ACTAVIS

desvenlafaxine

NAME OF THE MEDICINE

DESVENLAFAXINE ACTAVIS desvenlafaxine 50 mg and 100 mg modified release

tablets. DESVENLAFAXINE ACTAVIS contains the active ingredient desvenlafaxine as

the base drug.

The structural formula is shown below:

Chemical name:

4-[2-(dimethylamino)-1RS-(1-hydroxycyclohexyl)ethyl]phenol

Molecular formula:

Molecular weight:

263.38

CAS Registry Number:

93413-62-8

DESCRIPTION

DESVENLAFAXINE ACTAVIS is formulated as a modified release tablet for once-a-day oral

administration. Two strengths of DESVENLAFAXINE ACTAVIS tablets are available, containing

50 mg and 100 mg of desvenlafaxine.

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.

Inactive ingredients are alginic acid, citric acid monohydrate, microcrystalline cellulose, povidone,

purified talc, magnesium stearate and hypromellose. The

tablets

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).

PHARMACOLOGY

Actions

Non-clinical studies of the reference product (desvenlafaxine succinate) have shown that

desvenlafaxine is a selective serotonin and noradrenaline reuptake inhibitor (SNRI).

Pharmacodynamics

studies

reference

product,

desvenlafaxine,

lacked

significant

affinity

numerous

Desvenlafaxine Actavis PI 070415 Version 1

receptors, including muscarinic- cholinergic,

H1-histaminergic,

-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.

preclinical

rodent

models

reference

product,

desvenlafaxine

demonstrated

activity

predictive of antidepressant, anxiolytic and thermoregulatory actions, and pain inhibitory properties.

Pharmacokinetics

The single dose pharmacokinetics of the reference product, desvenlafaxine are linear and dose-

proportional

dose range

mg/day. The

mean

terminal

half-life,

approximately 11 hours. With once-daily dosing, steady-state plasma concentrations are achieved

within approximately 4-5 days. At

steady

state,

multiple-dose

accumulation

the reference

product desvenlafaxine is linear and predictable from the single-dose pharmacokinetic profile.

pharmacokinetics of

desvenlafaxine

have

been thoroughly evaluated in women and men in

trials of the reference product. There are minimal differences based on gender; data from all subjects

are presented below.

Absorption and Distribution

reference

product,

desvenlafaxine

succinate

well

absorbed,

with

absolute

oral

bioavailability of 80%. Mean time to peak plasma concentrations (T

) is about 7.5 hours after

oral administration. AUC and C

6,747 ng.hr/mL and 376 ng/mL, respectively, are predicted after a single dose of 100 mg.

Administration with food has minimal impact on drug absorption. Following administration of

reference

product

with

low,

medium,

high-fat

meals,

increases

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 in studies of the reference product for any of the meals; therefore,

desvenlafaxine can be taken without regard to meals.

Studies of the reference product showed, the plasma protein binding of desvenlafaxine in vitro is

low (approximately 30%) and is independent of drug concentration over the range 100-500 ng/mL.

studies

t he

reference

product

desvenlafaxine’s

volume

distribution

steady-state

following

intravenous

administration

L/kg,

indicating

distribution

into

nonvascular

compartments.

Metabolism and Excretion

Studies of t he

reference

product

showed

approximately 45%

desvenlafaxine

excreted

unchanged

urine.

Studies

t he

reference

product

showed

desvenlafaxine

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 of the reference

product showed that CYP3A4 is the predominant cytochrome P450 isozyme mediating the oxidative

metabolism (N- demethylation) of desvenlafaxine.

Desvenlafaxine Actavis PI 070415 Version 1

Special Populations

Elderly (>65 years)

In a trial of healthy subjects administered doses up to 300 mg of the reference product, there was an

age-dependent decrease in desvenlafaxine clearance, resulting in a 32% increase in C

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 the reference product desvenlafaxine succinate 100 mg were studied

in subjects with mild (n = 9), moderate (n = 8), severe (n = 7) and end-stage 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 (t

) 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

DOSAGE AND ADMINISTRATION).

Hepatic Impairment

The pharmacokinetics of the reference product 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 t

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, the reference

product desvenlafaxine did not cause QT prolongation. Additionally, no effect on QRS interval was

observed.

