Cuprofen Maximum Strength Tablets

1. Name Of The Medicinal Product

Cuprofen Tablets 400 mg

Ibuprofen Tablets BP 400 mg

Cuprofen Maximum Strength Tablets

Own label: UniChem Extra Strength Ibuprofen 400mg Tablets

2. Qualitative And Quantitative Composition

Ibuprofen BP 400 mg

3. Pharmaceutical Form

Coated tablets

4. Clinical Particulars

4.1 Therapeutic Indications

For the relief of rheumatic, muscular, dental and period pains and pain in backache, neuralgia, migraine and headache, and for the symptomatic relief of colds, flu and feverishness.

4.2 Posology And Method Of Administration

For oral administration and short-term use only.

Adults, the elderly and children over 12 years:

The lowest effective dose should be used for the shortest duration necessary to relieve symptoms. The patient should consult a doctor if symptoms persist or worsen, or if the product is required for more than 10 days.

One tablet up to three times as day as required.

Leave at least four hours between doses and do not take more than 3 tablets in any 24 hour period.

To be taken preferably after food.

Children under 12 years:

Not to be given to children under 12 years of age.

4.3 Contraindications

Hypersensitivity to ibuprofen or any of the excipients in the product.

Patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema or urticaria) in response to aspirin or other non steroidal anti-inflammatory drugs.

Active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).

History of gastrointestinal bleeding or perforation, relating to previous NSAIDs therapy.

Severe heart failure, renal failure or hepatic failure (see section 4.4).

Last trimester of pregnancy (see section 4.6).

4.4 Special Warnings And Precautions For Use

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see GI and cardiovascular risks below).

The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal.

Respiratory:

Bronchospasm may be precipitated in patients suffering from or with a previous history of bronchial asthma or allergic disease.

Other NSAIDs:

The use of Cuprofen Maximum Strength Tablets with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5).

SLE and mixed connective tissue disease:

Systemic lupus erythematosus and mixed connective tissue disease – increased risk of aseptic meningitis (see section 4.8)

Renal:

Renal impairment as renal function may further deteriorate (see sections 4.3 and 4.8)

Hepatic:

Hepatic dysfunction (see sections 4.3 and 4.8)

Cardiovascular and cerebrovascular effects:

Caution (discussion with doctor or pharmacist) is required prior to starting treatment in patients with a history of hypertension and/or heart failure as fluid retention, hypertension and oedema have been reported in association with NSAID therapy.

Clinical trial and epidemiological data suggest that use of ibuprofen, particularly at high doses (2400mg daily) and in long-term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Overall, epidemiological studies do not suggest that low dose ibuprofen (e.g.

Impaired female fertility:

There is limited evidence that drugs which inhibit cyclo-oxygenase/ prostaglandin synthesis may cause impairment of female fertility by an effect on ovulation. This is reversible upon withdrawal of treatment.

Gastrointestinal:

NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as these conditions may be exacerbated (see section 4.8).

GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at anytime during treatment, with or without warning symptoms or a previous history of serious GI events.

The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), and in the elderly. These patients should commence treatment on the lowest dose available.

Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.

Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or antiplatelet agents such as aspirin (see section 4.5).

When GI bleeding or ulceration occurs in patients receiving ibuprofen, the treatment should be withdrawn.

Dermatological:

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDSs (see section 4.8). Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first month of treatment. Cuprofen Maximum Strength Tablets should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

The label will include:

Read the enclosed leaflet before taking this product.

Do not take if you:

• have (or have had two or more episodes of) a stomach ulcer, perforation or bleeding

• are allergic to ibuprofen or any other ingredient of the product, aspirin or other related painkillers

• are taking other NSAID painkillers, or aspirin with a daily dose above 75mg

Speak to a pharmacist or your doctor before taking if you:

• have or have had asthma, diabetes, high cholesterol, high blood pressure, a stroke, heart, liver, kidney or bowel problems

• are a smoker

• are pregnant

If symptoms persist or worsen, consult your doctor.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Ibuprofen should be avoided in combination with:

Aspirin: Unless low-dose aspirin (not above 75mg daily) has been advised by a doctor, as this may increase the risk of adverse reactions (see section 4.4). ). Experimental data suggests that ibuprofen may inhibit the effect of low does aspirin on platelet aggregation when they are dosed concomitantly. However, the limitations of these data and the uncertainties regarding extrapolation of ex-vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 5.1).

Other NSAIDS including cyclooxygenase-2 selective inhibitors: Avoid concomitant use of two or more NSAIDs as this may increase the risk of adverse effects (see section 4.4).

Ibuprofen should be used with caution in combination with:

Anticoagulants: NSAIDS may enhance the effects of anti-coagulants, such as warfarin (see section 4.4).

Antihypertensives and diuretics: NSAIDs may diminish the effect of these drugs. Diuretics can increase the risk of nephrotoxicity of NSAIDs.

Corticosteroids: Increased risk of gastrointestinal ulceration or bleeding (see section 4.4).

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see section 4.4)

Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

Lithium: There is evidence for potential increases in plasma levels of lithium.

Methotrexate: There is a potential for an increase in plasma methotrexate.

Ciclosporin: Increased risk of nephrotoxicity.

Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.

Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Zidovudine: Increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in HIV(+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

Quinolone antibiotics: Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.

4.6 Pregnancy And Lactation

Whilst no teratogenic effects have been demonstrated in animal studies, the use of Cuprofen Maximum Strength Tablets should be avoided during the first 6 months of pregnancy.

During the 3^rd trimester, ibuprofen is contraindicated as there is there is a risk of premature closure of the foetal ductus arteriosus with possible persistent pulmonary hypertension. The onset of labour may be delayed and duration of labour increased with an increased bleeding tendency in both the mother and child. (see section 4.3).

In limited studies, ibuprofen appears in the breast milk in very low concentrations and is unlikely to affect the breast-fed infant adversely.

See section 4.4 regarding female fertility.

4.7 Effects On Ability To Drive And Use Machines

None expected at recommended doses and duration of therapy.

4.8 Undesirable Effects

Hypersensitivity reactions have been reported and these may consist of:

(a) non-specific allergic reactions and anaphylaxis

(b) respiratory tract reactivity, eg asthma, aggravated asthma, bronchospasm, dyspnoea

(c) various skin reactions, e.g. pruritus, urticaria, angioedema and more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme)

The following list of adverse effects relates to those experienced with ibuprofen at OTC doses, for short-term use. In the treatment of chronic conditions, under long-term treatment, additional adverse effects may occur.

Hypersensitivity reactions:

Uncommon: Hypersensitivity reactions with urticaria and pruritus.

Very rare: severe hypersensitivity reactions. Symptoms could be: facial, tongue and laryngeal swelling, dyspnoea, tachycardia, hypotension, (anaphylaxis, angioedema or severe shock).

