Seretide Accuhaler

Seretide_TM
Accuhaler_TM

50 microgram/100 microgram/dose inhalation powder, pre-dispensed

50 microgram/250 microgram/dose inhalation powder, pre-dispensed

50 microgram/500 microgram/dose inhalation powder, pre-dispensed

salmeterol/fluticasone propionate

Read all of this leaflet carefully before you start taking this medicine.

• Keep this leaflet. You may need to read it again.


• If you have any further questions, ask your doctor or pharmacist.


• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.


• If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

• 
  1 What Seretide is and what it is used for


• 
  2 Before you use Seretide


• 
  3 How to use Seretide


• 
  4 Possible side effects


• 
  5 How to store Seretide


• 
  6 Further information

What Seretide is and what it is used for

Seretide contains two medicines, salmeterol and fluticasone propionate:

• Salmeterol is a long-acting bronchodilator. Bronchodilators help the airways in the lungs to stay open. This makes it easier for air to get in and out. The effects last for at least 12 hours.


• Fluticasone propionate is a corticosteroid which reduces swelling and irritation in the lungs.

The doctor has prescribed this medicine to help prevent breathing problems such as:

• Asthma


• Chronic Obstructive Pulmonary Disease (COPD). Seretide Accuhaler, at a dose of 50/500 micrograms, reduces the number of flare ups of COPD symptoms.

You must use Seretide every day as directed by your doctor. This will make sure that it works properly in controlling your asthma or COPD.

Seretide helps to stop breathlessness and wheeziness coming on. It does not work once you are breathless or wheezy. If that happens you need to use a fast acting ‘reliever’ medication, such as salbutamol.

Before you use Seretide

Do not take Seretide if:

You are allergic (hypersensitive) to salmeterol xinafoate, fluticasone propionate or to the other ingredient lactose monohydrate.

Take special care with Seretide

Your doctor will supervise your treatment more closely if you have medical conditions such as:

• heart disease, including an irregular or fast heartbeat


• overactive thyroid gland


• high blood pressure


• diabetes mellitus (Seretide may increase your blood sugar)


• low potassium in your blood


• Tuberculosis (TB) now or in the past.

If you have ever had any of these conditions, tell your doctor before you use Seretide.

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines. This includes medicines for asthma or any medicines obtained without a prescription. This is because Seretide may not be suitable to be taken with some other medicines.

Tell your doctor if you are taking the following medicines, before starting to use Seretide:

• Beta-blockers (such as atenolol, propranolol, sotalol). Beta-blockers are mostly used for high blood pressure or other heart conditions.


• Antiviral and antifungal medicines (such as ritonavir, ketoconazole and itraconazole). Some of these medicines may increase the amount of fluticasone propionate or salmeterol in your body. This can increase your risk of experiencing side effects with Seretide, including irregular heartbeats, or may make side-effects worse.


• Corticosteroids (by mouth or by injection). If you have had these medicines recently, this might increase the risk of this medicine affecting your adrenal gland.

Pregnancy and breast-feeding

If you are pregnant, planning to get pregnant or breast-feeding, talk to your doctor before taking Seretide. Your doctor will assess whether you can take Seretide during this time.

Driving and using machines

Seretide is not likely to affect your ability to drive or use machines.

Important information about some of the ingredients of Seretide

Seretide Accuhaler contains up to 12.5 milligrams of lactose in each dose. The amount of lactose in this medicine does not normally cause problems in people who are lactose intolerant.

How to use Seretide

• Use your Seretide every day, until your doctor advises you to stop.


• Always use Seretide exactly as your doctor has told you.

For asthma

Adults and adolescents aged 12 years and over

• Seretide Accuhaler 50/100 - One inhalation twice a day


• Seretide Accuhaler 50/250 - One inhalation twice a day


• Seretide Accuhaler 50/500 - One inhalation twice a day

Children 4 to 12 years of age

• Seretide Accuhaler 50/100 - One inhalation twice a day


• Seretide is not recommended for use in children below 4 years of age.