Desvenlafaxine Actavis PI 070415 Version 1

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 of the reference product 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 the reference product desvenlafaxine once daily, or placebo (n =

118). In a second study, patients received either 200 mg (n = 121) or 400 mg (n = 124) of the

reference product

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

the reference product

desvenlafaxine once daily, or placebo (n = 150 and n = 161).

reference

product

desvenlafaxine

showed

superiority

over

placebo

measured

improvement in the 17-item Hamilton Rating Scale for Depression (HAM-D

) 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 drop-outs 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

the reference product 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-D

total score of ≤ 11 at the day 84 evaluation. Relapse during the double-

blind phase was defined as follows: (1) a HAM-D

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.

trials

reference

product,

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.

INDICATIONS

DESVENLAFAXINE ACTAVIS is indicated for the treatment of major depressive disorder,

including the prevention of relapse.

DESVENLAFAXINE ACTAVIS is not indicated for paediatric use.

CONTRAINDICATIONS

Hypersensitivity

desvenlafaxine,

venlafaxine

hydrochloride

excipients

DESVENLAFAXINE ACTAVIS formulation.

Monoamine Oxidase Inhibitors (MAOIs)

DESVENLAFAXINE

ACTAVIS must not be used in combination with monoamine oxidase

inhibitors (MAOIs) or reversible MAOIs (RIMA) (e.g. moclobemide, linezolid and intravenous

methylene

blue),

within

days

discontinuing

treatment

with

MAOI.

Similarly,

Desvenlafaxine Actavis PI 070415 Version 1

DESVENLAFAXINE ACTAVIS 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

have

recently

discontinued

SNRI

have

been

started

MAOI

(see

also

PRECAUTIONS and INTERACTIONS WITH OTHER MEDICINES).

PRECAUTIONS

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

known

risk

depression

certain

other

psychiatric

disorders,

these

disorders

themselves

strongest

predictors

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

the younger

patients

almost

medicines

studied. There

were

differences

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

given

changing

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

Desvenlafaxine Actavis PI 070415 Version 1

treatment or at times of dose increase or decrease.

Patients with co-morbid depression associated with other psychiatric or non-psychiatric disorders

being

treated

with

antidepressants

should

similarly

observed

clinical

worsening

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 non-psychiatric. 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 ACTAVIS 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 of the reference product, 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

established

in controlled

trials)

that

treating such

episode

with

antidepressant alone may increase the likelihood of

precipitation of

mixed/manic

episode

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 ACTAVIS is not approved

for use in treating bipolar depression.

with

antidepressants,

DESVENLAFAXINE

ACTAVIS should

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

ACTAVIS

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 CONTRAINDICATIONS).

Serotonin syndrome symptoms may include mental status changes (e.g.,

agitation, confusion,

hallucinations,

coma),

autonomic

instability

(e.g.,

diaphoresis,

tachycardia,

labile

blood

pressure,

hyperthermia),

neuromuscular

aberrations

(e.g.,

hyperreflexia,

incoordination,

Desvenlafaxine Actavis PI 070415 Version 1

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 INTERACTIONS WITH OTHER MEDICINES).

If concomitant treatment with DESVENLAFAXINE ACTAVIS 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 ACTAVIS with serotonin precursors (such as

tryptophan supplements) is not recommended.

Treatment with DESVENLAFAXINE ACTAVIS 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

studies of the reference product. Mydriasis has been reported in association with the reference

product

desvenlafaxine. It

recommended

that patients with raised intra-ocular pressure or

patients at risk for acute narrow-angle glaucoma (angle closure glaucoma) should be closely

monitored.

Co-administration 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

panic

disorders.

Products

containing

desvenlafaxine

should

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 with the reference

product, particularly with higher doses. Pre-existing hypertension should be controlled before

treatment with DESVENLAFAXINE ACTAVIS. Patients receiving D E S V E N L A F A X I N E

A C T A V I S should

have

regular

monitoring

blood pressure. Cases of

elevated

blood

pressure

requiring

immediate

treatment

have

been

reported

with

reference

product

desvenlafaxine.

Sustained

blood

pressure

increases

could

have

adverse

consequences.

patients

experience

sustained

increase

blood

pressure

while

receiving

DESVENLAFAXINE ACTAVIS, either dose reduction or discontinuation should be considered.