Exacerbation of asthma and bronchospasm.

Gastrointestinal:

The most commonly-observed adverse events are gastrointestinal in nature.

Uncommon: abdominal pain, nausea, dyspepsia.

Rare: diarrhoea, flatulence, constipation and vomiting

Very rare: peptic ulcer, perforation or gastrointestinal haemorrhage, melaena, haematemesis, sometimes fatal, particularly in the elderly. Ulcerative stomatitis, gastritis.

Exacerbation of colitis and Crohn's disease (see section 4.4).

Nervous System:

Uncommon: Headache

Very rare: Aseptic meningitis – single cases have been reported very rarely.

Renal:

Very rare: Acute renal failure, papillary necrosis, especially in long-term use, associated with increased serum urea and oedema.

Hepatic:

Very rare: liver disorders.

Haematological:

Very rare: Haematopoietic disorders (anaemia, leucopenia, thrombocytopenia, pancytopenia, agranulocytosis). First signs are: fever, sore throat, superficial mouth ulcers, flu-like symptoms, severe exhaustion, unexplained bleeding and bruising.

Dermatological:

Uncommon: Various skin rashes

Very rare: Severe forms of skin reactions such as bullous reactions, including Stevens-Johnson Syndrome, erythema multiforme and toxic epidermal necrolysis can occur.

Immune System:

In patients with existing auto-immune disorders (such as systemic lupus erythematosus, mixed connective tissue disease) during treatment with ibuprofen, single cases of symptoms of aseptic meningitis, such as stiff neck, headache, nausea, vomiting, fever or disorientation have been observed (see section 4.4).

Cardiovascular and Cerebrovascular:

Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment.

Clinical trial and epidemiological data suggest that use of ibuprofen (particularly at high doses 2400mg daily) and in long-term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke), (see section 4.4).

4.9 Overdose

In children ingestion of more than 400 mg/kg may cause symptoms. In adults the dose response effect is less clear cut. The half-life in overdose is 1.5-3 hours.

Symptoms

Most patients who have ingested clinically important amounts of NSAIDs will develop no more than nausea, vomiting, epigastric pain, or more rarely diarrhoea. Tinnitus, headache and gastrointestinal bleeding are also possible. In more serious poisoning, toxicity is seen in the central nervous system, manifesting as drowsiness, occasionally excitation and disorientation or coma. Occasionally patients develop convulsions. In serious poisoning metabolic acidosis may occur and the prothrombin time/ INR may be prolonged, probably due to interference with the actions of circulating clotting factors. Acute renal failure and liver damage may occur. Exacerbation of asthma is possible in asthmatics.

Management

Management should be symptomatic and supportive and include the maintenance of a clear airway and monitoring of cardiac and vital signs until stable. Consider oral administration of activated charcoal if the patient presents within 1 hour of ingestion of a potentially toxic amount. If frequent or prolonged, convulsions should be treated with intravenous diazepam or lorazepam. Give bronchodilators for asthma.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Ibuprofen is a propionic acid derivative NSAID that has demonstrated its efficacy by inhibition of prostaglandin synthesis. In humans ibuprofen reduces inflammatory pain, swellings and fever. Furthermore, ibuprofen reversibly inhibits platelet aggregation.

Experimental data suggests that ibuprofen may inhibit the effect of low does aspirin on platelet aggregation when they are dosed concomitantly. In one study, when a single does of ibuprofen 400mg was taken within 8 hours before or within 30 minutes after immediate release aspirin dosing (81mg), a decreased effect of aspirin on the formation of thromboxane or platelet aggregation occurred. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be like for occasional ibuprofen use.

5.2 Pharmacokinetic Properties

Ibuprofen is rapidly absorbed following administration and is rapidly distributed throughout the whole body. The excretion is rapid and complete via the kidneys.

Maximum plasma concentrations are reached 45 minutes after ingestion if taken on an empty stomach. When taken with food, peak levels are observed after 1 to 2 hours. These times may vary with different dosage forms.

The half-life of ibuprofen is about 2 hours.

In limited studies, ibuprofen appears in the breast milk in very low concentrations.

5.3 Preclinical Safety Data

Not applicable.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose BP

Ac-di-sol

Methyl cellulose (Celacol M450) BP

Magnesium stearate

Water

IMS

Polyethylene glycol

Methyl cellulose (Methocel E15)

Sepisperse Rose AP 5002 OR

Mastercote Pink FA0430

6.2 Incompatibilities

None known.

6.3 Shelf Life

Three years.

6.4 Special Precautions For Storage

Store at or below 25°C.

6.5 Nature And Contents Of Container

a. Polypropylene containers with a low density polythene tamper evident lid (21, 100, 250, 500, 1000 tablets).

b. Polythene bags free from additives, inside a cardboard outer (5,000, 10,000 tablets).

c. Blister packs comprised of 250.i plain white rigid UPVC and 20p~ hard temper aluminium foil (12, 24, 36, 48, 96 tablets).

6.6 Special Precautions For Disposal And Other Handling

None

7. Marketing Authorisation Holder

Cupal Limited

Venus

1 Old Park Lane

Trafford Park

Manchester

M41 7HA

8. Marketing Authorisation Number(S)

PL 0338/0085

9. Date Of First Authorisation/Renewal Of The Authorisation

17/06/2010

10. Date Of Revision Of The Text

16/07/2010

Maxidex eent

Generic Name: Dexamethasone eent
Class: Corticosteroids
ATC Class: S01CA01
VA Class: OP350
CAS Number: 50-02-2

Introduction

A synthetic fluorinated corticosteroid.^{a b d}

Uses for Maxidex

Ophthalmic Inflammation

Symptomatic relief of corticosteroid-responsive inflammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the globe (e.g., allergic conjunctivitis, acne rosacea, superficial punctate keratitis, herpes zoster keratitis, iritis, cyclitis, selected infective conjunctivitides).^{a c d e f g h}

Treatment of chronic anterior uveitis.^{e g h}

Treatment of corneal injury from chemical, radiation, or thermal burns or penetration of foreign bodies.^{a c d e f g h}

Bacterial Ophthalmic Infections

Used for anti-inflammatory properties in conjunction with appropriate anti-infective therapy in some bacterial infections of the eye;^{e f g h} used in fixed combination with neomycin and polymyxin B sulfates or tobramycin when such combination therapy is indicated.^{e f g h} If an ophthalmic corticosteroid is used in combination with an ophthalmic anti-infective, weigh benefits against risks.^d (See Infections under Cautions.)

