DESVENLAFAXINE

Main information

  • Trade name:
  • DESVENLAFAXINE SANDOZ desvenlafaxine 100mg modified release tablets bottle
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • DESVENLAFAXINE SANDOZ desvenlafaxine 100mg modified release tablets bottle
    Australia
  • Language:
  • English

Other information

Status

  • Source:
  • Dept. of Health,Therapeutic Goods Administration - Australia
  • Authorization number:
  • 218069
  • Last update:
  • 08-10-2017

Public Assessment Report

Public Summary

Summary for ARTG Entry:

218069

DESVENLAFAXINE SANDOZ desvenlafaxine 100mg 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 SANDOZ desvenlafaxine 100mg 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

1000

(S4) Prescription Only Medicine

(S4) Prescription Only Medicine

(S4) Prescription Only Medicine

(S4) Prescription Only Medicine

Components

1. DESVENLAFAXINE SANDOZ desvenlafaxine 100mg modified release tablets bottle

Dosage Form

Tablet, modified release

Route of Administration

Oral

Visual Identification

Dark brown to red colored, diamond shaped, biconvex tablets, debossed

with 'Ll90' on one side and plain on other side.

Active Ingredients

Desvenlafaxine

100 mg

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

written approval from the Commonwealth.Further details can be found at http://www.tga.gov.au/about/website-copyright.htm.

Public Summary

Page 1 of

Produced at 26.11.2017 at 05:34:46 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

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PRODUCT INFORMATION

DESVENLAFAXINE SANDOZ

50MG, 100MG TABLET

NAME OF THE MEDICINE

Desvenlafaxine

The structural formula is shown below:

Chemical name:

4-[2-(dimethylamino)-1

RS

-(1-hydroxycyclohexyl)ethyl]phenol

Molecular formula:

Molecular weight:

263.38

CAS Registry Number:

93413-62-8

DESCRIPTION

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.

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

administration. Two strengths of DESVENLAFAXINE SANDOZ 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).

PHARMACOLOGY

Actions

Non-clinical studies have shown that desvenlafaxine is a selective serotonin and noradrenaline

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reuptake inhibitor (SNRI).

Pharmacodynamics

Desvenlafaxine

lacked

significant

affinity

numerous

receptors,

including

muscarinic-

cholinergic, H1-histaminergic, or

-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.

Pharmacokinetics

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, t

, 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.

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 (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 with

low,

medium,

high-fat

meals,

increases

approximately

(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.

plasma

protein

binding

desvenlafaxine

in

vitro

(approximately

30%)

independent of drug concentration over the range 100-500 ng/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

conjugation

(shown

mediated

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

oxidative

metabolite

N,O

-didesmethylvenlafaxine)

urine.

In

vitro

studies

showed

that

CYP3A4 is the predominant cytochrome P450 isozyme mediating the oxidative metabolism (

N

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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 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 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 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.

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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.

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-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 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. 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

Treatment of major depressive disorder, including the prevention of relapse. Not indicated for

paediatric use.

CONTRAINDICATIONS

Hypersensitivity

desvenlafaxine,

venlafaxine

hydrochloride

other

ingredient

desvenlafaxine (see

DESCRIPTION

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Monoamine Oxidase Inhibitors (MAOIs)

Desvenlafaxine 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 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

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 also

PRECAUTIONS

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 is a known risk of depression and 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 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.

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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

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 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

clinical

trials,

mania

reported

approximately

0.1%

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 is not approved for use in treating bipolar

depression.

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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

occur

with

desvenlafaxine

treatment,

particularly

with

concomitant use of other serotonergic drugs (including SSRIs, SNRIs and triptans) and with drugs

that

impair

metabolism

serotonin

(e.g.

MAOIs,

including

reversible

MAOIs

such

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,

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 and other agents that may affect the serotonergic

and/or

dopaminergic

neurotransmitter

system

(such

SSRI,

another

SNRI

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

discontinued

serotonin

syndrome

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

been

reported

association

with 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, particularly with higher

doses.

Pre-existing hypertension should be controlled before treatment with desvenlafaxine.