Caution

should

exercised

treating

patients

with

underlying

conditions

that

might

compromised by increases in blood pressure.

Cardiovascular/Cerebrovascular Disease

Caution

advised

administering

DESVENLAFAXINE

ACTAVIS

patients

with

cardiovascular,

cerebrovascular,

lipid

metabolism

disorders

(see

ADVERSE

EFFECTS).

Increases in blood pressure and heart rate were observed in clinical trials with the reference product

desvenlafaxine. Desvenlafaxine has not been evaluated systematically in patients with a recent

history

myocardial

infarction,

unstable

heart

disease,

uncontrolled

hypertension,

cerebrovascular disease. Patients with these diagnoses, except for cerebrovascular disease, were

excluded from clinical trials with the reference product.

Serum Lipids

Desvenlafaxine Actavis PI 070415 Version 1

In the short-term,

placebo-controlled,

pre-marketing

trials

MDD,

desvenlafaxine treatment

with the reference product was associated with mean increases of 5.7, 1.4, 3.6 and 5.5 mg/dl in total

cholesterol, HDL, LDL cholesterol

triglycerides,

respectively

(0.11,

0.03,

0.07

0.04

mmol/L, respectively). The changes in fasting serum total cholesterol, LDL, and triglycerides were

dose-related.

Measurement

serum

lipids

should

considered

during

treatment

with

DESVENLAFAXINE ACTAVIS.

Seizures

Cases of seizures have been reported in clinical trials with the reference product 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 ACTAVIS

should be prescribed with caution in patients with a seizure disorder.

Discontinuation Effects

During

marketing

SNRIs

(Serotonin

Noradrenaline

Reuptake

Inhibitors),

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 ADVERSE EFFECTS and DOSAGE AND 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 Anti-Diuretic Hormone (SIADH)

secretion

have

been

described

with

SNRIs

(including

reference

product

desvenlafaxine

succinate) and SSRIs, usually in volume-depleted or dehydrated patients, including elderly patients

and patients taking diuretics.

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

using the reference product desvenlafaxine. However, it is not possible to predict on the basis of

pre-marketing 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

Desvenlafaxine Actavis PI 070415 Version 1

There are no clinical

data establishing the risks and/or benefits of electroconvulsive therapy

combined with desvenlafaxine treatment for MDD.

Use in Pregnancy

CATEGORY B2.

The safety of desvenlafaxine in human pregnancy has not been established. Only administer

DESVENLAFAXINE ACTAVIS to pregnant

women

expected

benefits

outweigh

possible

risk.

DESVENLAFAXINE

ACTAVIS

used

until,

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

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. T hese 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 ACTAVIS taking into account the related

mechanism of action (inhibition of the re-uptake of serotonin).

Use in Lactation

Studies of the reference product showed, 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

importance

drug

mother.

Only

administer

DESVENLAFAXINE

ACTAVIS to breastfeeding women if the expected benefits outweigh any possible risk.

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 DOSAGE AND

ADMINISTRATION and PHARMACOLOGY - Pharmacokinetics).

Greater sensitivity to desvenlafaxine in some older patients cannot be ruled out.

Of the 3,292 patients in pre-marketing clinical trials of the reference product 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 of the reference product,

there

was a

higher

incidence

systolic

orthostatic hypotension in patients ≥ 65

years of age compared to patients <65 years of age

treated with desvenlafaxine.

Carcinogenicity, Mutagenicity, Impairment of Fertility

Desvenlafaxine Actavis PI 070415 Version 1

Carcinogenicity

In studies of the reference product desvenlafaxine did not increase the incidence of tumours in

long-term mouse and rat carcinogenicity studies at oral doses up to7 (mice), 14 (male rats) and 23

(female rats) times the maximal recommended human dose of 200 mg/day, on a mg/m

basis.

Genotoxicity

In studies of the reference product 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.

Effects on Fertility

In studies of the reference product, 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.

Teratogenicity

In studies of the reference product 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.

Studies of the reference product showed 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.

Effects on Ability to Drive and Use of Machines

The results of a clinical study of the reference product 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

reasonably

certain

that

DESVENLAFAXINE ACTAVIS therapy does not adversely affect their ability to engage in such

activities.

