Depreger 50mg & 100mg Film-Coated Tablets

4. CLINICAL PARTICULARS

4.1 Therapeutic I indications

4.5 Interaction with other medicinal products and other forms of interaction

Special precautions

Other drug interactions, digoxin, atenolol, cimetidine
Co-administration with cimetidine caused a substantial decrease in sertraline clearance. The clinical significance of these changes is unknown. Sertraline had no effect on the beta-adrenergic blocking ability of atenolol. No interaction of sertraline 200 mg daily was observed with digoxin.

Neuromuscular Blockers
SSRIs may reduce plasma cholinesterase activity resulting in a prolongation of the neuromuscular blocking action of mivacurium or other neuromuscular blockers.

Drugs affecting platelet function
The risk of bleeding may be increased when medicines acting on platelet function (e.g. NSAIDs, acetylsalicylic acid and ticlopidine) or other medicines that might increase bleeding risk are concomitantly administered with SSRIs, including sertraline (see section 4.4).

4.8 Undesirable effects

Very Common (>1/10)	Common (>1/100 to <1/10)	Uncommon (>1/1,000 to <1/100)	Rare (>1/10,000 to <1/1,000)	Very Rare (<1/10,000)	Not Known (cannot be estimated from the available data)
Infections and infestations
	Pharyngitis	Upper Respiratory Tract Infection, Rhinitis	Diverticulitis, Gastroenteritis, Otitis Media
Neoplasms benign, malignant and unspecified (including cysts and polyps)
			Neoplasm†
Blood and lymphatic system disorders
			Lymphadenopathy		Leucopenia, Thrombocytopenia
Immune system disorders
		Hypersensitivity	Anaphylactoid Reaction		Allergy
Endocrine disorders
		Hypothyroidism			Hyperprolactinaemia, Inappropriate Antidiuretic Hormone (ADH) Secretion
Metabolism and nutrition disorders
	Decreased Appetite, Increased Appetite*		Diabetes Mellitus, Hypercholesterolaemia, Hypoglycaemia		Hyponatraemia, Hyperglycaemia
Psychiatric disorders
Insomnia (19%)	Depression*, Depersonalisation, Nightmare, Anxiety*, Agitation*, Nervousness, Libido Decreased*, Bruxism	Hallucination*, Aggression*, Euphoric Mood*, Apathy, Thinking Abnormal	Conversion Disorder, Drug Dependence, Psychotic disorder*, Paranoia, Suicidal ideation/behaviour***, Sleep Walking, Premature Ejaculation		Paroniria
Nervous system disorders
Dizziness (11%), Somnolence (13%), Headache (21%)*	Paraesthesia*, Tremor, Hypertonia, Dysgeusia, Disturbance in Attention	Convulsion*, Muscle Contractions Involuntary*, Coordination Abnormal, Hyperkinesia, Amnesia, Hypoaesthesia*, Speech Disorder, Dizziness Postural, Syncope, Migraine*	Coma*, Choreoathetosis, Dyskinesia, Hyperaesthesia, Sensory Disturbance		Movement Disorders (including extrapyramidal symptoms such as hyperkinesia, hypertonia, dystonia, teeth grinding or gait abnormalities). Also reported were signs and symptoms associated with serotonin syndrome or Neuroleptic Malignant Syndrome: In some cases associated with concomitant use of serotonergic drugs that included agitation, confusion, diaphoresis, diarrhoea, fever, hypertension, rigidity and tachycardia. Akathisia and psychomotor restlessness (see section 4.4). Cerebrovascular Spasm (including reversible Cerebral vasoconstriction syndrome and Call-Fleming syndrome).
Eye disorders
	Visual Disturbance	Mydriasis*	Glaucoma, Lacrimal Disorder, Scotoma, Diplopia, Photophobia, Hyphaema		Vision Abnormal, Pupils Unequal
Ear and labyrinth disorders
	Tinnitus*	Ear Pain
Cardiac disorders
	Palpitations*	Tachycardia	Myocardial Infarction, Bradycardia, Cardiac Disorder		QTc Prolongation, Torsade de Pointes