Patients receiving desvenlafaxine should

have

regular

monitoring

blood pressure. Cases of

elevated

blood pressure requiring immediate treatment have been reported with desvenlafaxine.

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Sustained

blood

pressure

increases

could

have

adverse

consequences.

patients

experience

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

ADVERSE 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,

pre-marketing

trials

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

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.

intolerable

symptoms

occur

following

decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed

dose may be considered (see

ADVERSE EFFECTS

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.

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Hyponatraemia

Cases of hyponatraemia and/or the Syndrome of Inappropriate Anti-Diuretic Hormone (SIADH)

secretion have been described with SNRIs (including desvenlafaxine) and SSRIs, usually in volume-

depleted

dehydrated

patients,

including

elderly

patients

patients

taking

diuretics

(see

ADVERSE 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 pre-marketing experience, the extent to which a

CNS-active

drug

will

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.

Use in Pregnancy

CATEGORY B2.

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

Only administer

desvenlafaxine to pregnant

women

expected

benefits

outweigh

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 re-uptake of serotonin).

Use in Lactation

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

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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

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 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

younger

subjects;

however,

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.

Carcinogenicity, Mutagenicity, Impairment of Fertility

Carcinogenicity

Desvenlafaxine

increase

incidence

tumours

long-term

mouse

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

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

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

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

desvenlafaxine

pregnant

rats

from

early

gestation

weaning

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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

results

clinical

study

that

assessed

effects

desvenlafaxine

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.

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.

INTERACTIONS WITH OTHER MEDICINES

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)

started

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

patients

taking

monoamine

oxidase

inhibitors

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 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 as tryptophan supplements). Serotonin syndrome symptoms may include mental status

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

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CONTRAINDICATIONS

PRECAUTIONS

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

PRECAUTIONS

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.

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ADVERSE 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.

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

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

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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 post-approval use.

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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. More patients experienced these events

during

desvenlafaxine

treatment

compared

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 at a rate of

5% include: dizziness, withdrawal

syndrome,

nausea,

headache,

irritability,

diarrhoea,

anxiety,

abnormal

dreams,

fatigue,

hyperhidrosis. In general, discontinuation symptoms occurred more frequently with longer duration

of therapy (see

DOSAGE AND

ADMINISTRATION

PRECAUTIONS - Discontinuation

Effects

Orthostatic hypotension

Of the 3,292 patients in clinical trials with Prisitq, 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%).

DOSAGE AND 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, 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

ADVERSE EFFECTS)

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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 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

desvenlafaxine

should

considered

when

determining

dose

(see

PHARMACOLOGY

Discontinuing desvenlafaxine

When

discontinuing

therapy

gradual

dose

reduction

should

considered

minimise

discontinuation symptoms (see

PRECAUTIONS

ADVERSE EFFECTS

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

have been reported (see

PRECAUTIONS

). Patients should be monitored for these symptoms when

discontinuing

treatment.

gradual

reduction

dose

rather

than

abrupt

cessation

recommended whenever possible. If intolerable symptoms occur following a decrease in the dose

upon

discontinuation

treatment,

then

resuming

previously prescribed

dose

may be

considered. Subsequently, the physician may continue decreasing the dose, but at a more gradual

rate (see

PRECAUTIONS

ADVERSE 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

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colostomy.

Patients should be informed that the active medication has already been absorbed by the time the

patient sees the inert matrix tablet.

OVERDOSAGE

Contact the Poisons Information Centre on telephone 13 11 26 for advice on management of

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.

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 SANDOZ

(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,

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 may be marketed in Australia

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Storage

Store below 25°C.

NAME AND ADDRESS OF THE SPONSOR

Medis Pharma Pty Ltd

Level 10, 53 Walker Street

North Sydney, NSW 2060

Australia

POISON SCHEDULE OF THE MEDICINE

Schedule 4 – Prescription Only Medicine.

DATE OF FIRST INCLUSION IN THE AUSTRALIAN REGISTER OF THERAPEUTIC

GOODS (THE ARTG):

26 November 2014

DATE OF MOST RECENT AMENDMENT:

03/07/2017

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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