For adults with Chronic Obstructive Pulmonary Disease (COPD)

• Seretide Accuhaler 50/500 - One inhalation twice a day

Your symptoms may become well controlled using Seretide twice a day. If so, your doctor may decide to reduce your dose to once a day. The dose may change to:

• once at night - if you have night-time symptoms


• once in the morning - if you have daytime symptoms.

It is very important to follow your doctor’s instructions on how many inhalations to take and how often to take your medicine.

If you are using Seretide for asthma, your doctor will want to regularly check your symptoms.

If your asthma or breathing gets worse tell your doctor straight away. You may find that you feel more wheezy, your chest feels tight more often or you may need to use more of your fast acting ‘reliever’ medicine. If any of these happen, you should continue to take Seretide but do not increase the number of puffs you take. Your chest condition may be getting worse and you could become seriously ill. See your doctor as you may need additional treatment.

Instructions for use

• Your doctor, nurse or pharmacist should show you how to use your inhaler. They should check how you use it from time to time. Not using the Seretide Accuhaler properly or as prescribed may mean that it will not help your asthma or COPD as it should.


• The Accuhaler device holds blisters containing Seretide as a powder.


• There is a counter on top of the Accuhaler which tells you how many doses are left. It counts down to 0. The numbers 5 to 0 will appear in red to warn you when there are only a few doses left. Once the counter shows 0, your inhaler is empty.

Using your inhaler

• 1 To open your Accuhaler, hold the outer case in one hand and put the thumb of your other hand on the thumbgrip. Push your thumb away from you as far as it will go. You will hear a click. This will open a small hole in the mouthpiece.

• 2 Hold your Accuhaler with the mouthpiece towards you. You can hold it in either your right or left hand. Slide the lever away from you as far as it will go. You will hear a click. This places a dose of your medicine in the mouthpiece.

Every time the lever is pulled back a blister is opened inside and the powder made ready for you to inhale. Do not play with the lever as this opens the blisters and wastes medicine.

• 3 Hold the Accuhaler away from your mouth, breathe out as far as is comfortable. Do not breathe into your Accuhaler.


• 4 Put the mouthpiece to your lips; breathe in steadily and deeply through the Accuhaler, not through your
  nose.
  
  Remove the Accuhaler from your mouth.
  
  Hold your breath for about 10 seconds or for as long as is comfortable.
  
  Breathe out slowly.

• 5 Afterwards rinse your mouth with water and spit it out. This may help to stop you getting thrush and being hoarse.


• 6 To close the Accuhaler, slide the thumbgrip back towards you, as far as it will go. You will hear a click.
  
  The lever will return to its original position and is reset.
  
  Your Accuhaler is now ready for you to use again.

Cleaning your inhaler

Wipe the mouthpiece of the Accuhaler with a dry tissue to clean it.

If you use more Seretide than you should

It is important to use the inhaler as instructed. If you accidentally take a larger dose than recommended, talk to your doctor or pharmacist. You may notice your heart beating faster than usual and that you feel shaky. You may also have a headache, muscle weakness and aching joints.

If you have used larger doses for a long period of time, you should talk to your doctor or pharmacist for advice. This is because larger doses of Seretide may reduce the amount of steroid hormones produced by the adrenal gland.

If you forget to use Seretide

If you forget to use your inhaler, take your next dose when it is due.

Do not take a double dose to replace the one you forgot.

If you stop using Seretide

It is very important that you take your Seretide every day as directed.

Keep taking it until your doctor tells you to stop. Do not stop or suddenly reduce your dose of Seretide. This could make your breathing problem worse and very rarely side effects could occur. These include:

• stomach pain


• tiredness and loss of appetite


• sickness and diarrhoea


• weight loss


• headache or drowsiness


• low levels of potassium in your blood


• low blood pressure and seizures.

Very rarely, if you get an infection or at times of extreme stress (such as after a serious accident or if you have surgery), you may get similar side effects.

To prevent these symptoms occurring, your doctor may prescribe extra corticosteroids (like prednisolone).

If you have any further questions on using the inhaler, ask your doctor or pharmacist.

Seretide Accuhaler Side Effects

Like all medicines, Seretide can cause side effects, although not everybody gets them. To reduce the chance of side effects, your doctor will prescribe the lowest dose of Seretide to control your asthma or COPD.