Vascular disorders
	Hot flush*	Hypertension*, Flushing	Peripheral Ischaemia, Haematuria		Abnormal Bleeding (such as gastrointestinal bleeding)
Respiratory, thoracic, and mediastinal disorders
	Yawning*	Bronchospasm*, Dyspnoea, Epistaxis	Laryngospasm, Hyperventilation, Hypoventilation, Stridor, Dysphonia, Hiccups		Interstitial Lung Disease
Gastrointestinal disorders
Diarrhoea (18%), Nausea (24%), Dry Mouth (14%)	Abdominal Pain* Vomiting*, Constipation* Dyspepsia, Flatulence	Oesophagitis, Dysphagia, Haemorrhoids, Salivary Hypersecretion, Tongue Disorder, Eructation	Melaena, Haematochezia, Stomatitis, Tongue Ulceration, Tooth Disorder, Glossitis, Mouth Ulceration		Pancreatitis
Hepatobiliary disorders
			Hepatic Function Abnormal		Serious liver events (including hepatitis, jaundice and liver failure)
Skin and subcutaneous tissue disorders
	Rash*, Hyperhidrosis	Periorbital Oedema*, Face Oedema, Purpura*, Alopecia*, Cold Sweat, Dry Skin, Urticaria*, Pruritus	Dermatitis, Dermatitis Bullous, Rash Follicular, Hair Texture Abnormal, Skin Odour Abnormal		Rare reports of Severe Cutaneous Adverse Reactions (SCAR): e.g. Stevens-Johnson syndrome and epidermal necrolysis, Angioedema, Photosensitivity, Skin Reaction
Musculoskeletal and connective tissue disorders
	Arthralgia,  Myalgia	Osteoarthritis, Muscular Weakness, Back Pain, Muscle Twitching	Bone Disorder		Muscle Cramps
Renal and urinary disorders
		Nocturia, Urinary Retention*, Polyuria, Pollakiura, Micturition Disorder, Urinary Incontinence*	Oliguria, Urinary Hesitation
Reproductive system and breast disorders**
Ejaculation Failure (14%)	Erectile Dysfunction	Vaginal Haemorrhage, Sexual Dysfunction, Female Sexual Dysfunction, Menstruation Irrelugar Irregular	Menorrhagia, Atrophic Vulvovaginitis, Balanoposthitis, Genital Discharge, Priapism*, Galactorrhoea*		Gynaecomastia
General disorders and administration site conditions
Fatigue (10%)*	Chest Pain*, Malaise*	Oedema Peripheral, Chills, Pyrexia*, Asthenia*, Thirst	Hernia, Drug Tolerance Decreased, Gait Disturbance
Investigations
		Alanine Aminotransferase Aminotransferarase Increased*, Aspartate Aminotransferase Increased*, Weight Decreased*, Weight Increased*	Semen Abnormal, Blood Cholesterol Increased		Abnormal Clinical Laboratory Results, Altered Platelet Function
Injury, poisoning and procedural complications
			Injury
Surgical and medical procedures
			Vasodilation Procedure
If adverse experience occurred in depression, OCD, panic disorder, PTSD and social anxiety disorder, body term reclassified by depression studies body term. † One case of neoplasm was reported in one patient receiving sertraline compared with no cases in the placebo arm. * these adverse reactions also occurred in post-marketing experience ** the denominator uses the number of patients in that sex group-combined: sertraline (1118 males, 1424 females) placebo (926 males, 1219 females) For OCD, short term, 1-12 week studies only *** Cases of suicidal ideation and suicidal behaviours have been reported during sertraline therapy or early after treatment discontinuation (see section 4.4).

6.5 Nature and contents of container

High dDensity Polyethylene polypropylene (HDPE) bottles with polypropylene polyethylene caps (with optional polyethylene filler) in *packages of 14, 15, 20, 28, 30, 50, 60, 98, 100, 250, 300, 500.
PVC/PVdC/aluminium blisters in *packs of 14, 15, 20, 28, 30, 50, 60, 98, 100, 250, 300, 500.
PVC/aluminium blisters in *packs of 14, 15, 20, 28, 30, 50, 60, 98, 100, 250, 300, 500.
*Not all pack sizes may be marketed.