Otic Inflammation

Symptomatic relief of corticosteroid-responsive inflammatory conditions of the ear canal (e.g., allergic otitis externa).^{b c i}

Bacterial Otic Infections

Used for anti-inflammatory properties in conjunction with ciprofloxacin for treatment of acute otitis externa and in pediatric patients with tympanostomy tubes for acute otitis media.ⁱ

Used to reduce edema and inflammation in select cases of purulent and nonpurulent infective otitis externa.^c

If a corticosteroid is used alone or in combination with an otic anti-infective, weigh benefits against risks.^d (See Infections under Cautions.)

Maxidex Dosage and Administration

Administration

Apply topically to the eye or ear.^{a b c e f g h i}

Ophthalmic Administration

Apply topically to the eye as an ophthalmic ointment, solution, or suspension.^{a b c e f g h}

Not for injection.^{e f g h}

Shake suspension well prior to each use.^{a g}

Avoid contamination of preparation container.^{a b e f}

Do not administer solutions or suspensions containing benzalkonium chloride while wearing soft contact lenses.^{a c g} Wait ≥15 minutes after instilling drops before inserting contact lenses.^c (See Advice to Patients.)

Otic Administration

Apply topically to the ear as an otic suspension or an ophthalmic solution.^{b c i}

Not for injection.ⁱ Do not instill otic preparations into the eye.ⁱ

May use dexamethasone sodium phosphate ophthalmic solution in the ear.^{b c}

Shake suspension well prior to each use.ⁱ

To avoid dizziness that may result from instilling a cold preparation into the ear, warm the preparation by holding the bottle in the hands for 1–2 minutes prior to administration.ⁱ

Clean and dry ear canal prior to administration;^{b c d} pH of otic preparations should be neutral or acidic.^b

Lie with the affected ear upward and instill drops.ⁱ For pediatric patients with otitis media and tympanostomy tubes, pump the tragus 5 times to ease penetration of drops into the middle ear.ⁱ For acute otitis externa, pull outer ear lobe upward and backward to facilitate entry of drug into ear canal.ⁱ

Keep affected ear upward for ≥60 seconds following drug administration.ⁱ If necessary, repeat procedure for the opposite ear.ⁱ

Use otic corticosteroids sparingly to prevent an accumulation of excess debris in the ear canal.^{b d}

Dosage

Commercially available alone or in fixed combination with anti-infectives; available as dexamethasone or dexamethasone sodium phosphate.^{a c d e f g h i} Solution available as dexamethasone sodium phosphate; dosage expressed in terms of dexamethasone phosphate.^c

Pediatric Patients

Bacterial Ophthalmic Infections

Duration of therapy depends on the type and severity of the disease and response to therapy.^g Do not discontinue prematurely.^g

When discontinuing therapy, gradually taper dosing frequency to avoid exacerbation of the disease.^b

Dexamethasone 0.1% and Tobramycin 0.3%

Ophthalmic Suspension

Children ≥2 years of age: Initial 24–48 hours, 1 or 2 drop(s) into the conjunctival sac of the affected eye(s) every 2 hours.^g Thereafter, 1 or 2 drops every 4–6 hours.^g Gradually reduce dosing frequency as infection improves.^g

Ophthalmic Ointment

Children ≥2 years of age: Apply a 1.25-cm ribbon into the conjunctival sac of the affected eye(s) up to 3 or 4 times daily.^h

Bacterial Otic Infections

Acute Otitis Externa

Otic Suspension (Dexamethasone 0.1% and Ciprofloxacin 0.3%)

Children ≥6 months of age: 4 drops into the affected ear(s) twice daily for 7 days.ⁱ

Acute Otitis Media

Otic Suspension (Dexamethasone 0.1% and Ciprofloxacin 0.3%)

Children ≥6 months of age with tympanostomy tubes: 4 drops into the affected ear(s) twice daily for 7 days.ⁱ

Adults

Ophthalmic Inflammation and Bacterial Infections

Duration of therapy depends on the type and severity of the disease and response to therapy.^g Do not discontinue prematurely.^g

When discontinuing therapy, gradually taper dosing frequency to avoid exacerbation of the disease.^b

Dexamethasone 0.1%

Ophthalmic Suspension

For mild inflammation: 1 or 2 drops into the conjunctival sac of the affected eye(s) up to 4–6 times daily.^a

For severe inflammation: 1 or 2 drops into the conjunctival sac of the affected eye(s) every hour.^a Taper dosing frequency as inflammation subsides.^a

Dexamethasone Sodium Phosphate 0.1%

Ophthalmic Solution

Initially, 1 or 2 drops into the conjunctival sac of the affected eye(s) every hour during the day and every 2 hours during the night.^c When a favorable response is attained, decrease to 1 drop every 4 hours.^c May decrease to 1 drop 3 or 4 times daily to control symptoms.^c

Dexamethasone 0.1%, Neomycin 0.35%, and Polymyxin B Sulfates 10,000 units

Ophthalmic Suspension

For mild inflammation: 1 or 2 drop(s) into the conjunctival sac of the affected eye(s) up to 4–6 times daily.^f

For severe inflammation: 1 or 2 drops into the conjunctival sac of the affected eye(s) hourly.^f As inflammation subsides, gradually reduce dosing frequency to discontinue.^f

Ophthalmic Ointment

Apply a 1.25-cm ribbon into the conjunctival sac of the affected eye(s) up to 3 or 4 times daily.^e

Dexamethasone 0.1% and Tobramycin 0.3%

Ophthalmic Suspension

Initial 24–48 hours, 1 or 2 drops into the conjunctival sac of the affected eye(s) every 2 hours; thereafter, 1 or 2 drops every 4 to 6 hours.^g Gradually reduce dosing frequency as infection improves.^g

Ophthalmic Ointment

Apply a 1.25-cm ribbon into the conjunctival sac of the affected eye(s) up to 3 or 4 times daily.^h

Otic Inflammation

Dexamethasone Sodium Phosphate 0.1% Ophthalmic Solution

Otic

Initially, 3 or 4 drops of the ophthalmic solution into the ear canal 2 or 3 times daily.^{b c} May reduce dosing frequency as symptoms improve.^{b c} Gradually taper the drug when it is discontinued.^c

Alternatively, a cotton wick saturated with the ophthalmic solution may be packed into the ear canal; keep the wick moist with the ophthalmic solution; remove saturated wick from ear after 12 to 24 hours.^{b c} Repeat as necessary.^{b c}

Duration of treatment may range from a few days to several weeks.^b

Bacterial Otic Infections: Acute Otitis Externa

Dexamethasone 0.1% and Ciprofloxacin 0.3%

Otic

4 drops into the affected ear(s) twice daily for 7 days.ⁱ

Special Populations

No special population dosage recommendations at this time.^{a c e f g h i}

Cautions for Maxidex

Contraindications

• 
  

  Known hypersensitivity to dexamethasone or any ingredient in the formulation.^{a c e f g h i}

  
  

