Section 2 - addition of sexual disfunction warning

Section 4.4 addition warning about sexual disfunction

Update of section 4.8 (‘Undesirable effects’) of the SmPC to add ‘Bruxism’ with a frequency not known in ‘Psychiatric disorders’

Section 6.5 – addition of child resistant packs and changes to the material components.

Section 6.5 – addition of child resistant packs and changes to the material components.

Section 4.8 – addition of aggression as an AE under psychiatric disorders

6.5         Nature and contents of container – following text has been added:

20     mg tablet - Child-resistant blister packs comprising opaque polyvinyl chloride (PVC) backed with aluminium foil laminated with paper.

Update section 4.4, 4.5 and 4.8 of the SPC in order to include warnings of:

·         gynaecological bleeding/menstrual period disorders

·         interactions between pravastatin and paroxetine

·         AE information updated for the following: Immune system disorders, Metabolism and nutrition disorders, Skin and subcutaneous tissue disorders, Reproductive system and breast disorders

2 QUALITATIVE AND QUANTITATIVE COMPOSITION – minor editorial changes

3.         PHARMACEUTICAL FORM – additional information on break bar and minor editorial changes

4.2       Posology and method of administration – change of layout and minor editorial changes

4.3      Contraindications – minor editorial changes

4.4      Special warnings and precautions for use – minor editorial changes

4.5     Interaction with other medicinal products and other forms of interaction - SSRIs may reduce plasma cholinesterase activity resulting in a prolongation of the neuromuscular blocking action of mivacurium and suxamethonium.

4.6 Fertility, pregnancy and lactation – minor editorial changes and a change in layout

4.8 Undesirable effects – addition of HPRA contact details

SPC UPDATES

3. PHARMACEUTICAL FORM

Specifically for the 30 mg tablet, a the following statement regarding breaking:

The tablet must only be broken to ease swallowing.

4.2 Posology and Method of Administration

Minor editorial change under the subheading ‘Special Populations’:

Changed the term ‘elderly’ to ‘older people’

4.6   Undesirable Effects

Added the details of the IMB Pharmacovigilance department, required for the reporting of adverse events:

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 the online reporting option (preferred method) accessible from the IMB homepage (www.imb.ie).  A downloadable report form is also accessible from the IMB website, which may be completed manually and submitted to the IMB via ‘freepost’ (see details below). Alternatively, the traditional post-paid ‘yellow card’ option may also be used.

FREEPOST

Pharmacovigilance Section, Irish Medicines Board, Kevin O’Malley House, Earlsfort Centre, Earlsfort Terrace, Dublin 2. Tel: +353 1 676497. Fax: +353 1 6762517. Website: www.imb.ie. e-mail: imbpharmacovigilance@imb.ie

5.2      Pharmacokinetic properties

Minor editorial changes:

Changed the term ‘Metabolism’ to ‘Biotransformation’.

Under the subheading ‘Special Populations’:

Changed the term ‘elderly’ to ‘older people’

4.6        Pregnancy and Lactation

4.4       Special Warnings and Special Precautions for use

Under the subheading ‘Interaction with tamoxifen’, updated warning from:

Paroxetine may lead to reduced efficacy of tamoxifen (see section 4.5). It is recommended that prescribers consider using an alternative antidepressant with minimal CYP2D6 activity.

to read:

Paroxetine, a potent inhibitor of CYP2D6, may lead to reduced concentrations of endoxifen, one of the most important active metabolites of tamoxifen. Therefore, paroxetine should whenever possible be avoided during tamoxifen treatment (see Section 4.5).