4.4 Special warnings and precautions for use

Serotonin Syndrome (SS) or Neuroleptic Malignant Syndrome (NMS)

The development of potentially life-threatening syndromes like serotonin syndrome (SS) or Neuroleptic Malignant Syndrome (NMS) has been reported with SSRIs, including treatment with sertraline. The risk of SS or NMS with SSRIs is increased with concomitant use of

 

other serotonergic drugs (including other serotonergic antidepressants, triptans), with drugs which impair metabolism of serotonin (including MAOIs e.g. methylene blue), antipsychotics, and other dopamine antagonists and with opiate drugs. Patients should be monitored for the emergence of signs and symptoms of SS or NMS syndrome (see section 4.3).

 

Switching from Selective Serotonin Reuptake Inhibitors (SSRIs), antidepressants or anti

 

-obsessional drugs

 

There is limited controlled experience regarding the optimal timing of switching from SSRIs, antidepressants or anti

 

-obsessional drugs to sertraline. Care and prudent medical judgment should be exercised when switching, particularly from long-acting agents such as fluoxetine.

 

Other serotonergic drugs e.g. tryptophan, fenfluramine and 5-HT agonists

Co-administration of sertraline with other drugs which enhance the effects of serotonergic neurotransmission such as tryptophan or fenfluramine or 5-HT agonists, or the herbal medicine, St John’s

 

Wwort (Hypericum perforatum), should be undertaken with caution and avoided whenever possible due to the potential for a pharmacodynamic interaction.

 

QTc prolongation/Torsade de Pointes (TdP)

Cases of QTc prolongation and Torsade de Pointes (TdP) have been reported during post-marketing use of sertraline. The majority of reports occurred in patients with other risk factors for QTc prolongation/TdP. Therefore sertraline should be used with caution in patients with risk factors for QTc prolongation.

 

Paediatric population

 

 

 

Use in children and adolescents under 18 years of age

 

 

 

 

Sertraline should not be used in the treatment of children and adolescents under the age of 18 years, except for patients with obsessive compulsive disorder aged 6-17 years old. Suicide-related behaviours (suicide attempt and suicidal thoughts), and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo. If, based on clinical need, a decision to treat is nevertheless taken; the patient should be carefully monitored for appearance of suicidal symptoms. In addition,

only limited clinical evidence is available concerning long term safety data in children and adolescents including effects on growth, sexual maturation and cognitive and behavioural developments. A few cases of retarded growth and delayed puberty have been reported post-marketing. The clinical relevance and causality are yet unclear (see section 5.3 for corresponding preclinical safety data)long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking. Physicians must monitor paediatric patients on long term treatment for abnormalities in growth and developmentthese body systems.

 

Abnormal bleeding/

Hhaemorrhage

 

There have been reports of

bleeding abnormalities with SSRIs including cutaneous bleeding abnormalities such as (ecchymoses and purpura) and other haemorrhagic events such as gastrointestinal or gynaecological bleeding, including fatal haemorrhageswith SSRIs. Caution is advised in patients taking SSRIs, particularly in concomitant use with drugs known to affect platelet function (e.g. anticoagulants, atypical antipsychotics and phenothiazines, most tricyclic antidepressants, acetylsalicylic acid and non-steroidal anti-inflammatory drugs (NSAIDs)) as well as in patients with a history of bleeding disorders (see section 4.5).

 

4.5 Interaction with other medicinal products and other forms of interaction

 

Severe adverse reactions have been reported in patients who have recently been discontinued from an MAOI (e.g. methylene blue) and started on sertraline, or have recently had sertraline therapy discontinued prior to initiation of an MAOI. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, and hyperthermia with features resembling neuroleptic malignant syndrome, seizures, and death.

 

 

Other serotonergic drugs

 

See section 4.4.

Caution is also advised with fentanyl

 

(used in general anaesthesia or in the treatment of chronic pain), other serotonergic drugs (including other serotonergic antidepressants, triptans) and with other opiate drugs.