Effects on Laboratory Tests

studies

reference

product,

false-positive

urine

immunoassay

screening

tests

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.

INTERACTIONS WITH OTHER MEDICINES

Desvenlafaxine Actavis PI 070415 Version 1

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 had

SNRI or SSRI therapy discontinued prior to initiation of an MAOI

(see

PRECAUTIONS).

Concomitant

DESVENLAFAXINE

ACTAVIS

patients

taking

monoamine

oxidase

inhibitors is contraindicated (see CONTRAINDICATIONS).

Central Nervous System (CNS)-Active Agents

The risk

of using desvenlafaxine in

combination

with

other CNS-active drugs

not been

systematically evaluated. Consequently, caution is advised when DESVENLAFAXINE ACTAVIS

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

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 non-selective MAOI] and intravenous methylene blue), or with serotonin precursors

(such

tryptophan

supplements).

Serotonin

syndrome

symptoms

include

mental

status

changes, autonomic instability, neuromuscular aberrations and/or gastrointestinal symptoms (see

CONTRAINDICATIONS and PRECAUTIONS).

If concomitant treatment with DESVENLAFAXINE ACTAVIS 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

dose

increases.

concomitant

DESVENLAFAXINE ACTAVIS with serotonin precursors (such as tryptophan supplements) is not

recommended (see PRECAUTIONS).

Ethanol

A clinical study of the reference product 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

ACTAVIS.

Potential for Other Drugs to Affect Desvenlafaxine

Inhibitors of CYP3A4

CYP3A4 is minimally involved in desvenlafaxine elimination. In a clinical study of the reference

product, ketoconazole (200 mg BID) increased the AUC of desvenlafaxine (400 mg single dose) by

approximately 43%, a weak interaction.

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

Desvenlafaxine Actavis PI 070415 Version 1

Drugs metabolised by CYP2D6

When the reference product desvenlafaxine was administered at a dose of 400 mg daily in

conjunction

with

single

50 mg

dose

desipramine,

CYP2D6

substrate,

desipramine

increased

approximately

90%.

Concomitant

desvenlafaxine

with

drug

metabolised by CYP2D6 may result in higher concentrations of that drug.

Drugs metabolised by CYP3A4

In vitro testing of the reference product showed desvenlafaxine does not inhibit, or induce the

CYP3A4 isozyme.

In a clinical study of the reference product 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 testing ofthe reference product, showed 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 testing of the reference product showed desvenlafaxine is not a substrate or an

inhibitor for the P-glycoprotein transporter.

ADVERSE EFFECTS

Clinical Trials Experience

In a trial of the reference product, 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. In a trial of the reference product, 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 of

the reference product. 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.

Desvenlafaxine Actavis PI 070415 Version 1

System Organ Class Adverse Reaction

Cardiac disorders

Common

Palpitations, tachycardia

Ear and labyrinth disorders

Common

Tinnitus, vertigo**

Eye disorders

Common

Vision blurred, mydriasis

Gastrointestinal disorders

Very Common

Nausea, dry mouth, constipation

Common

Diarrhoea, vomiting

General disorders and administration site conditions

Very Common

Fatigue

Common

Chills, asthenia, feeling jittery, irritability

Immune system disorders

Uncommon

Hypersensitivity

Investigations

Common

Weight increased, blood pressure increased, weight decreased,

blood cholesterol increased

Uncommon

Blood triglycerides increased, liver function test abnormal, 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

Common

Somnolence, tremor, paraesthesia, dysgeusia, disturbance in

attention

Uncommon

Syncope

Rare

Convulsion, extrapyramidal disorder

Psychiatric disorder

Very Common

Insomnia

Common

Anxiety, abnormal dreams, nervousness, libido decreased,

anorgasmia, orgasm abnormal

Uncommon

Depersonalisation, hypomania, withdrawal syndrome

Rare

Hallucinations

Renal and urinary disorders

Common

Urinary hesitation

Uncommon

Proteinuria, urinary retention**

Reproductive system and breast disorders

Desvenlafaxine Actavis PI 070415 Version 1

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

Not known

Stevens-Johnson syndrome**

Vascular disorders

Common

Hot flush

Uncommon

Orthostatic hypotension, peripheral coldness

* Frequency is calculated based on men only

** Adverse reaction identified during post-approval 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

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. In trials of the reference product,

more patients experienced these events during desvenlafaxine treatment as compared to placebo (see

PRECAUTIONS – Cardiovascular/Cerebrovascular Disease).