Allergic reactions: you may notice your breathing suddenly gets worse after using Seretide. You may be very wheezy and cough. You may also notice itching and swelling (usually of the face, lips, tongue, or throat). If you get these effects or if they happen suddenly after using Seretide, tell your doctor straight away. Allergic reactions to Seretide are very rare (they affect less than 1 person in 10,000).

Other side effects are listed below:

Very Common (affects more than 1 person in 10)

• Headache - this usually gets better as treatment continues.


• Increased number of colds have been reported in patients with COPD.

Common (affects less than 1 person in 10)

• Thrush (sore, creamy-yellow, raised patches) in the mouth and throat. Also sore tongue, throat and hoarse voice. Rinsing your mouth out with water and spitting it out immediately after taking each puff may help. Your doctor may prescribe an anti fungal medication to treat the thrush.


• Feeling shaky and fast or uneven heartbeat (palpitations) - these are usually harmless and get less as treatment continues.


• Muscle cramps.

The following side effects have also been reported in patients with Chronic Obstructive Pulmonary Disease (COPD):

• Pneumonia and bronchitis (lung infection). Tell your doctor if you notice any of the following symptoms: increase in sputum production, change in sputum colour, fever, chills, increased cough, increased breathing problems.


• Bruising and fractures.


• Inflammation of sinuses (a feeling of tension or fullness in the nose, cheeks and behind the eyes, sometimes with a throbbing ache).


• A reduction in the amount of potassium in the blood (you may get an uneven heartbeat, muscle weakness, cramp).

Uncommon (affects less than 1 person in 100)

• Rash.


• Very fast heartbeat (tachycardia).

Very rare (affects less than 1 in 10,000)

• 
  Breathing difficulties or wheezing that get worse straight after taking Seretide. If this happens stop using your Seretide inhaler. Use your fast-acting ‘reliever’ inhaler to help your breathing and tell your doctor straight away.


• Seretide may affect the normal production of steroid hormones in the body, particularly if you have taken high doses for long periods of time. The effects includes:
  
  
  • slowing of growth in children and adolescents
  • thinning of the bones
  • cataract and glaucoma
  • weight gain
  • rounded (moon shaped) face (Cushing’s Syndrome).
    .
  Your doctor will check you regularly for any of these side effects and make sure you are taking the lowest dose of Seretide to control your asthma


• Uneven heartbeat or heart gives an extra beat (arrhythmias). Tell your doctor, but do not stop taking Seretide unless they tell you to stop.


• Increases in the amount of sugar (glucose) in your blood (hyperglycaemia). If you have diabetes, more frequent blood sugar monitoring and possibly adjustment of your usual diabetic treatment may be required.


• Feeling worried, disturbed sleep and behavioural changes, such as being unusually active and irritable (these effects mainly occur in children).


• Aching, swollen joints and muscle pain.

If any of the side effects become serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

How to store Seretide

• 
  Keep out of the reach and sight of children.
  


• Do not store above 30°C.


• Do not use Seretide after the expiry date which is stated on the label and carton. The expiry date refers to the last day of that month.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Further information

What Seretide Accuhaler contains

• The active substances are 50 micrograms salmeterol (as salmeterol xinafoate) and 100, 250 or 500 micrograms fluticasone propionate.


• The other ingredient is lactose monohydrate (which contains milk proteins).

What Seretide Accuhaler looks like and contents of the pack

• The Seretide Accuhaler contains a foil strip. The foil protects the powder for inhalation from the effects of the atmosphere.


• Each dose is pre-dispensed.