 

 

 

Special Pprecautions

 

Drugs that prolong the QT interval

 

 

The risk of QTc prolongation and/or ventricular arrhythmias (e.g. TdP) may be increased with concomitant use of other drugs which prolong the QTc interval (e.g. some antipsychotics and antibiotics) (see section 4.4)

 

 

 

 

 

 

4.8 Undesirable effects

 

Very Common (>1/10)	Common (>1/100 to <1/10)		Uncommon (>1/1   ,000 to   <1/100)		Rare (>1/10   ,000 to   <1/1   ,000)	Very rRare   (<1/10   ,000)		Not kKnown (cannot be estimated from the available data)
Infections and   Iinfestations
Pharyngitis			Upper Respiratory Tract Infection, Rhinitis			Diverticulitis, Gastroenteritis, Otitis Media
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Neoplasm†
Blood and lymphatic system disorders
Lymphadenopathy					Leucopenia, Thrombocytop   aenia
Immune system disorders
Hypersensitivity			Anaphylactoid Reaction			Anaphylactoid Reaction, Allergic Reaction, Allergy
Endocrine disorders
Hypothyroidism					Hyperprolactinaemia, Hypothyroidism and syndrome of i     Inappropriate Antidiuretic Hormone   (     ADH) sSecretion
Metabolism and   Nnutrition Ddisorders
Anorexia     Decreased aAppetite,   Increased Appetite*			Diabetes Mellitus,     Hypercholesterolaemia, Hypoglycaemia			Hyponatr   aemia, Diabetes Mellitus, Hyperglycaemia
Psychiatric   Ddisorders
Insomnia (19%)		Depression*, Depersonalisation, Nightmare, Anxiety*, Agitation*, Nervousness, Libido		Hallucination*,   Aggression*,   Euphoric Mood*, Apathy, Thinking Abnormal			Conversion Disorder, Drug Dependence, Psychotic disorder*, Aggression*, Paranoia, Suicidal ideation/behaviour***,

Very Common (>1/10)

Common (>1/100 to <1/10)

Uncommon (>1/1   ,000 to   <1/100)

Rare (>1/10   ,000 to   <1/1   ,000)

Very rRare   (<1/10   ,000)

Not kKnown (cannot be estimated from the available data)

Decreased*, Bruxism

Walking, Premature Ejaculation

Nervous   Ssystem Ddisorders

Dizziness (11%), Somnolence (13%), Headache (21%)*

Paraesthesia*, Tremor, Hypertonia, Dysgeusia, Disturbance in Attention

Convulsion*, Muscle Contractions Involuntary*, Coordination Abnormal, Hyperkinesia, Amnesia, Hypoaesthesia*, Speech Disorder, Dizziness Postural,   Syncope,   Migraine*

Coma*, Choreoathetosis, Dyskinesia, Hyperaesthesia, Sensory Disturbance

Movement Disorders (including extrapyramidal symptoms such as hyperkinesia, hypertonia, dystonia, teeth grinding or gait abnormalities)   ,   Syncope     . Also reported were signs and symptoms associated with serotonin syndrome or Neuroleptic Malignant Syndrome: In some cases associated with concomitant use of serotonergic drugs that included agitation,   confusion, diaphoresis, diarrhoea, fever, hypertension, rigidity and tachycardia. Akathisia and psychomotor restlessness (see section 4.4). Cerebrovascular Spasm (including reversible Cerebral vasoconstriction syndrome and   cCall-fFleming syndrome).

Eye   Ddisorders

Visual Disturbance

Mydriasis*

Glaucoma, Lacrimal Disorder, Scotoma, Diplopia, Photophobia, Hyphaema   ,   Mydriasis*

Vision a     Abnormal, Pupils Unequal

Ear and   Llabyrinth Ddisorders

Tinnitus*

Ear Pain

Cardiac   Ddisorders

Palpitations*

Tachycardia

Myocardial Infarction, Bradycardia, Cardiac Disorder

QTc Prolongation, Torsade de Pointes

Very Common (>1/10)

Common (>1/100 to <1/10)

Uncommon (>1/1   ,000 to   <1/100)

