Allergan Ltd

Section Number

Subject

Change

2

Qualitative and quantitative composition

Word “Excipient(s)” inserted before “Contains benzalkonium chloride 0.05 mg/ml.”

4.2

Posology and method of administration

Wording change:

Use in children and neonates

Replaced with

Use in paediatric subjects

Following text added:

No clinical studies have been performed in adolescents (12 to 17 years).

Words inserted:

Alphagan is not recommended for use in children below 12 years and is contraindicated in neonates and infants (less than 2 years of age) (see sections 4.3, 4.4 and 4.9). 

4.3

Contraindications

Words inserted:

Neonates and infants (see section 4.8)

4.4

Special warnings and precautions for use

Text deleted:

Symptoms of brimonidine overdose have been reported in a few neonates receiving Alphagan as part of medical treatment of congenital glaucoma.

Text added:

Children of 2 years of age and above, especially those in the 2-7 age range and/or weighing < 20 Kg, should be treated with caution and closely monitored due to the high incidence of somnolence (see section 4.8).

4.7

Effects on ability to drive and use machines

Text added:

The patient should wait until these symptoms have cleared before driving or using machinery.

4.8

Undesirable effects

Punctuation:

a) deleted

Section restructured and summary of “common etc” definitions included at beginning:

New text:

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. The following terminologies have been used in order to classify the occurrence of 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).

Restructured text:

Cardiac disorders

Uncommon: palpitations/arrhythmias (including bradycardia and tachycardia)

Nervous system disorders

Very common: headache, drowsiness

Common: dizziness, abnormal taste

Very rare: syncope

Eye disorders

Very common:

-             ocular irritation including allergic reactions (hyperaemia, burning and stinging, pruritus, foreign body sensation, conjunctival follicles)

-             blurred vision

Common:

-             local irritation (eyelid hyperaemia and oedema, blepharitis, conjunctival oedema and discharge, ocular pain and tearing)

-             photophobia

-             corneal erosion and staining

-             ocular dryness

-             conjunctival blanching

-             abnormal vision

-             conjunctivitis

Very rare:

-             iritis (anterior uveitis)

-             miosis

Respiratory, thoracic and mediastinal disorders

Common: upper respiratory symptoms

Uncommon: nasal dryness

Rare: dyspnoea

Gastrointestinal disorders

Very common: oral dryness

Common: gastrointestinal symptoms

Vascular disorders

Very rare: hypertension, hypotension

General disorders and administration site conditions

Very common: fatigue

Common: asthenia

Immune system disorders

Uncommon: systemic allergic reactions

Psychiatric disorders

Uncommon: depression

Very rare: insomnia

Text deleted:

c) Symptoms of brimonidine overdose such as hypotension, bradycardia, hypothermia and apnea have been reported in a few neonates receiving Alphagan as part of medical treatment of congenital glaucoma.

Text added:

In cases where brimonidine has been used as part of the medical treatment of congenital glaucoma, symptoms of brimonidine overdose such as loss of consciousness, hypotension, hypotonia, bradycardia, hypothermia, cyanosis and apnoea have been reported in neonates and infants receiving brimonidine (see section 4.3).

In a 3-month, phase 3 study in children aged 2-7 years with glaucoma, inadequately controlled by beta-blockers, a high prevalence of somnolence (55%) was reported with Alphagan as adjunctive treatment. In 8% of children, this was severe and led to discontinuation of treatment in 13%. The incidence of somnolence decreased with increasing age, being least in the 7-year-old age group (25%), but was more affected by weight, occurring more frequently in those children weighing £20 kg (63%) compared to those weighing >20 kg (25%) (see section 4.4).

4.9

Overdose

New information inserted / punctuation amendments

Old Text:

Ophthalmic overdose:

There is no experience in adults with the unlikely case of an overdosage via the ophthalmic route.  However, symptoms of brimonidine overdose such as hypotension, bradycardia, hypothermia and apnea have been reported in a few neonates receiving Alphagan as part of medical treatment of congenital glaucoma.

Systemic overdose resulting from accidental ingestion:

One report of accidental human adult ingestion of Alphagan has been received.  The patient ingested about 10 drops of Alphagan.  He experienced a hypotensive episode a few hours after the ingestion and then a rebound hypertension approximately 8 hours after ingestion.

Oral overdoses of other alpha-2-agonists have been reported to cause symptoms such as hypotension, asthenia, vomiting, lethargy, sedation, bradycardia, arrhythmias, miosis, apnea, hypotonia, hypothermia, respiratory depression and seizure.

New text:

Ophthalmic overdose:

There is no experience in adults with the unlikely case of an overdosage via the ophthalmic route.  However, symptoms of brimonidine overdose (including loss of consciousness, hypotension, hypotonia, bradycardia, hypothermia, cyanosis and apnoea) have been reported in neonates and infants receiving Alphagan as part of medical treatment of congenital glaucoma.

Systemic overdose resulting from accidental ingestion:

Two cases of adverse effects following inadvertent ingestion of 9-10 drops of Alphagan by adult subjects have been received. The subjects experienced a hypotensive episode, followed in one instance by rebound hypertension approximately 8 hours after ingestion. Both subjects were reported to have made a full recovery within 24 hours. No adverse effects were noted in a third subject who also ingested an unknown amount of Alphagan orally.

Reports of serious adverse effects following inadvertent ingestion of Alphagan by paediatric subjects have been published or reported to Allergan. The subjects experienced symptoms of CNS depression, typically temporary coma or low level of consciousness, hypotonia, bradycardia, hypothermia and apnoea, and required admission to intensive care with intubation if indicated. All subjects were reported to have made a full recovery, usually within 6-24 hours.