Discontinuation Symptoms

Adverse drug reactions reported in association with abrupt discontinuation, dose reduction or

tapering of treatment in MDD clinical trials of the reference product 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 DOSAGE AND ADMINISTRATION and PRECAUTIONS

Discontinuation Effects).

Orthostatic hypotension

Of the 3,292 patients in clinical trials with the reference product desvenlafaxine, 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 the reference product desvenlafaxine.

Adverse Reactions Leading to Discontinuation of Therapy

Desvenlafaxine Actavis PI 070415 Version 1

The most common adverse reactions leading to discontinuation in at least 2% of the desvenlafaxine-

treated patients in the short-term trials of the reference product, 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%).

DOSAGE AND ADMINISTRATION

DESVENLAFAXINE ACTAVIS 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 ACTAVIS is 50 mg once daily, with or without

food. In clinical trials of the reference product, doses of 50-400 mg/day were shown to be effective,

although 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 PRECAUTIONS and ADVERSE 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. The efficacy of desvenlafaxine (200-400 mg) in major

depressive disorder was demonstrated in the 24-week double-blind phase of a relapse prevention

trial of the reference product in patients who had responded during an initial, 12-week open-label

phase (see CLINICAL TRIALS). 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 end-stage 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 PHARMACOLOGY).

Dosage Adjustment in Hepatic Impairment

No adjustment of dose is necessary in patients with mild, moderate, and severe hepatic impairment

(see PHARMACOLOGY).

Dosage Adjustment in the Elderly

No dosage adjustment is required solely on the basis of age; however, possible reduced renal

clearance of DESVENLAFAXINE ACTAVIS should be considered when determining dose (see

PHARMACOLOGY).

Discontinuing DESVENLAFAXINE ACTAVIS

When

discontinuing

therapy

gradual

dose

reduction

should

considered

minimise

discontinuation symptoms (see PRECAUTIONS and ADVERSE EFFECTS).

Symptoms associated with discontinuation of desvenlafaxine, as well as other SNRIs and SSRIs

have been reported in trials of the reference product (see PRECAUTIONS). Patients should be

Desvenlafaxine Actavis PI 070415 Version 1

monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather

than

abrupt

cessation

recommended

whenever

possible.

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 PRECAUTIONS and ADVERSE EFFECTS).

Switching Patients from Other Antidepressants to DESVENLAFAXINE ACTAVIS

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 ACTAVIS 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.

OVERDOSAGE

There is limited clinical experience with desvenlafaxine overdosage in humans. In clinical trials

of the reference product, no cases of fatal acute overdose of desvenlafaxine were reported.

Among the patients included in the major depressive disorder trials of the reference product

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.

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.

PRESENTATION AND STORAGE CONDITIONS

DESVENLAFAXINE ACTAVIS

(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 7, 14 or 28 tablets and bottles (HDPE) of 7, 14,

Desvenlafaxine Actavis PI 070415 Version 1

28 or 1000 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 7, 14, or 28 tablets and bottles (HDPE)

of 7, 14, 28 or 1000 tablets*.

*not all presentations and pack sizes are marketed in Australia

Storage

Store below 25°C.

NAME AND ADDRESS OF THE SPONSOR

Medis Pharma Pty Ltd

Level 3, 5 Essex Street

The Rocks, NSW 2000

Australia

POISON SCHEDULE OF THE MEDICINE

Schedule 4 – Prescription Only Medicine.

DATE OF FIRST INCLUSION IN THE AUSTRALIAN REGISTER OF

THERAPEUTIC GOODS

26 November 2014

DATE OF MOST RECENT AMENDMENT

8 April 2015

20-3-2018

Medicines Safety Update, Volume 9, Number 1, February-March 2018

Medicines Safety Update, Volume 9, Number 1, February-March 2018

First-generation oral sedating antihistamines – use in children, Suvorexant (Belsomra) – next day effects, Desvenlafaxine (Pristiq) recommended dose, Miconazole and potential interaction with warfarin

Therapeutic Goods Administration - Australia

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