Rare (>1/10   ,000 to   <1/1   ,000)

Very rRare   (<1/10   ,000)

Not kKnown (cannot be estimated from the available data)

Vascular   Ddisorders

Hot flush*

Hypertension*, Flushing

Peripheral Ischaemia   , Haematuria

Abnormal Bleeding (such As   epistaxis, gastrointestinal   bleeding   or haematuria)

Respiratory,   Tthoracic, and Mmediastinal Ddisorders

Yawning*

Bronchospasm*, Dyspnoea, Epistaxis

Laryngospasm, Hyperventilation, Hypoventilation, Stridor, Dysphonia, Hiccups

Interstitial Lung Disease

Gastrointestinal   Ddisorders

Diarrhoea (18%), Nausea (24%), Dry Mouth (14%)

Abdominal Pain* Vomiting*, Constipation* Dyspepsia, Flatulence

Oesophagitis, Dysphagia, Haemorrhoids, Salivary Hypersecretion, Tongue Disorder, Eructation

Melaena, Haematochezia, Stomatitis, Tongue u     Ulceration, Tooth   Disorder, Glossitis, Mouth Ulceration

Pancreatitis

Hepatobiliary   Ddisorders

Hepatic Function Abnormal

Serious liver events (including hepatitis, jaundice and liver failure)

Skin and   Ssubcutaneous Ttissue Ddisorders

Rash*, Hyperhidrosis

Periorbital Oedema*,   Face Oedema,   Purpura*, Alopecia*, Cold Sweat, Dry   sSkin,   Urticaria*   , Pruritus

Dermatitis, Dermatitis Bullous, Rash Follicular, Hair Texture Abnormal, Skin Odour Abnormal

Rare reports of   sSevere   Cutaneous   aAdverse   Reactions (SCAR): e.g. Stevens-Johnson syndrome and epidermal necrolysis, Angioedema, Face Oedema, Photosensitivity, Skin Reaction   ,   Pruritus

Musculoskeletal and   Cconnective Ttissue Ddisorders

Arthralgia,     Myalgia

Osteoarthritis, Muscular Weakness, Back Pain, Muscle Twitching

Bone Disorder

Arthralgia, Muscle Cramps

Renal and   Uurinary Ddisorders

Nocturia, Urinary Retention*, Polyuria, Pollakiura, Micturition d     Disorder, Urinary

Oliguria,   Urinary   Incontinence*, Urinary Hesitation

Very Common (>1/10)	Common (>1/100 to <1/10)		Uncommon (>1/1   ,000 to   <1/100)		Rare (>1/10   ,000 to   <1/1   ,000)		Very rRare   (<1/10   ,000)		Not kKnown (cannot be estimated from the available data)
Incontinence*
Reproductive   Ssystem and Bbreast Ddisorders**
Ejaculation Failure (14%)		Sexual Dysfunction, Erectile Dysfunction		Vaginal Haemorrhage,   Sexual   Dysfunction, Female Sexual Dysfunction,   Menstruation Irrelugar		Menorrhagia, Atrophic Vulv   uovaginitis,   Balanoposthitis, Genital Discharge, Priapism*, Galactorrhoea*		Gynaecomastia   ,   Menstrual Irregularities
General   Ddisorders and Aadministration Ssite Cconditions
Fatigue (10%)*		Chest Pain*,   Malaise*		Malaise*     Oedema Peripheral,   Chills, Pyrexia*, Asthenia*, Thirst		Hernia, Drug Tolerance Decreased, Gait Disturbance		Oedema Peripheral
Investigations
Alanine Aminotransferarase Increased*, Aspartate Aminotransferase Increased*,     Weight   Decreased*, Weight Increased*			Alanine Aminotransferarase Increased*, Aspartate Aminotransferase Increased*,     Semen   Abnormal   , Blood Cholesterol Increased				Abnormal Clinical Laboratory Results, Altered Platelet Function   ,   Increased Serum Cholesterol
Injury, poisoning and procedural complications
Injury
Surgical and medical procedures
Vasodilation Procedure
If adverse experience occurred in depression, OCD, panic disorder, PTSD and social anxiety disorder, body term reclassified by depression studies body term. †   One case of neoplasm was reported in one patient receiving sertraline compared with no cases in the placebo arm.   * these adverse reactions also occurred in post   -marketing experience   ** the denominator uses the number of patients in that sex group-combined: sertraline (1118 males, 1424 females) placebo (926 males, 1219 females) For OCD, short term, 1-12 week studies only *** Cases of suicidal ideation and suicidal behaviours have been reported during sertraline therapy or early after treatment discontinuation (see section 4.4).