• The devices are packed in cartons which hold:
  1 x Accuhaler 28 inhalations
  or 1,2,3 or 10 x Accuhaler each containing 60 inhalations. Not all pack sizes are marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder:

GlaxoWellcome UK Ltd.

trading as Allen & Hanburys

Stockley Park West

Uxbridge

Middlesex

UB11 1BT

Manufacturer:

Glaxo Operations UK Ltd.

trading as Glaxo Wellcome Operations

Priory Street

Ware

Hertfordshire

SG12 ODJ

United Kingdom

This medicinal product is authorised in the Member States of the EEA under the following names:

Austria Seretide Diskus

Belgium Seretide Diskus

Denmark Seretide

Finland Seretide Diskus

France Seretide Diskus

Germany atmadisc Diskus

Greece Seretide Diskus

Ireland Seretide Diskus

Italy Seretide Diskus

Luxembourg Seretide Diskus

The Netherlands Seretide Diskus

Portugal Seretaide Diskus

Spain Seretide Accuhaler

Sweden Seretide Diskus

United Kingdom Seretide Accuhaler

Other formats:

To listen to or request a copy of this leaflet in Braille, large print or audio please call free of charge:

0800 198 5000 (UK Only)

Please be ready to give the following information:

Product name Seretide Accuhaler


Reference number 10949/0314

This is a service provided by the Royal National Institute of Blind People.

Leaflet date: June 2009

Accuhaler and Seretide are trademarks of the GlaxoSmithKline group of companies

© 2009 GlaxoSmithKline group of companies

10000000067234

Codeine Phosphate

Class: Opiate Agonists
Note: This monograph also contains information on Codeine, Codeine Sulfate
VA Class: CN101
Chemical Name: (5α,6α)-7,8-Didehydro-4,5-epoxy-3-methoxy-17-methyl-morphan-6-ol monohydrate
Molecular Formula: C₁₈H₂₁NO₃•H₂OC₁₈H₂₁NO₃•H₃PO₄•½H₂O
CAS Number: 6059-47-8
Brands: Ambenyl, Bromanyl, BenzaClin, Brontex, Capital and Codeine, Cheracol with Codeine, Codimal PH, Colrex Compound, Cycofed Expectorant Pediatric, Decohistine DH, Dihistine DH Elixir, Duac, Fioricet with Codeine, Fiorinal with Codeine, Gani-Tuss NR, Guiatuss AC, Guiatussin with Codeine, HaNew Riversin, KG-Fed Pediatric Expectorant, Mytussin AC, Novahistine DH, Nucofed, Nucotuss Pediatric, Pediacof, Phenergan VC with Codeine, Phenhist DH with Codeine Modified Formula, Prometh VC with Codeine Phosphate, Robafen AC, Robitussin A-C, Ryna-C, Ryna-CX, Soma Compound with Codeine, Triacin-C, Tussar SF, Tussar-2 Syrup, Tussi-Organidin NR, Tussi-Organidin-S NR, Tylenol with Codeine

Introduction

Opiate agonist; phenanthrene derivative.^{a b}

Uses for Codeine Phosphate

Pain

Symptomatic relief of mild to moderate pain that is not relieved by a non-opiate analgesic.^{b d e f}

Combinations of codeine and aspirin or acetaminophen may produce additive analgesic effects because of differing mechanisms of action.^b

Cough

Symptomatic relief of nonproductive cough, alone or in combination with other antitussives or expectorants.^a

Codeine Phosphate Dosage and Administration

Administration

Oral Administration

Administer orally.^{a b}

Dispense a calibrated measuring device with cough preparations intended for children 2–5 years of age.¹⁰³

Dosage

Available as codeine phosphate and codeine sulfate; dosage expressed in terms of the salt.^{d e g}

Pediatric Patients

Cough

Oral

Usual Pediatric Antitussive Dosages

Age	Daily Dosage
2–5 years	1 mg/kg daily in 4 equally divided doses every 4–6 hours100 101 103
6–11 years	5–10 mg every 4–6 hours100 101 103
≥12 years	10–20 mg every 4–6 hoursa

Alternatively, use the following dosages as a guide based on average body weight; reduce dosage for low-weight children.¹⁰⁰

Antitussive Dosages for Pediatric Patients Based on Weight100

Age	Daily Dosage
2 years (averaging 12 kg)	3 mg every 4–6 hours (maximum 12 mg daily)
3 years (averaging 14 kg)	3.5 mg every 4–6 hours (maximum 14 mg daily)
4 years (averaging 16 kg)	4 mg every 4–6 hours (maximum 16 mg daily)
5 years (averaging 18 kg)	4.5 mg every 4–6 hours (maximum 18 mg daily)