• Ophthalmic Preparations


• 
  

  Viral diseases of the cornea and conjunctiva (e.g., epithelial herpes simplex keratitis [dendritic keratitis], vaccinia, varicella).^{a c e f g h}

  
  


• 
  

  Mycobacterial infection (e.g., ocular tuberculosis) of the eye.^{a c e f g h}

  
  


• 
  

  Fungal disease of ocular structures.^{a c e f g h}

  
  

• Otic Preparations


• 
  

  Viral infections of the external ear canal (e.g., herpes simplex).ⁱ

  
  


• 
  

  Perforation of the ear drum.^c

  
  


• 
  

  Fungal diseases of auricular structures.^c

  
  

Warnings/Precautions

Warnings

Ocular Effects

Risk of glaucoma with possible damage to the optic nerve, defects in visual acuity and fields of vision, and posterior subcapsular cataract formation with prolonged use of corticosteroids.^{a c d e f g h} Use with caution in patients with glaucoma because IOP may increase.^{a c d e f g h}

If used for ≥10 days, monitor IOP routinely even though monitoring may be difficult in children and uncooperative patients.^{a c d e f g h}

In conditions causing thinning of the cornea or sclera, perforations reported with use of topical corticosteroids.^{a c d e f g h}

Use of high-dose corticosteroids may delay healing.^{c h} Use after cataract surgery may delay healing and increase incidence of bleb formation.^c

Infections

Prolonged use may suppress the host response and thus increase the risk of secondary ocular infections.^{a c e f g}

In acute purulent conditions of the eye or ear, corticosteroids may mask infection or enhance existing infection.^{a c d e f g h} (See Contraindications under Cautions.)

Herpes Simplex

Use of corticosteroids in the treatment of herpes simplex infections other than epithelial herpes simplex keratitis, in which corticosteroids are contraindicated, requires great caution; periodic slit-lamp microscopy is essential.^{a c e f}

General Precautions

Evaluation of Ocular Condition

Initial prescription or renewal of medication order beyond 8 g of 0.1% ointment or 20 mL of 0.1% suspension should be provided only after examination of the patient with the aid of magnification (e.g., slit lamp biomicroscopy, fluorescein staining where appropriate).^{e f g h}

Fungal Infections

Long-term local corticosteroid application associated with development of fungal infections of the cornea.^{a d e f g h} Consider possibility of fungal infection in patients with persistent corneal ulceration who have been or are receiving corticosteroid therapy.^{a c d e f h}

Corneal Reepithelialization

Use of ophthalmic ointments may decrease rate of corneal reepithelialization.^h

Use of Fixed Combination

When used in fixed combination with ciprofloxacin, neomycin and polymyxin B sulfates, or tobramycin, consider the cautions, precautions, and contraindications associated with the concomitant agents.^{e f g h i}

Specific Populations

Pregnancy

Category C.^{a c e f g h i}

Lactation

Not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in milk.^{a e f g h i}

Caution if used in nursing women.^{a e f g h}

Dexamethasone sodium phosphate ophthalmic solution and dexamethasone in fixed combination with ciprofloxacin otic suspension: Manufacturers recommend discontinuing nursing or the drug.^{c i}

Pediatric Use

Safety and efficacy of ophthalmic dexamethasone suspension or dexamethasone sodium phosphate solution not established.^{a c}

Safety and efficacy of ophthalmic dexamethasone in fixed combination with neomycin and polymyxin B sulfates not established.^{e f}

Safety and efficacy of ophthalmic dexamethasone in fixed combination with tobramycin not established in children <2 years of age.^{g h}

Safety and efficacy of otic dexamethasone suspension in fixed combination with ciprofloxacin not established in infants <6 months of age.ⁱ

Geriatric Use

No substantial differences in safety or efficacy relative to younger patients.^{a e h}

Common Adverse Effects

Ophthalmic administration: Elevated IOP,^{a c e f g h} posterior subcapsular cataract formation,^{a c e g h} optic nerve damage,^{a c e f g h} delayed wound healing.^{e f h}

Otic administration: Ear discomfort, ear pain, ear pruritus.ⁱ

Maxidex Pharmacokinetics

Absorption

Bioavailability

Corticosteroids are absorbed through the aqueous humor; because only low doses are given, little if any systemic absorption occurs after ophthalmic administration.^d

Distribution

Extent

Systemically absorbed corticosteroids are distributed into milk; not known whether topical corticosteroids could produce detectable levels in human milk.^{a e f g h i}

Stability

Storage

Ophthalmic

Ointment

Neomycin and polymyxin B sulfates and dexamethasone: 2–25°C.^e

Tobramycin and dexamethasone: 8–27°C.^h

Solution

Dexamethasone sodium phosphate: 15–30°C.^c

Suspension

Dexamethasone: Tight, light-resistant containers^b at 8–27°C;^a store upright.^a

Neomycin and polymyxin B sulfates and dexamethasone: 8–27°C.^f

Tobramycin and dexamethasone: Upright containers at 8–27°C.^g

Otic

Suspension

Ciprofloxacin and dexamethasone: 15–30°C; protect from light.ⁱ Do not freeze.ⁱ

ActionsActions

• 
  

  Corticosteroids suppress the inflammatory response to mechanical, chemical, or immunologic agents.^{a c d e f g h}

  
  


• 
  

  Corticosteroids inhibit edema, fibrin deposition, capillary dilation, leukocyte and phagocyte migration; in addition, the drugs reduce capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated with inflammation.^d

  
  

Advice to Patients

• 
  

  Importance of removing soft contact lenses prior to administering preparations containing benzalkonium chloride^{a g h} and of delaying reinsertion of the lenses for ≥15 minutes after administration.^c Importance of not wearing contact lenses if signs or symptoms of an eye infection occur.^e

  
  


• 
  

  Importance of learning and adhering to proper administration techniques to avoid contamination of the tip of the container.^{a e f i}

  
  


• 
  

  Importance of advising patients not to touch tip of dropper to eye or surrounding tissue.^{a c f g h i}

  
  


• 
  

  Importance of informing a clinician if another eye condition (e.g., trauma, surgery, infection) develops during ophthalmic therapy.^c

  
  


• 
  

  Advise patients to warm the ear suspension by holding the bottle in the hands for 1–2 minutes prior to administration.ⁱ

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant illnesses.^{a c e g h i}

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{a c e g h i}

  
  


• 
  

  Importance of informing patients of other important precautionary information. (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Dexamethasone

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Ophthalmic	Suspension	0.1%	Maxidex (with benzalkonium chloride; viscous)	Alcon

Ciprofloxacin and Dexamethasone

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Otic	Suspension	Ciprofloxacin 0.3% and Dexamethasone 0.1% per mL	Ciprodex (with benzalkonium chloride)	Alcon

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Neomycin and Polymyxin B Sulfates and Dexamethasone