4.5       Interactions with other medicinal products and other forms of interaction

Under the subheading ‘CYP2D6 inhibitory potency of paroxetine’, updated the statement from:

Tamoxifen is a pro‑drug requiring metabolic activation by CYP2D6.  Inhibition of CYP2D6 by paroxetine may lead to reduced plasma concentrations of an active metabolite and hence reduced efficacy of tamoxifen, especially in extensive metabolisers. It is recommended that prescribers consider using an alternative antidepressant with minimal CYP2D6 activity.

to read:

Pharmacokinetic interaction between CYP2D6 inhibitors and tamoxifen, showing a 65-75% reduction in plasma levels of one of the more active forms of tamoxifen, i.e. endoxifen, has been reported in the literature. Reduced efficacy of tamoxifen has been reported with concomitant usage of some SSRI antidepressants in some studies. As a reduced effect of tamoxifen cannot be excluded, co-administration with potent CYP2D6 inhibitors (including paroxetine) should whenever possible be avoided (see section 4.4).

4.8          Undesirable Effects

Under the subheading ‘Nervous system disorders’ added the common undesirable effect:

Concentration impaired

1.       NAME OF MEDICINAL PRODUCT

SEROXAT 10 mg film‑coated tablets.

SEROXAT 20 mg film‑coated tablets.

SEROXAT 30 mg film‑coated tablets.

SEROXAT 20 mg/10 ml oral suspension.

2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

10mg Tablets:

Each film‑coated tablet contains 10 mg paroxetine (as paroxetine hydrochloride hemihydrate).

20mg Tablets:

Each film‑coated tablet contains 20 mg paroxetine (as paroxetine hydrochloride hemihydrate).

30mg Tablets:

Each film‑coated tablet contains 30 mg paroxetine (as paroxetine hydrochloride hemihydrate).

Oral Suspension:

Each 10 ml of oral suspension contains 20 mg paroxetine (as paroxetine hydrochloride hemihydrate).

Excipient – each 10 ml of oral suspension contains:

-          20 mg methyl parahydroxybenzoate

-          6 mg propyl parahydroxybenzoate

-          0.9 mg FD&C Yellow No. 6 (sunset yellow, FCF (EEEC No. 110)

-          4 g sorbitol (E420).

For a full list of excipients, see section 6.1.

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4.3    Contraindications

Known hypersensitivity to paroxetine or any of the excipients.

Paroxetine is contraindicated in combination with monoamine oxidase inhibitors (MAOIs).  In exceptional circumstances, linezolid (an antibiotic which is a reversible non‑selective MAOI) can be given in combination with paroxetine provided that there are facilities for close observation of symptoms of serotonin syndrome and monitoring of blood pressure (see section 4.5).    

Treatment with paroxetine can be initiated:

-           two weeks after discontinuation of an irreversible MAOI, or

-        at least 24hrs after discontinuation of a reversible MAOI (e.g. moclobemide, linezolid, methylthioninium chloride (methylene blue; a preoperative visualizing agent which is a reversible non-selective MAOI)).

At least one week should elapse between discontinuation of paroxetine and initiation of therapy with any MAOI.

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4.5     Interactions with other medicinal products and other forms of interaction

Serotonergic drugs

As with other SSRIs, co-administration with serotonergic drugs may lead to an incidence of 5‑HT associated effects (serotonin syndrome: see Section 4.4 Special Warnings and Special Precautions for Use). Caution should be advised and a closer clinical monitoring is required when serotonergic drugs (such as L‑tryptophan, triptans, tramadol, linezolid, methylthioninium chloride (methylene blue), SSRIs, lithium, pethidine and St. John's Wort – Hypericum perforatum – preparations) are combined with paroxetine. Caution is also advised with fentanyl used in general anaesthesia or in the treatment of chronic pain. Concomitant use of paroxetine and MAOIs is contraindicated because of the risk of serotonin syndrome (see Section 4.3 Contraindications).

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4.8  Undesirable Effects

Skin and subcutaneous tissue disorders
Common:  sweating.
Uncommon:  skin rashes, pruritus
Very rare:  severe cutaneous adverse reactions (including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis), photosensitivity reactions.

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6.4     Special precautions for storage

10/20/30 mg tablet

Do not store above 30ºC.

Store in the original package in order (to protect from light).