Pain

Oral

3 mg/kg or 100 mg/m² daily in 6 divided doses.^b Alternatively, 0.5 mg/kg or 15 mg/m² every 4–6 hours.^{b f}

Adults

Cough

Oral

10–20 mg every 4–6 hours.^a

Pain

Oral

30 mg every 4 hours as needed; usual dosage range is 15–60 mg every 4 hours as needed.^{b d e}

Nonopiate-containing analgesic fixed combinations: Nonopiate component may limit dosage of opiate component.^{117 119 120 121} Nonopiate analgesics are available in various fixed ratios with codeine and also are available in many other prescription and OTC preparations; ensure that therapy is not duplicated and that nonopiate dosage does not exceed maximum recommended dosages.^{117 118 119 121}

Prescribing Limits

Pediatric Patients

Cough

Oral

Maximum Daily Antitussive Dosages for Pediatric Patients

Age	Maximum Daily Dosage
2 years (averaging 12 kg)	12 mg100
3 years (averaging 14 kg)	14 mg 100
4 years (averaging 16 kg)	16 mg 100
5 years (averaging 18 kg)	18 mg 100
6–11 years	60 mg a
≥12 years	120 mg a

Adults

Cough

Oral

Maximum 120 mg daily.^a

Special Populations

Geriatric Patients

Reduce dosage in older patients.^{a b}

Ultra-rapid Metabolizers of CYP2D6 Substrates

Use lowest effective dosage for shortest period of time.^{104 105 106 113} (See Special Populations under Pharmacokinetics.)

Cautions for Codeine Phosphate

Contraindications

• 
  

  Known hypersensitivity to codeine or any ingredient in the formulation.^{c d e f}

  
  

Warnings/Precautions

Warnings

CNS Depression

Performance of activities requiring mental alertness and physical coordination may be impaired.^{a c d e f}

Concurrent use of other CNS depressants may potentiate CNS depression.^{d e} (See Specific Drugs under Interactions.)

Abuse Potential

Possible tolerance, psychologic dependence, and physical dependence following prolonged administration.^a Abuse potential similar to that of morphine.^{d e f}

Sulfite Sensitivity

Some formulations contain sulfites, which may cause allergic-type reactions (including anaphylaxis and life-threatening or less severe asthmatic episodes) in certain susceptible individuals.^f

General Precautions

Increased Intracranial Pressure or Head Trauma

Potential for increased respiratory depressant effects and elevation of CSF pressure in patients with increased intracranial pressure, head trauma, or other intracranial lesions.^{c d e f}

Adverse effects of opiates may obscure the existence, extent, or course of intracranial pathology.^{d e f g}

Acute Abdominal Conditions

Administration may complicate assessment of patients with acute abdominal conditions.^{c d e f}

Respiratory Depression

Possible dose-related respiratory depression^{c d e} (occurs infrequently with oral antitussive doses).^a

Potential for increased viscosity of bronchial secretions and suppression of cough reflex, with subsequent respiratory insufficiency, in patients with asthma or pulmonary emphysema who indiscriminately use antitussives.^a

Postoperative Patients

Suppression of cough reflex following thoracotomy or laparotomy may lead to postoperative retention of secretions; cautious use recommended.^a

Debilitated and Special Risk Patients

Use with caution in debilitated patients and in those with hypothyroidism, Addison’s disease, and prostatic hypertrophy or urethral stricture.^{a d e f}

Fixed-combination Preparations

When used in fixed combination with other drug(s), consider the cautions, precautions, and contraindications associated with the other drug(s).^b

Specific Populations

Pregnancy

Category C.^f

Lactation

Distributed into milk. ^a Use with caution in nursing women who are known or suspected ultra-rapid metabolizers of CYP2D6 substrates; opioid toxicity resulting in neonatal death reported in the nursing infant of mother receiving codeine; mother was an ultra-rapid metabolizer of codeine.^{104 105 106 107 113} (See Metabolism and see Special Populations under Pharmacokinetics.)