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Ophthalmic	Ointment	Neomycin Sulfate 0.35% (of neomycin), Polymyxin B Sulfate 10,000 units (of polymyxin B) and Dexamethasone 0.1% per g*	Maxitrol	Alcon
			Neomycin and Polymyxin B Sulfates and Dexamethasone	Bausch & Lomb, Falcon, Fougera
	Suspension	Neomycin Sulfate 0.35% (of neomycin), Polymyxin B Sulfate 10,000 units (of polymyxin B) and Dexamethasone 0.1% per mL*	Maxitrol (with benzalkonium chloride; viscous)	Alcon
			Neomycin and Polymyxin B Sulfates and Dexamethasone	Bausch & Lomb, Falcon

Tobramycin and Dexamethasone

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Ophthalmic	Ointment	0.3% Tobramycin and Dexamethasone 0.1% per g	TobraDex (with chlorobutanol)	Alcon
	Suspension	0.3% Tobramycin and Dexamethasone 0.1% per mL	TobraDex (with benzalkonium chloride)	Alcon

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Dexamethasone Sodium Phosphate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Ophthalmic	Solution	0.1% (of dexamethasone phosphate)*	Dexamethasone Sodium Phosphate (with benzalkonium chloride)	Falcon

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Ciprodex 0.3-0.1% Suspension (ALCON VISION): 7/$142.98 or 22/$407.95

Dexamethasone Sodium Phosphate 0.1% Solution (FALCON PHARMACEUTICALS): 5/$19.99 or 10/$30.97

Maxidex 0.1% Suspension (ALCON VISION): 5/$56.27 or 15/$154.48

TobraDex 0.3-0.1% Ointment (ALCON VISION): 3/$139.99 or 10/$400.95

TobraDex 0.3-0.1% Suspension (ALCON VISION): 5/$112.99 or 15/$320.96

TobraDex 0.3-0.1% Suspension (ALCON VISION): 2/$61.99 or 7/$159.97

Tobramycin-Dexamethasone 0.3-0.1% Suspension (FALCON PHARMACEUTICALS): 10/$129.98 or 30/$359.96

Tobramycin-Dexamethasone 0.3-0.1% Suspension (FALCON PHARMACEUTICALS): 5/$69.99 or 15/$179.98

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions April 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

a. Alcon Laboratories, Inc. Maxidex 0.1% (dexamethasone ophthalmic suspension) prescribing information. Fort Worth, TX; 2007 May.

b. AHFS drug information 2008. McEvoy GK, ed. Dexamethasone. Bethesda, MD: American Society of Health-System Pharmacists; 2008: 2874-5.

c. Falcon Pharmaceuticals. Dexamethasone sodium phosphate ophthalmic solution, USP prescribing information. Fort Worth, TX; 2007 Jul.

d. AHFS drug information 2008. McEvoy GK, ed. EENT corticosteroids general statement. Bethesda, MD: American Society of Health-System Pharmacists; 2008: 2867-9.

e. Alcon Laboratories, Inc. Maxitrol(neomycin and polymyxin B sulfates, and dexamethasone ophthalmic ointment) prescribing information. Fort Worth, TX; 2003 Oct.

f. Alcon Laboratories, Inc. Maxitrol (neomycin and polymyxin B sulfates, and dexamethasone ophthalmic suspension) prescribing information. Fort Worth, TX; 2003 Aug.

g. Alcon Laboratories, Inc. TobraDex (tobramycin and dexamethasone ophthalmic suspension) prescribing information. Fort Worth, TX; 2006 May.

h. Alcon Laboratories, Inc. TobraDex (tobramycin and dexamethasone ophthalmic ointment) prescribing information. Fort Worth, TX; 2003 Oct.

i. Alcon Laboratories, Inc. Ciprodex (ciprofloxacin 0.3% and dexamethasone 0.1% sterile otic suspension) prescribing information. Fort Worth, TX; 2003 Jul.

Tritace Tablets

1. Name Of The Medicinal Product

Tritace 1.25 mg Tablets

Tritace 2.5 mg Tablets

Tritace 5 mg Tablets

Tritace 10 mg Tablets

2. Qualitative And Quantitative Composition

Each tablet contains ramipril 1.25 mg.

Each tablet contains ramipril 2.5 mg.

Each tablet contains ramipril 5 mg.

Each tablet contains ramipril 10 mg.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Tablet

1.25mg: White to almost white oblong tablets with score-line.

Upper stamp: 1.25 & logo (

Lower stamp: HMN & 1.25

The score-line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

2.5mg: Yellowish to yellow oblong tablets with score-line.

Upper stamp: 2.5 & logo (

Lower stamp: HMR & 2.5

The tablet can be divided into equal halves.

5mg: Pale red oblong tablets with score-line.

Upper stamp: 5 & logo (

Lower stamp: HMP & 5.

The tablet can be divided into equal halves.

10mg: White to almost white, oblong tablets with a score-line

Upper stamp: HMO/HMO

The tablet can be divided into equal halves.

4. Clinical Particulars

4.1 Therapeutic Indications

- Treatment of hypertension.

- Cardiovascular prevention: reduction of cardiovascular morbidity and mortality in patients with:

o manifest atherothrombotic cardiovascular disease (history of coronary heart disease or stroke, or peripheral vascular disease) or o diabetes with at least one cardiovascular risk factor (see section 5.1).

- Treatment of renal disease:

o Incipient glomerular diabetic nephropathy as defined by the presence of microalbuminuria, o Manifest glomerular diabetic nephropathy as defined by macroproteinuria in patients with at least one cardiovascular risk factor (see section 5.1), o Manifest glomerular non diabetic nephropathy as defined by macroproteinuria

- Treatment of symptomatic heart failure.

- Secondary prevention after acute myocardial infarction: reduction of mortality from the acute phase of myocardial infarction in patients with clinical signs of heart failure when started> 48 hours following acute myocardial infarction.

4.2 Posology And Method Of Administration

Oral use

It is recommended that TRITACE is taken each day at the same time of the day.

TRITACE can be taken before, with or after meals, because food intake does not modify its bioavailability (see section 5.2). TRITACE has to be swallowed with liquid. It must not be chewed or crushed.

Adults

Diuretic-Treated patients

Hypotension may occur following initiation of therapy with TRITACE; this is more likely in patients who are being treated concurrently with diuretics. Caution is therefore recommended since these patients may be volume and/or salt depleted.

If possible, the diuretic should be discontinued 2 to 3 days before beginning therapy with TRITACE (see section 4.4).

In hypertensive patients in whom the diuretic is not discontinued, therapy with TRITACE should be initiated with a 1.25 mg dose. Renal function and serum potassium should be monitored. The subsequent dosage of TRITACE should be adjusted according to blood pressure target.

Hypertension

The dose should be individualised according to the patient profile (see section 4.4) and blood pressure control.