Oral suspension

Do not store above 25ºC.

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9   DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation:

SEROXAT 10 mg film‑coated tablets.                           5^th March 2004

SEROXAT 20 mg film‑coated tablets.                           19^th March 1991

SEROXAT 30 mg film‑coated tablets.                           19^th March 1991

SEROXAT 20 mg/10 ml oral suspension.                     6^th May 1998

Date of last renewal: 27th September 201005.

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10    DATE OF REVISION OF THE TEXT

September 2010March 2011

4.4     Special Warnings and Special Precautions for use

Mania
As with all antidepressants, paroxetine should be used with caution in patients with a history of mania. Paroxetine should be discontinued in any patient entering a manic phase.

Section 2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Minor change to the SPC for Oral Suspension, adding quantitative description of excipients, i.e. added:

Excipient – each 10 ml of oral suspension contains:

-          20 mg methyl parahydroxybenzoate

-          6 mg propyl parahydroxybenzoate

-          0.9 mg FD&C Yellow No. 6 (sunset yellow, EEC No. 110)

-          4 g sorbitol (E420).

SPECIFIC TO SEROXAT 30 mg film‑coated tablets (PA 1077/97/3)

Section 3 PHARMACEUTICAL FORM

Updated the description of the tablet marking to include the alternative marking ‘30’, i.e. from ‘debossed with “SEROXAT 30” on one side and a break bar on the other’ to ‘debossed with “SEROXAT 30” or ‘30’on one side and a break bar on the other’.

Section 4.4 Special Warnings and Special Precautions for use

Added the following warning regarding bone fracture:

Bone fracture

Epidemiological studies show an increased risk of bone fractures in patients receiving certain antidepressants, including SSRIs, such as paroxetine. The risk occurs during treatment and is greatest in the first months of therapy.

Section 4.5 Interactions with other medicinal products and other forms of interaction

Under the subheading ‘Serotonergic drugs’, added pethedine to the list of serotonergic drugs and added the following warning regarding fenanyl:

Caution is also advised with fentanyl used in general anaesthesia or in the treatment of chronic pain.

Section 4.6 Pregnancy and Lactation

Under the subheading ‘Pregnancy’, added the following statement regarding the increased risk of persistent pulmonary hypertension of the newborn:

Epidemiological data have suggested that the use of SSRIs in pregnancy, particularly in late pregnancy, may have an increased risk of persistent pulmonary hypertension of 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.

Section 4.8 Undesirable Effects

Under the category ‘Psychiatric disorders’ added the side effect (frequency common) abnormal dreams (including nightmares).

Under the category ‘Nervous system disorders’ added the side effect (frequency rare) restless legs syndrome (RLS).

Under the category ‘Gastrointestinal disorders’ disorders’ added the side effect (frequency common) vomiting

Section 4.9 Overdose

Under the subheading ‘Symptoms and Signs’, removed the side effect vomiting.

Under the subheading ‘Treatment’, updated the instructions to include the following:

·         Administration of 20-30 g activated charcoal may be considered if possible within a few hours after overdose intake to decrease absorption of paroxetine.

·         Patient management should be as clinically indicated.

Section 5.2 Pharmacokinetic properties

Under the subheading ‘Distribution’, removed the statement:

Transfer to human breast milk, and to the foetuses of laboratory animals, occurs in small amounts.

 New text highlighted in Red:

3.       PHARMACEUTICAL FORM

White, film‑coated tablet, oval shaped biconvex tablets debossed with SEROXAT 20 or 20 on one side and a break bar on the other

4.4

Additional Text:

Interaction with tamoxifen

Paroxetine may lead to reduced efficacy of tamoxifen (see section 4.5). It is recommended that prescribers consider using an alternative antidepressant with minimal CYP2D6 activity.