Oral overdoses of other alpha-2-agonists have been reported to cause symptoms such as hypotension, asthenia, vomiting, lethargy, sedation, bradycardia, arrhythmias, miosis, apnoea, hypotonia, hypothermia, respiratory depression and seizure

6.1

List of excipients

Text added:

Hydrochloric acid (for pH-adjustment) or

Sodium hydroxide (for pH-adjustment)

6.3

Shelf Life

Text deleted:

After first opening:   Use within 28 days.

6.5

Nature and contents of container

Text deleted / added:

White low density polyethylene dropper bottles with a 35 microlitre tip. The cap is either a conventional polystyrene white or purple screw cap or a Compliance Cap (C-Cap).

10

Date of revision of text

Amended to 8^th February 2008.

All

^® Removed throughout document

2

Qualitative and Quantitative composition

Text updated

One ml solution contains 2.0 mg brimonidine tartrate, equivalent to 1.3 mg of brimonidine.

Contains benzalkonium chloride 0.05 mg/ml.

For a full list of excipients, see section 6.1.

Replaces

Brimonidine [(R,R)-tartrate] 0.2% (2.0 mg/ml)

(equivalent to brimonidine base 0.13%, 1.3 mg/ml)

1 drop of Alphaganâ = approximately 35 ml = 70 mg brimonidine tartrate

For excipients, see 6.1.

4.2

Posology and method of administration

Text added

The following heading were added

Recommended dosage in adults

Use in renal and hepatic impairment

Use in children and neonates

Text updated in Use in children and neonate section

Alphagan is not recommended for use in children below 12 years and is contraindicated in neonates (see sections 4.3, 4.4 and 4.9) replaces Alphaganâ should not be used in neonates and is not recommended for use in children (see Section 4.3 Contra-indications; Section 4.4 Special warning and precautions for use and Section 4.9 Overdose). 

4.3

Contraindications

Text updated

·         Hypersensitivity to the active substance or to any of the excipients. 

·         Neonates.

·         Patients receiving monoamine oxidase (MAO) inhibitor therapy and patients on antidepressants which affect noradrenergic transmission (e.g. tricyclic antidepressants and mianserin).

Replaces

Alphaganâ is contraindicated for use in neonates and in patients with hypersensitivity to brimonidine tartrate or any component of this medication.  Alphaganâ is also contra-indicated in patients receiving monoamine oxidase (MAO) inhibitor therapy and patients on antidepressants which affect noradrenergic transmission (e.g. tricyclic antidepressants and mianserin).

4.4

Special warnings and precautions for use

Heading updated (in red)

Special warnings and precautions for use

Text added

Avoid contact with soft contact lenses

4.8

Undesirable effects

Text updated

Heading Eye disorders replaces Ocular effects

Text

Immune system disorders

Uncommon (>1/1,000 and <1/100): systemic allergic reactions

Psychiatric disorders

Uncommon (>1/1,000 and <1/100): depression

Very rare (<1/10,000): insomnia

Nervous system disorders

Very common (>1/10): headache, drowsiness

Common (>1/100 and <1/10): dizziness, abnormal taste

Very rare (<1/10,000): syncope

Cardiac disorders

Uncommon (>1/1,000 and <1/100): palpitations/arrhythmias (including bradycardia and tachycardia)

Vascular disorders

Very rare (<1/10,000): hypertension, hypotension

Respiratory, thoracic and mediastinal disorders

Common (>1/100 and <1/10): upper respiratory symptoms

Uncommon (>1/1,000 and <1/100): nasal dryness

Rare (>1/10,000 and <1/1,000): dyspnoea

Gastrointestinal disorders

Very common (>1/10): oral dryness

Common (>1/100 and <1/10): gastrointestinal symptoms

General disorders and administration site conditions

Very common (>1/10): fatigue

Common (>1/100 and <1/10): asthenia

Replaces

Systemic effects        

Very Common:(>1 in 10)       

Headache

Oral dryness

Fatigue/drowsiness

Common:(>1 in 100 and <1 in 10)    

Upper respiratory symptoms

Dizziness

Gastrointestinal symptoms

Asthenia

Abnormal taste

Uncommon:(>1 in 1,000 and<1 in 100)        

Palpitations/arrythmias (including bradycardia and tachycardia)

Systemic allergic reactions

Depression

Nasal dryness

Rare:(>1 in 10,000 and<1 in 1,000)

Dyspnoea

Very Rare:(<1 in 10,000)       

Syncope

Hypertension

Hypotension

Insomnia

5.1

Pharmacodynamic properties

Text added

Pharmacotherapeutic group: Sympathomimetics in glaucoma therapy

5.3

Preclinical safety data

Text updated

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

Replaces

The available mutagenicity and carcinogenicity data indicate that Alphaganâ will exert neither mutagenic nor carcinogenic activities under the conditions of clinical use

6.1

List of excipients

Text updated

Poly(vinyl alcohol) replaces Polyvinyl alcohol

Sodium citrate replaces Sodium citrate, dehydrate

Sodium hydroxide for pH adjustment replaces Sodium hydroxide to adjust pH

9

Date of first authorisation/Renewal of the authorisation

Text updated

Date of first authorisation: 18 March 1997

Date of last renewal: 17 September 2006

Replaces 18^th March 2002

10

Date of revision of text

Text updated

1^st August 2007 replaces 11^th August 2006