TRITACE may be used in monotherapy or in combination with other classes of antihypertensive medicinal products.

Starting dose

TRITACE should be started gradually with an initial recommended dose of 2.5 mg daily.

Patients with a strongly activated renin-angiotensin-aldosterone system may experience an excessive drop in blood pressure following the initial dose. A starting dose of 1.25 mg is recommended in such patients and the initiation of treatment should take place under medical supervision (see section 4.4).

Titration and maintenance dose

The dose can be doubled at interval of two to four weeks to progressively achieve target blood pressure; the maximum permitted dose of TRITACE is 10 mg daily. Usually the dose is administered once daily.

Cardiovascular prevention

Starting dose

The recommended initial dose is 2.5 mg of TRITACE once daily.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose should be gradually increased. It is recommended to double the dose after one or two weeks of treatment and - after another two to three weeks - to increase it up to the target maintenance dose of 10 mg TRITACE once daily.

See also posology on diuretic treated patients above.

Treatment of renal disease

In patients with diabetes and microalbuminuria:

Starting dose:

The recommended initial dose is 1.25 mg of TRITACE once daily.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose is subsequently increased. Doubling the once daily dose to 2.5 mg after two weeks and then to 5 mg after a further two weeks is recommended.

In patients with diabetes and at least one cardiovascular risk

Starting dose:

The recommended initial dose is 2.5 mg of TRITACE once daily.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose is subsequently increased. Doubling the daily dose to 5 mg TRITACE after one or two weeks and then to 10 mg TRITACE after a further two or three weeks is recommended. The target daily dose is 10 mg.

In patients with non- diabetic nephropathy as defined by macroproteinuria

Starting dose:

The recommended initial dose is 1.25 mg of TRITACE once daily.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose is subsequently increased. Doubling the once daily dose to 2.5 mg after two weeks and then to 5 mg after a further two weeks is recommended.

Symptomatic heart failure

Starting dose

In patients stabilized on diuretic therapy, the recommended initial dose is 1.25 mg daily.

Titration and maintenance dose

TRITACE should be titrated by doubling the dose every one to two weeks up to a maximum daily dose of 10 mg. Two administrations per day are preferable.

Secondary prevention after acute myocardial infarction and with heart failure

Starting dose

After 48 hours, following myocardial infarction in a clinically and haemodynamically stable patient, the starting dose is 2.5 mg twice daily for three days. If the initial 2.5 mg dose is not tolerated a dose of 1.25 mg twice a day should be given for two days before increasing to 2.5 mg and 5 mg twice a day. If the dose cannot be increased to 2.5 mg twice a day the treatment should be withdrawn.

See also posology on diuretic treated patients above.

Titration and maintenance dose

The daily dose is subsequently increased by doubling the dose at intervals of one to three days up to the target maintenance dose of 5 mg twice daily.

The maintenance dose is divided in 2 administrations per day where possible.

If the dose cannot be increased to 2.5 mg twice a day treatment should be withdrawn. Sufficient experience is still lacking in the treatment of patients with severe (NYHA IV) heart failure immediately after myocardial infarction. Should the decision be taken to treat these patients, it is recommended that therapy be started at 1.25 mg once daily and that particular caution be exercised in any dose increase.

Special populations

Patients with renal impairment

Daily dose in patients with renal impairment should be based on creatinine clearance (see section 5.2):

- if creatinine clearance is

- if creatinine clearance is between 30-60 ml/min, it is not necessary to adjust the initial dose (2.5 mg/day); the maximal daily dose is 5 mg;

- if creatinine clearance is between 10-30 ml/min, the initial dose is 1.25 mg/day and the maximal daily dose is 5 mg;

- in haemodialysed hypertensive patients: ramipril is slightly dialysable; the initial dose is 1.25 mg/day and the maximal daily dose is 5 mg; the medicinal product should be administered few hours after haemodialysis is performed.

Patients with hepatic impairment (see section 5.2)

In patients with hepatic impairment, treatment with TRITACE must be initiated only under close medical supervision and the maximum daily dose is 2.5 mg TRITACE.

Elderly

Initial doses should be lower and subsequent dose titration should be more gradual because of greater chance of undesirable effects especially in very old and frail patients. A reduced initial dose of 1.25 mg ramipril should be considered.

Paediatric population

TRITACE is not recommended for use in children and adolescents below 18 years of age due to insufficient data on safety and efficacy.

4.3 Contraindications

- Hypersensitivity to the active substance, to any of the excipients or any other ACE (Angiotensin Converting Enzyme) inhibitors (see section 6.1)

- History of angioedema (hereditary, idiopathic or due to previous angioedema with ACE inhibitors or AIIRAs)

- Extracorporeal treatments leading to contact of blood with negatively charged surfaces (see section 4.5)

- Significant bilateral renal artery stenosis or renal artery stenosis in a single functioning kidney

- 2nd and 3rd trimester of pregnancy (see sections 4.4 and 4.6)

- Ramipril must not be used in patients with hypotensive or haemodynamically unstable states.

4.4 Special Warnings And Precautions For Use

Special populations

- Pregnancy: ACE inhibitors such as ramipril, or Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued ACE inhibitor/ AIIRAs therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors/ AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

- Patients at particular risk of hypotension

- Patients with strongly activated renin-angiotensin-aldosterone system

Patients with strongly activated renin-angiotensin-aldosterone system are at risk of an acute pronounced fall in blood pressure and deterioration of renal function due to ACE inhibition, especially when an ACE inhibitor or a concomitant diuretic is given for the first time or at first dose increase.

Significant activation of renin-angiotensin-aldosterone system is to be anticipated and medical supervision including blood pressure monitoring is necessary, for example in:

- patients with severe hypertension

- patients with decompensated congestive heart failure

- patients with haemodynamically relevant left ventricular inflow or outflow impediment (e.g. stenosis of the aortic or mitral valve)

- patients with unilateral renal artery stenosis with a second functional kidney

- patients in whom fluid or salt depletion exists or may develop (including patients with diuretics)

- patients with liver cirrhosis and/or ascites

- patients undergoing major surgery or during anaesthesia with agents that produce hypotension.

Generally, it is recommended to correct dehydration, hypovolaemia or salt depletion before initiating treatment (in patients with heart failure, however, such corrective action must be carefully weighed out against the risk of volume overload).

- Transient or persistent heart failure post MI

- Patients at risk of cardiac or cerebral ischemia in case of acute hypotension

The initial phase of treatment requires special medical supervision.

- Elderly patients

See section 4.2.

- Surgery

It is recommended that treatment with angiotensin converting enzyme inhibitors such as ramipril should be discontinued where possible one day before surgery.