The FDA-approved AmpliChip CYP450 Test can be used to identify CYP2D6 genotype.^{106 111 113} Testing alone may not adequately predict risk of adverse reactions and should not substitute for clinical judgment.¹⁰⁴ If codeine is used in nursing women, administer lowest effective dosage for shortest possible time; closely monitor for opioid toxicity in both mother and infant.^{104 105 106 113}

Pediatric Use

Safety for the management of mild to moderate pain not established in children <3 years of age.^{d e f}

Use as antitussive not recommended in children <2 years of age; possible respiratory arrest, coma, and death due to increased susceptibility to respiratory depressant effects.^a

Risk of overdosage and toxicity (including death) in children <2 years of age receiving OTC preparations containing antihistamines, cough suppressants, expectorants, and nasal decongestants alone or in combination for relief of symptoms of upper respiratory tract infection.^{115 116} Limited evidence of efficacy for these preparations in this age group; appropriate dosages not established.¹¹⁵ Therefore, FDA recommends not to use such preparations in children <2 years of age; safety and efficacy in older children currently under evaluation. Because children 2–3 years of age also are at increased risk of overdosage and toxicity, some manufacturers of oral nonprescription cough and cold preparations recently agreed to voluntarily revise the product labeling to state that such preparations should not be used in children <4 years of age. During the transition period, some preparations on pharmacy shelves will have the new recommendation (“do not use in children <4 years of age”), while others will have the previous recommendation (“do not use in children <2 years of age”). FDA recommends that parents and caregivers adhere to dosage instructions and warnings on the product labeling that accompanies the preparation and consult a clinician about any concerns. Clinicians should ask caregivers about use of OTC cough/cold preparations to avoid overdosage.

Geriatric Use

Use with caution.^{d e f g} (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Use with caution in patients with severe hepatic impairment.^{d e f g}

Renal Impairment

Use with caution in patients with severe renal impairment.^{d e f}

Common Adverse Effects

When used for pain relief (particularly in ambulatory patients not experiencing severe pain): lightheadedness, dizziness, sedation, nausea, vomiting, sweating.^{d e f}

When used at antitussive doses: nausea, vomiting, constipation (with repeated doses), dizziness, sedation, palpitation, pruritus.^a

Interactions for Codeine Phosphate

Specific Drugs

Drug	Interaction	Comments
Anticholinergic agents	Possible paralytic ileusf
Antidepressants, MAO inhibitors and tricyclics	Potentiation of antidepressant effectc	Use with caution; reduce dosage of codeinec
CNS depressants (e.g., opiate agonists, general anesthetics, tranquilizers, phenothiazines, sedatives/hypnotics, alcohol)	Additive CNS effectsa d e f	Reduce dosage of one or both agentsd e f

Codeine Phosphate Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration.^{a b e f g}

Onset

Onset occurs in 15–30 minutes.^{a b} Peak analgesic effects occur within 2 hours;^g peak antitussive effects within 1–4 hours.ⁱ

Duration

Analgesic effects persist for 4–6 hours.^{b g} Antitussive effects may persist for 4 hours.ⁱ

Distribution

Extent

Rapidly distributed into various body tissues, with preferential uptake by parenchymatous organs such as the liver, spleen, and kidney.^g Distributed into milk.^b Readily crosses the placenta.^c

Protein Binding

Not bound to plasma proteins.^g

Elimination

Metabolism

Metabolized in liver, principally by CYP3A4 and to a lesser extent (10%) by CYP2D6 to O-demethylated morphine, the active metabolite.^{b 108 109 110 112}

Metabolism of codeine influenced by CYP2D6 polymorphism; genetic differences in drug metabolism affect drug response.^{108 109 110 112 114} Individuals may be described as poor, extensive, or ultra-rapid metabolizers of CYP2D6 substrates.^{108 109 110 112 114}

Elimination Route

Excreted mainly in urine with negligible amounts of codeine and its metabolites found in feces.^{b g}

Half-life

About 2.5–3 hours.^{f g}

Special Populations

Individuals who carry the genotype associated with ultra-rapid metabolism of CYP2D6 substrates (approximately 1–7% of Caucasians, 10–30% of Ethiopians and Saudi Arabians) convert codeine to morphine more rapidly and completely than other individuals; ultra-rapid metabolizers are likely to have higher than expected serum concentrations of morphine.^{107 108 110 112 114}