4.5

Additional Text:

Tamoxifen is a pro‑drug requiring metabolic activation by CYP2D6.  Inhibition of CYP2D6 by paroxetine may lead to reduced plasma concentrations of an active metabolite and hence reduced efficacy of tamoxifen, especially in extensive metabolisers. It is recommended that prescribers consider using an alternative antidepressant with minimal CYP2D6 activity.

4.6

Nature of Change:

Amendment of pregnancy text as a result of updated meta-analysis

4.3    Contraindications

Known hypersensitivity to paroxetine or any of the excipients.

Paroxetine is contraindicated in combination with monoamine oxidase inhibitors (MAOIs).  In exceptional circumstances, linezolid (an antibiotic which is a reversible non‑selective MAOI) can be given in combination with paroxetine provided that there are facilities for close observation of symptoms of serotonin syndrome and monitoring of blood pressure (see section 4.5).    

Treatment with paroxetine can be initiated:

-           two weeks after discontinuation of an irreversible MAOI, or

-           at least 24hrs after discontinuation of a reversible MAOI (e.g. moclobemide, linezolid).

At least one week should elapse between discontinuation of paroxetine and initiation of therapy with any MAOI.

Paroxetine should not be used in combination with thioridazine, because, as with other drugs which inhibit the hepatic enzyme CYP450 2D6, paroxetine can elevate plasma levels of thioridazine (see section 4.5 Interactions with other medicinal products and other forms of interaction). Administration of thioridazine alone can lead to QTc interval prolongation with associated serious ventricular arrhythmia such as torsades de pointes, and sudden death.

Paroxetine should not be used in combination with pimozide (see section 4.5 Interactions with other medicinal products and other forms of interaction).

4.4     Special Warnings and Special Precautions for use

……………………………….

Glaucoma
As with other SSRIs, paroxetine can cause mydriasis and should be used with caution in patients with narrow angle glaucoma or history of glaucoma.

…………………………

Parabens

Paroxetine oral suspension contains methyl and propyl parahydroxybenzoate (parabens), which are known to cause urticaria; generally delayed type reactions, such as contact dermatitis, but rarely immediate reaction with bronchospasm.

4.5     Interactions with other medicinal products and other forms of interaction

Serotonergic drugs

As with other SSRIs, co-administration with serotonergic drugs preparations)may lead to an incidence of 5‑HT associated effects (serotonin syndrome: see Section 4.4 Special Warnings and Special Precautions for Use). Caution should be advised and a closer clinical monitoring is required when serotonergic drugs (such as L‑tryptophan, triptans, tramadol, linezolid, SSRIs, lithium and St. John's Wort – Hypericum perforatum – preparations) are combined with paroxetine. Concomitant use of paroxetine and MAOIs is contraindicated because of the risk of serotonin syndrome (see Section 4.3 Contraindications).

Pimozide

Increased pimozide levels of on average 2.5 times have been demonstrated in a study of a single low dose pimozide (2 mg) when co‑administered with 60 mg paroxetine. This may be explained by the known CYP2D6 inhibitory properties of paroxetine. Due to the narrow therapeutic index of pimozide and its known ability to prolong QT interval, concomitant use of pimozide and paroxetine is contraindicated (see Section 4.3 Contraindications).

4.8       Undesirable Effects

……………………………..

Nervous system disorders
Common:  dizziness, tremor, headache.
Uncommon:  extrapyramidal disorders.  

Rare:  convulsions.
Very rare:  serotonin syndrome (symptoms may include agitation, confusion, diaphoresis, hallucinations, hyperreflexia, myoclonus, shivering, tachycardia and tremor).

Reports of extrapyramidal disorder including oro-facial dystonia have been received in patients sometimes with underlying movement disorders or who were using neuroleptic medication. 

Eye disorders
Common: blurred vision.
Uncommon: mydriasis (see section 4.4 Special Warnings and Special Precautions for Use). 
Very rare:  acute glaucoma.

Ear and labyrinth disorders

Frequency not known:  tinnitus.

Cardiac disorders
Uncommon:  sinus tachycardia.
Rare: bradycardia.