 

Class effects

 

Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving SSRIs and TCAs. The mechanism leading to this risk is unknown.

 

 

 

 

 

 

Uncommon (≥1/1

,000 to <1/100): ECG QT prolonged, suicide attempt, convulsion, extrapyramidal disorder, paraesthesia, depression, hallucination, purpura, hyperventilation, anaemia, hepatic function abnormal, alanine aminotransferase increased, cystitis, herpes simplex, otitis externa, ear pain, eye pain, mydriasis, malaise, haematuria, rash pustular, rhinitis, injury, weight decreased, muscle twitching, abnormal dreams, apathy, albuminuria, pollakiuria, polyuria, breast pain, menstrual disorder, alopecia, dermatitis, skin disorder, skin odour abnormal, urticaria, bruxism, flushing.

 

 

 

Frequency not known: enuresis.

 

 

 

 

Class effects
Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving SSRIs and TCAs. The mechanism leading to this risk is unknown.

 

 

 

 

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517; website: www.hpra.ie; e-mail: medsafety@hpra.ie.FREEPOST, Pharmacovigilance Section, Irish Medicines Board, Kevin O’Malley House, Earlsfort Centre, Earlsfort Terrace, Dublin 2. Tel: +353 1 6764971, Fax: +353 1 6762517 Website: http://www.imb.ie E-mail: imbpharmacovigilance@imb.ie

 

4.9 Overdose

 

Toxicity
On the evidence available, sSertraline has a wide margin of safety dependent on patient population and/or concomitant medicationin overdose. Overdoses of sertraline alone of up to 13.5 g have been reported. Deaths have been reported involving overdoses of sertraline, alone or primarily in combination with other drugs and/or alcohol. Therefore, any overdosage should be medically treated aggressively.

 

 

 

Symptoms
Symptoms of overdose include serotonin-mediated side effects such as somnolence, gastrointestinal disturbances (such as nausea and vomiting), tachycardia, tremor, agitation and dizziness. Less frequently reported was coma.

 

 

 

QTc prolongation/Torsade de Pointes has been reported following sertraline overdose; therefore, ECG-monitoring is recommended in all ingestions of sertraline overdoses.

 

Treatment

There are no specific antidotes to sertraline. It is recommended to Eestablish and maintain an airway and, if necessary, ensure adequate oxygenation and ventilation, if necessary. Activated charcoal, which may be used with a cathartic, may be as or more effective than lavage, and should be considered in treating overdose. Induction of emesis is not recommended. Cardiac (e.g. ECG) and other vital sign monitoring is also recommended, along with general symptomatic and supportive measures. Due to the large volume of distribution of sertraline, forced diuresis, dialysis, haemoperfusion and exchange transfusion are unlikely to be of benefit.

 

 

 

Sertraline overdose may prolong the QT-interval, and ECG-monitoring is recommended in all ingestions of sertraline overdoses.

 

 

 

 

 

 

 

5.1 Pharmacodynamic properties

 

Paediatric population
No data is available for children under 6 years of age.

 

 

5.2 Pharmacokinetic properties

 

 

Absorption
Sertraline exhibits dose proportional pharmacokinetics in the range of 50 to 200 mg. In man, following an oral once-daily dosage of 50 to 200 mg for 14 days, peak plasma concentrations of sertraline occur at 4.5 to 8.4 hours after the daily administration of the drug. Food does not significantly change the bioavailability of sertraline tablets.

 

 

 

Linearity/non-linearity
Sertraline exhibits dose proportional pharmacokinetics in the range of 50 to 200 mg.