Stability

Storage

Oral

Tablets

Tight, light-resistant containers at <40°C (preferably 15–30°C).^b

Solution

Tight, light-resistant containers at <40°C (preferably 15–30°C).^h Protect from freezing.^h

ActionsActions

• 
  

  Principal pharmacologic effects are on CNS and intestines.^{c d e}

  
  


• 
  

  Mild analgesic effect.^{b d e f} Acts at several sites within the CNS involving several systems of neurotransmitters to produce analgesia; precise mechanism of action not fully elucidated.^c

  
  


• 
  

  Suppresses cough reflex by direct effect on cough center in medulla of brain.^a

  
  


• 
  

  Exerts drying effect on respiratory tract mucosa and increases viscosity of bronchial secretions.^a

  
  


• 
  

  Antitussive activity is less than that of morphine (on a weight basis).^a

  
  

Advice to Patients

• 
  

  Potential for drug to impair mental alertness or physical coordination; use caution when driving or operating machinery until effects on individual are known.^{d e f}

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as alcohol consumption and any concomitant diseases.^{d e f} Importance of limiting alcohol intake.^f

  
  


• 
  

  Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.^{d e f}

  
  


• 
  

  Risk of morphine toxicity in nursing infants of mothers taking codeine who are ultra-rapid metabolizers of codeine.^{104 105 106 113} Importance of monitoring infants for manifestations of morphine overdose (e.g., sedation, difficulty breathing, hypotonia, poor feeding); immediately seek medical attention if any symptoms develop.^{104 105 113}

  
  


• 
  

  Importance of advising patients of other important precautionary information.^{d e} (See Cautions.)

  
  

Preparations

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

Subject to control under the Federal Controlled Substances Act of 1970.^{d e}

Codeine

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Bulk	Crystals

Codeine Phosphate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Bulk	Powder
Oral	Solution	15 mg/5 mL	Codeine Phosphate Oral Solution ( C-II)
	Tablets, soluble	30 mg	Codeine Phosphate Soluble Tablets ( C-II)
		60 mg	Codeine Phosphate Soluble Tablets ( C-II)

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

Acetaminophen and Codeine Phosphate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Solution	120 mg/5 mL Acetaminophen and Codeine Phosphate 12 mg/5 mL*	Tylenol with Codeine Elixir ( C-V)	Ortho-McNeil
	Suspension	120 mg/5 mL Acetaminophen and Codeine Phosphate 12 mg/5 mL	Capital and Codeine ( C-V)	Amarin
	Tablets	300 mg Acetaminophen and Codeine Phosphate 15 mg*
		300 mg Acetaminophen and Codeine Phosphate 30 mg*	Tylenol with Codeine ( C-III)	Ortho-McNeil
		300 mg Acetaminophen and Codeine Phosphate 60 mg*	Tylenol with Codeine ( C-III)	Ortho-McNeil

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

Aspirin and Codeine Phosphate (Co-codaprin)

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	325 mg Aspirin and Codeine Phosphate 30 mg*	Aspirin and Codeine Phosphate Tablets ( C-III)
		325 mg Aspirin and Codeine Phosphate 60 mg*	Aspirin and Codeine Phosphate Tablets ( C-III)

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

Guaifenesin and Codeine Phosphate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Solution	75 mg/5 mL Guaifenesin and Codeine Phosphate 2.5 mg/5 mL	Brontex ( C-V)	Kenwood
		100 mg/5 mL Guaifenesin and Codeine Phosphate 10 mg/5 mL*	Cheracol with Codeine Syrup ( C-V)	Lee Pharmaceuticals
			Gani-Tuss NR ( C-V)	Cypress
			Guiatuss AC Syrup ( C-V)	Alpharma, IVAX
			Guiatussin with Codeine ( C-V)	Rugby
			HaNew Riversin AC ( C-V)	Halsey
			Mytussin AC Cough Syrup ( C-V;)	Morton Grove Pharmaceuticals
			Robafen AC Syrup ( C-V)	Major
			Robitussin A-C Syrup ( C-V)	Robins
			Tussi-Organidin NR ( C-V)	Wallace
			Tussi-Organidin-S NR ( C-V; with graduated oral syringe)	Wallace
	Tablets	300 mg Guaifenesin and Codeine Phosphate 10 mg	Brontex ( C-III)	Kenwood