- Monitoring of renal function

Renal function should be assessed before and during treatment and dosage adjusted especially in the initial weeks of treatment. Particularly careful monitoring is required in patients with renal impairment (see section 4.2). There is a risk of impairment of renal function, particularly in patients with congestive heart failure or after a renal transplant.

- Angioedema

Angioedema has been reported in patients treated with ACE inhibitors including ramipril (see section 4.8).

In case of angioedema, TRITACE must be discontinued.

Emergency therapy should be instituted promptly. Patient should be kept under observation for at least 12 to 24 hours and discharged after complete resolution of the symptoms.

Intestinal angioedema has been reported in patients treated with ACE inhibitors including TRITACE (see section 4.8). These patients presented with abdominal pain (with or without nausea or vomiting).

- Anaphylactic reactions during desensitization

The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens are increased under ACE inhibition. A temporary discontinuation of TRITACE should be considered prior to desensitization.

- Hyperkalaemia

Hyperkalaemia has been observed in some patients treated with ACE inhibitors including TRITACE. Patients at risk for development of hyperkalaemia include those with renal insufficiency, age (> 70 years), uncontrolled diabetes mellitus, or those using potassium salts, potassium retaining diuretics and other plasma potassium increasing active substances, or conditions such as dehydration, acute cardiac decompensation, metabolic acidosis. If concomitant use of the above mentioned agents is deemed appropriate, regular monitoring of serum potassium is recommended (see section 4.5).

Neutropenia/agranulocytosis

Neutropenia/agranulocytosis, as well as thrombocytopenia and anaemia, have been rarely seen and bone marrow depression has also been reported. It is recommended to monitor the white blood cell count to permit detection of a possible leucopoenia. More frequent monitoring is advised in the initial phase of treatment and in patients with impaired renal function, those with concomitant collagen disease (e.g. lupus erythematosus or scleroderma), and all those treated with other medicinal products that can cause changes in the blood picture (see sections 4.5 and 4.8).

Ethnic differences

ACE inhibitors cause higher rate of angioedema in black patients than in non black patients.

As with other ACE inhibitors, ramipril may be less effective in lowering blood pressure in black people than in non black patients, possibly because of a higher prevalence of hypertension with low renin level in the black hypertensive population.

Cough

Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is nonproductive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Contra-indicated combinations

Extracorporeal treatments leading to contact of blood with negatively charged surfaces such as dialysis or haemofiltration with certain high-flux membranes (e.g. polyacrylonitril membranes) and low density lipoprotein apheresis with dextran sulphate due to increased risk of severe anaphylactoid reactions (see section 4.3). If such treatment is required, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.

Precautions for use

Potassium salts, heparin, potassium-retaining diuretics and other plasma potassium increasing active substances (including Angiotensin II antagonists, trimethoprim, tacrolimus, ciclosporin): Hyperkalaemia may occur, therefore close monitoring of serum potassium is required.

Antihypertensive agents (e.g. diuretics) and other substances that may decrease blood pressure (e.g.nitrates, tricyclic antidepressants, anaesthetics, acute alcohol intake, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin): Potentiation of the risk of hypotension is to be anticipated (see section 4.2 for diuretics)

Vasopressor sympathomimetics and other substances (e.g. isoproterenol, dobutamine, dopamine, epinephrine) that may reduce the antihypertensive effect of TRITACE: Blood pressure monitoring is recommended.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other substances that may change the blood cell count: Increased likelihood of haematological reactions (see section 4.4).

Lithium salts: Excretion of lithium may be reduced by ACE inhibitors and therefore lithium toxicity may be increased. Lithium level must be monitored.

Antidiabetic agents including insulin: Hypoglycaemic reactions may occur. Blood glucose monitoring is recommended.

Non-steroidal anti-inflammatory drugs and acetylsalicylic acid: Reduction of the antihypertensive effect of TRITACE is to be anticipated. Furthermore, concomitant treatment of ACE inhibitors and NSAIDs may lead to an increased risk of worsening of renal function and to an increase in kalaemia.

4.6 Pregnancy And Lactation

TRITACE is not recommended during the first trimester of pregnancy (see section 4.4) and contraindicated during the second and third trimesters of pregnancy (see section 4.3).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started. ACE inhibitor/ Angiotensin II Receptor Antagonist (AIIRA) therapy exposure during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See also 5.3 'Preclinical safety data'). Should exposure to ACE inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Newborns whose mothers have taken ACE inhibitors should be closely observed for hypotension, oliguria and

hyperkalaemia (see also sections 4.3 and 4.4).

Because insufficient information is available regarding the use of ramipril during breastfeeding (see section 5.2), ramipril is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

4.7 Effects On Ability To Drive And Use Machines

Some adverse effects (e.g. symptoms of a reduction in blood pressure such as dizziness) may impair the patient's ability to concentrate and react and, therefore, constitute a risk in situations where these abilities are of particular importance (e.g. operating a vehicle or machinery).

This can happen especially at the start of treatment, or when changing over from other preparations. After the first dose or subsequent increases in dose it is not advisable to drive or operate machinery for several hours.

4.8 Undesirable Effects

The safety profile of ramipril includes persistent dry cough and reactions due to hypotension. Serious adverse reactions include angioedema, hyperkalaemia, renal or hepatic impairment, pancreatitis, severe skin reactions and neutropenia/agranulocytosis.

Adverse reactions frequency is defined using the following convention:

Very common (

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

	Common	Uncommon	Rare	Very rare	Not known
Cardiac disorders		Myocardial ischaemia including angina pectoris or myocardial infarction, tachycardia, arrhythmia, palpitations, oedema peripheral
Blood and lymphatic system disorders		Eosinophilia	White blood cell count decreased (including neutropenia or agranulocytosis), red blood cell count decreased, haemoglobin decreased, platelet count decreased		Bone marrow failure, pancytopenia, haemolytic anaemia
Nervous system disorders	Headache, dizziness	Vertigo, paraesthesia, ageusia, dysgeusia,	Tremor, balance disorder		Cerebral ischaemia including ischaemic stroke and transient ischaemic attack, psychomotor skills impaired, burning sensation, parosmia
Eye disorders		Visual disturbance including blurred vision	Conjunctivitis
Ear and labyrinth disorders			Hearing impaired, tinnitus
Respiratory, thoracic and mediastinal disorders	Non-productive tickling cough, bronchitis, sinusitis, dyspnoea	Bronchospasm including asthma aggravated, nasal congestion
Gastrointestinal disorders	Gastrointestinal inflammation, digestive disturbances, abdominal discomfort, dyspepsia, diarrhoea, nausea, vomiting	Pancreatitis (cases of fatal outcome have been very exceptionally reported with ACE inhibitors), pancreatic enzymes increased, small bowel angioedema, abdominal pain upper including gastritis, constipation, dry mouth	Glossitis		Aphtous stomatitis
Renal and urinary disorders		Renal impairment including renal failure acute, urine output increased, worsening of a pre-existing proteinuria, blood urea increased, blood creatinine increased
Skin and subcutaneous tissue disorders	Rash in particular maculo-papular	Angioedema; very exceptionally, the airway obstruction resulting from angioedema may have a fatal outcome; pruritus, hyperhidrosis	Exfoliative dermatitis, urticaria, onycholysis,	Photosensitivity reaction	Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, psoriasis aggravated, dermatitis psoriasiform, pemphigoid or lichenoid exanthema or enanthema, alopecia
Musculoskeletal and connective tissue disorders	Muscle spasms, myalgia	Arthralgia
Metabolism and nutrition disorders	Blood potassium increased	Anorexia, decreased appetite,			Blood sodium decreased
Vascular disorders	Hypotension, orthostatic blood pressure decreased, syncope	Flushing	Vascular stenosis, hypoperfusion, vasculitis		Raynaud's phenomenon
General disorders and administration site conditions	Chest pain, fatigue	Pyrexia	Asthenia
Immune system disorders					Anaphylactic or anaphylactoid reactions, antinuclear antibody increased
Hepatobiliary disorders		Hepatic enzymes and/or bilirubin conjugated increased,	Jaundice cholestatic, hepatocellular damage		Acute hepatic failure, cholestatic or cytolytic hepatitis (fatal outcome has been very exceptional).
Reproductive system and breast disorders		Transient erectile impotence, libido decreased			Gynaecomastia
Psychiatric disorders		Depressed mood, anxiety, nervousness, restlessness, sleep disorder including somnolence	Confusional state		Disturbance in attention

4.9 Overdose

Symptoms associated with overdosage of ACE inhibitors may include excessive peripheral vasodilatation (with marked hypotension, shock), bradycardia, electrolyte disturbances, and renal failure. The patient should be closely monitored and the treatment should be symptomatic and supportive. Suggested measures include primary detoxification (gastric lavage, administration of adsorbents) and measures to restore haemodynamic stability, including, administration of alpha 1 adrenergic agonists or angiotensin II (angiotensinamide) administration. Ramiprilat, the active metabolite of ramipril is poorly removed from the general circulation by haemodialysis.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: ACE Inhibitors, plain, ATC code C09AA05.

Mechanism of action

Ramiprilat, the active metabolite of the prodrug ramipril, inhibits the enzyme dipeptidylcarboxypeptidase I (synonyms: angiotensin-converting enzyme; kininase II). In plasma and tissue this enzyme catalyses the conversion of angiotensin I to the active vasoconstrictor substance angiotensin II, as well as the breakdown of the active vasodilator bradykinin. Reduced angiotensin II formation and inhibition of bradykinin breakdown lead to vasodilatation.

Since angiotensin II also stimulates the release of aldosterone, ramiprilat causes a reduction in aldosterone secretion. The average response to ACE inhibitor monotherapy was lower in black (Afro-Caribbean) hypertensive patients (usually a low-renin hypertensive population) than in non-black patients.

Pharmacodynamic effects

Antihypertensive properties:

Administration of ramipril causes a marked reduction in peripheral arterial resistance. Generally, there are no major changes in renal plasma flow and glomerular filtration rate. Administration of ramipril to patients with hypertension leads to a reduction in supine and standing blood pressure without a compensatory rise in heart rate.

In most patients the onset of the antihypertensive effect of a single dose becomes apparent 1 to 2 hours after oral administration. The peak effect of a single dose is usually reached 3 to 6 hours after oral administration. The antihypertensive effect of a single dose usually lasts for 24 hours.

The maximum antihypertensive effect of continued treatment with ramipril is generally apparent after 3 to 4 weeks. It has been shown that the antihypertensive effect is sustained under long term therapy lasting 2 years.

Abrupt discontinuation of ramipril does not produce a rapid and excessive rebound increase in blood pressure.

Heart failure:

In addition to conventional therapy with diuretics and optional cardiac glycosides, ramipril has been shown to be effective in patients with functional classes II-IV of the New-York Heart Association. The drug had beneficial effects on cardiac haemodynamics (decreased left and right ventricular filling pressures, reduced total peripheral vascular resistance, increased cardiac output and improved cardiac index). It also reduced neuroendocrine activation.

Clinical efficacy and safety

Cardiovascular prevention/Nephroprotection;

A preventive placebo-controlled study (the HOPE-study), was carried out in which ramipril was added to standard therapy in more than 9,200 patients. Patients with increased risk of cardiovascular disease following either atherothrombotic cardiovascular disease (history of coronary heart disease, stroke or peripheral vascular disease) or diabetes mellitus with at least one additional risk factor (documented microalbuminuria, hypertension, elevated total cholesterol level, low high-density lipoprotein cholesterol level or cigarette smoking) were included in the study.

The study showed that ramipril statistically significantly decreases the incidence of myocardial infarction, death from cardiovascular causes and stroke, alone and combined (primary combined events).

The HOPE Study: Main Results;

	Ramipril	Placebo	relative risk (95% confidence interval)	p-value
	%	%
All patients	n=4,645	N=4,652
Primary combined events	14.0	17.8	0.78 (0.70-0.86)	<0.001
Myocardial infarction	9.9	12.3	0.80 (0.70-0.90)	<0.001
Death from cardiovascular causes	6.1	8.1	0.74 (0.64-0.87)	<0.001
Stroke	3.4	4.9	0.68 (0.56-0.84)	<0.001
Secondary endpoints
Death from any cause	10.4	12.2	0.84 (0.75-0.95)	0.005
Need for Revascularisation	16.0	18.3	0.85 (0.77-0.94)	0.002
Hospitalisation for unstable angina	12.1	12.3	0.98 (0.87-1.10)	NS
Hospitalisation for heart failure	3.2	3.5	0.88 (0.70-1.10)	0.25
Complications related to diabetes	6.4	7.6	0.84 (0.72-0.98)	0.03

The MICRO-HOPE study, a predefined substudy from HOPE, investigated the effect of the addition of ramipril 10 mg to the current medical regimen versus placebo in 3,577 patients at least

The primary analysis showed that 117 (6.5 %) participants on ramipril and 149 (8.4 %) on placebo developed overt nephropathy, which corresponds to a RRR 24 %; 95 % CI [3-40], p = 0.027.

The REIN study, a multicenter randomized, double-blind parallel group, placebo-controlled study aimed at assessing the effect of treatment with ramipril on the rate of decline of glomerular function rate (GFR) in 352 normotensive or hypertensive patients (18-70 years old) suffering from mild (i.e. mean urinary protein excretion> 1 and < 3 g/24 h) or severe proteinuria (

The main analysis of patients with the most severe proteinuria (stratum prematurely disrupted due to benefit in ramipril group) showed that the mean r