 

 

 

 

Pharmacokinetics in specific patient groups

 

Paediatric

patients population with OCD

 

 

Pharmacokinetics of sertraline was studied in 29 paediatric patients aged 6-12 years old, and 32 adolescent patients aged 13-17 years old. Patients were gradual uptitrated to a 200 mg daily dose within 32 days, either with 25 mg starting dose and increment steps, or with 50 mg starting dose or increments. The 25 mg regimen and the 50 mg regimen were equally tolerated. In steady state for the 200 mg dose, the sertraline plasma levels in the 6-12 year old group were approximately 35% higher compared to the 13-17 year old group, and 21% higher compared to adult reference group. There were no significant differences between boys and girls regarding clearance. A low starting dose and titration steps of 25 mg are therefore recommended for children, especially with low bodyweight.

 

Adolescents could be dosed like adults.

 

 

Liver functionHepatic impairment
In patients with liver damage, the half life of sertraline is prolonged and AUC is increased three fold (see sections 4.2 and 4.4).

 

 

 

 

5.3 Preclinical safety data

 

Preclinical data does not indicate any special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenesis. Reproduction toxicity studies in animals showed no evidence of teratogenicity or adverse effects on male fertility. Observed foetotoxicity was probably related to maternal toxicity. Postnatal pup survival and body weight were decreased only during the first days after birth. Evidence was found that the early postnatal mortality was due to in-utero exposure after day 15 of pregnancy. Postnatal developmental delays found in pups from treated dams were probably due to effects on the dams and therefore not relevant for human risk.

 

Animal data from rodents and non-rodents does not reveal effects on fertility.

 

Juvenile animal studies
A juvenile toxicology study in rats has been conducted in which sertraline was administered orally to male and female rats on Postnatal Days 21 through 56 (at doses of 10, 40, or 80 mg/kg/day) with a nondosing recovery phase up to Postnatal Day 196. Delays in sexual maturation occurred in males and females at different dose levels (males at 80 mg/kg and females at ≥10 mg/kg), but despite this finding there were no sertraline-related effects on any of the male or female reproductive endpoints that were assessed. In addition, on Postnatal Days 21 to 56, dehydration, chromorhinorrhea, and reduced average body weight gain was also observed. All of the aforementioned effects attributed to the administration of sertraline were reversed at some point during the nondosing recovery phase of the study. The clinical relevance of these effects observed in rats administered sertraline has not been established.

 

 

 

6.6 Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product
No special requirementsNot applicable.

 

 

 

8. MARKETING AUTHORISATION NUMBER(S)

 

 

PA0577/067/001
PA0577/067/002

 

 

 

 

 

 

• 2, pharmaceutical form is changed, the colour is changed to to white to off-white capsule shaped
• 4.2, patients changed to population
• 4.2, Withdrawal symptoms seen on discontinuation of sertraline treatment
• 4.4, Triptans and tramadol added, Contraindications  was deleted
• 4.4, Under subsection

  Suicide/suicidal thoughts/suicide attempts or clinical worsening, self harm changed to self-harm

• 4.4, Renal impairment - AUC_0-24 or C_max was formatted correctly

• 4.4, Diabetes - . 'Insulin and/or oral hypoglycaemic dosage may need to be adjusted' replaced text following 'In patients with diabetes, treatment with an SSRI may alter glycaemic control'

• 4.4, Grapefruit juice - 'The intake of grapefruit juice should be avoided during treatment with sertraline' replaced previous text

• 4.5, e.g. added ahead of the drug examples

• 4.5, 'such as ritonavir'  added in the second last paragraph

• 4.6, Lactation changed to Breast-feeding

• 4.6, negligible spelling correction

• 4.6, fertility - grammar change

• 4.8, refer to table 1. for changes

• 4.8, reporting of side effects updated according to new IMB guideline

• 5.1, Paediatric OCD, sumbols added '+/-'

• 5.2 - Biotransformation, '

   

  Based on clinical and in vitro data, it can be concluded that sertraline is metabolised by multiple pathways including CYP3A4, CYP2C19 (see section 4.5) and CYP2B6. Sertraline and its major metabolite desmethylsertraline are also substrate of P-glycoprotein in vitro.' was added