Vascular disorders
Uncommon:  transient increases or decreases in blood pressure, postural hypotension.

Transient increases or decreases of blood pressure have been reported following treatment with paroxetine, usually in patients with pre-existing hypertension or anxiety.

4.9              Overdose

Symptoms and Signs

A wide margin of safety is evident from available overdose information on paroxetine.

Experience of paroxetine in overdose has indicated that, in addition to those symptoms mentioned under section 4.8 "Undesirable Effects", vomiting, fever and involuntary muscle contractions have been reported.  Patients have generally recovered without serious sequelae even when doses of up to 2000 mg have been taken alone.  Events such as coma or ECG changes have occasionally been reported and, very rarely with a fatal outcome, but generally when paroxetine was taken in conjunction with other psychotropic drugs, with or without alcohol.

………………………………

6.1     List of Excipients

10 mg Tablet:

Tablet core:

Dibasic calcium phosphate dihydrate

Sodium starch glycolate (Type A)

Magnesium stearate.

Tablet coating:

Hypromellose

Macrogol 400

Polysorbate 80

Titanium dioxide (E171)

Iron oxide red (E172).

20 mg Tablet:

Tablet core:

Dibasic calcium phosphate dihydrate

Sodium starch glycolate (Type A)

Magnesium stearate.

Tablet coating:

Hypromellose

Macrogol 400

Polysorbate 80

Titanium dioxide (E171).

30 mg tablet:

Tablet core:

Dibasic calcium phosphate dihydrate

Sodium starch glycolate (Type A)

Magnesium stearate.

Tablet coating:

Hypromellose

Macrogol 400

Polysorbate 80

Titanium dioxide (E171)

Indigo carmine (E132).

Oral suspension:

Polacrilin potassium

Dispersible cellulose

Propylene glycol

Glycerol

Sorbitol (E420)

Methyl parahydroxybenzoate (E218)

Propyl parahydroxybenzoate (E216)

Sodium citrate dihydrate

Citric acid anhydrate

Sodium saccharin

Natural orange flavour

Natural lemon flavour

Yellow colouring (E110)

Simethicone emulsion

Purified water.

10. Date of Revision of the Text

06 December 2007.

Small amounts of paroxetine are excreted into breast milk. In published studies, serum concentrations in breast-fed infants were undetectable (<2 ng/ml) or very low (<4 ng/ml) and Nno signs of drug effects were observed in these infants. Nevertheless, paroxetine should not be used during lactation unless the expected benefits to the mother justify the potential risks for the infant. Since no effects are anticipated, breast-feeding can be considered.

Common: increases in cholesterol levels, decreased appetite.

Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt (see section 4.8 Undesirable effects). In clinical trials adverse events seen on treatment discontinuation occurred in 30% of patients treated with paroxetine compared to 20% of patients treated with placebo. The occurrence of withdrawal symptoms is not the same as the drug being addictive or dependence producing. The risk of withdrawal symptoms may be dependent on several factors including the duration and dose of therapy and the rate of dose reduction.Dizziness, sensory disturbances (including paraesthesia, electric shock sensations and tinnitus), sleep disturbances (including intense dreams), agitation or anxiety, nausea, tremor, confusion, sweating, headache, diarrhoea, palpitations, emotional instability, irritability,

No initial dosage adjustment is considered necessary when the drug is to be co-administered with known drug metabolising enzyme inducers (e.g. carbamazepine, rifampicin, phenobarbital, phenytoin) or with fosamprenavir/ritonavir. Any paroxetine dosage adjustment (either after initiation or following discontinuation of an enzyme inducer) should be guided by clinical effect (tolerability and efficacy).

Uncommon: urinary retention, urinary incontinence.

Discontinuation of paroxetine (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia,electric shock sensations and tinnitus), sleep disturbances (including intense dreams), agitation or anxiety, nausea, tremor, confusion, sweating, headache, diarrhoea, palpitations, emotional instability, irritability, and visual disturbances have been reported.