• 5.2 - Renal Impairment, '

  Pharmacogenomics

  Plasma levels of sertraline were about 50 % higher in poor metabolizers of CYP2C19 versus extensive metabolizers. The clinical meaning is not clear, and patients need to be titrated based on clinical response.' was added

• 6.4 - store in the original packaging

• 10. date of revision updated

•  

   

$04.4 Special warnings and precautions for use$0$0$0$0$0Addition warning added:$0$0Serotonin Syndrome (SS) or Neuroleptic Malignant Syndrome (NMS)$0$0Grapefruit juice$0$0Interference with urine screening tests$0$0Angle-Closure Glaucoma$0$0$0$0$0$0$0$04.5 Interaction with other medicinal products and other forms of interaction$0$0$0$0$0Caution with use if fentanyl is added$0$0$0$0$0Special Precautions for Phenytoin is updated. Following sentenced added:$0$0It cannot be excluded that other CYP3A4 inducers, e.g. phenobarbital, carbamazepine, St John’s Wort, rifampicin may cause a reduction of sertraline plasma levels.$0$0$0$0$0Interaction with grapefruit juice added$0$0$0$0$0$0$0$04.8 Undesirable effects$0$0$0$0$0Side effecs for adults: Diabetes Mellitus, hyperglycaemia, dystonia, Neuroleptic Malignant Syndrome,Cerebrovascular Spasm, Pupils Unequal, Interstitial Lung Disease - added under Frequency not Known category$0$0$0$0$0Side effect Suicidal ideation/behaviour changed from Frequency not$0$0Known category to Rare frequency$0$0$0$0$0Side effect for paidiatroc patients: enuresis added under Frequency not Known category$0$0$0$0$0$0$0$04.9 Overdose$0$0$0$0$0Following statement added:$0$0Sertraline overdose may prolong the QT-interval, and ECG-monitoring is recommended in all ingestions of sertraline overdoses.$0$0$0$0$0$0$0$010. DATE OF REVISION OF THE TEXT$0$0$0$0$0Date changed to May 2013$0$0$0$0$0$0$0$0(Internal Ref: IT/H/0210/IB/008)$0

3. PHARMACEUTICAL FORM
Added -
The tablet can be divided into equal doses.

4.6 Fertility, pregnancy and lactation
Added -
Fertility
Animal data did not show an effect of sertraline in fertility parameters (see section 5.3). Human case reports with some SSRIs have been shown that an effect on sperm quality is reversible. Impact on human fertility has not been observed so far.

5.3 Preclinical safety data
Added -
Animal data from rodents and non-rodents does not reveal effects on fertility.

6.1 List of excipients
Film Coating:
Changing Triacetin to Glycerol triacetate

10. DATE OF REVISION OF THE TEXT
Change to November 2012


(internal ref: IT/H/0210/IB/007)

Following paragraph added to section 4.6 Pregnancy and lactation

Epidemiological data have suggested that the use of SSRIs in pregnancy, particular in late
pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn
(PPHN). The observed risk was approximately 5 cases per 1000 pregnancies. In the general population 1 to 2 cases of PPHN per 1000 pregnancies occur.


Following paragraph added to section 4.8 Undesirable effects

Class effects
Epidemiological studies, mainly conducted in patients 50 years of age and older, show an
increased risk of bone fractures in patients receiving SSRIs and TCAs. The mechanism
leading to this risk is unknown


Changes due to approval of Renewal Application

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorization: 05 August 2005
Date of last renewal: 24 March 2011

10. DATE OF REVISION OF THE TEXT

June 2011

The SPC sections 4.4 and 4.8 have been updated to include the recommended PhVWP warnings on Suicide/ Suicidal behaviour.

 

 SPC has been updated to included warnings on Suicide/ Suicidal behaviour, Withdrawal Symptoms and Akathisia / Psychomotor restlessness.

 The sections affected are : 4.2, 4.4 and 4.8.

 Also updated:

 6.1 – Excipient names updated.

6.3 – Shelf life updted from 2 years to 3 years.