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

Other Codeine Phosphate Combinations

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	30 mg with Acetaminophen 325 mg, Butalbital 50 mg, and Caffeine 40 mg	Fioricet with Codeine ( C-III)	Watson
		16 mg with Acetaminophen 325 mg, Chlorpheniramine Maleate 2 mg and Phenylephrine Hydrochloride 10 mg	Colrex Compound ( C-III)	Numark
		30 mg with Aspirin 325 mg, Butalbital 50 mg, and Caffeine 40 mg*	Fiorinal with Codeine ( C-III)	Watson
		20 mg with Pseudoephedrine Hydrochloride 60 mg	Nucofed ( C-III)	Monarch
	Solution	5 mg/5 mL with Chlorpheniramine Maleate 0.75 mg/5 mL, Phenylephrine Hydrochloride 2.5 mg/5 mL, and Potassium Iodide 75 mg/5 mL	Pediacof Cough Syrup ( C-V)	Sanofi-Synthelabo
		10 mg/5 mL with Bromodiphenhydramine Hydrochloride 12.5 mg/5 mL	Ambenyl Cough Syrup ( C-V)	Forest
			Bromanyl Cough Syrup ( C-V)	Alpharma, Moore
			Bromodiphenhydramine Hydrochloride and Codeine Phosphate Cough Syrup ( C-V)
		10 mg/5 mL with Chlorpheniramine Maleate 2 mg/5 mL, and Pseudoephedrine Hydrochloride 30 mg/5 mL	Decohistine DH ( C-V)	Morton Grove
			Dihistine DH Elixir ( C-V)	Alpharma, IVAX, Moore
			Novahistine DH ( C-V)	GlaxoSmithKline
			Phenhist DH with Codeine Modified Formula ( C-V)	Rugby
			Ryna-C ( C-V)	Wallace
		10 mg/5 mL with Guaifenesin 100 mg/5 mL and Pseudoephedrine Hydrochloride 30 mg/5 mL	Cycofed Expectorant Pediatric ( C-V)	Cypress
			Decohistine Expectorant ( C-V)	Morton Grove
			Dihistine Expectorant ( C-V)	Alpharma, Moore
			Guaifenesin DAC ( C-V)	Cypress
			Guiatuss DAC Syrup ( C-V)	Alpharma, IVAX, Moore
			Guiatussin DAC Syrup ( C-V)	Rugby
			HaNew Riversin DAC ( C-V)	Halsey
			KG-Fed Pediatric Expectorant Syrup ( C-V)	King
			Mytussin DAC ( C-V)	Morton Grove
			Novahistine Expectorant with Codeine ( C-V)	GlaxoSmithKline
			Nucofed Pediatric Expectorant Syrup ( C-V)	Monarch
			Nucotuss Pediatric Expectorant ( C-V)	Alpharma
			Robitussin-DAC ( C-V)	Robins
			Ryna-CX ( C-V)	Wallace
			Tussar SF Syrup ( C-V)	Aventis
			Tussar-2 Syrup ( C-V)	Aventis
		10 mg/5 mL with Phenylephrine Hydrochloride 5 mg/5 mL and Promethazine Hydrochloride 6.25 mg/5 mL	Phenergan VC with Codeine Syrup ( C-V)	Wyeth
			Promethazine VC with Codeine Syrup ( C-V)
			Prometh VC with Codeine Phosphate Cough Syrup ( C-V)	Alpharma
		10 mg/5 mL with Phenylephrine Hydrochloride 5 mg/5 mL and Pyrilamine Maleate 8.33 mg/5 mL	Codimal PH Syrup ( C-V)	Schwarz
		10 mg/5 mL with Promethazine Hydrochloride 6.25 mg/5 mL*	Phenergan with Codeine Syrup ( C-V)	Wyeth
		10 mg/5 mL with Pseudoephedrine Hydrochloride 30 mg/5 mL and Triprolidine Hydrochloride 1.25 mg/5 mL*	Triacin-C Cough Syrup ( C-V)	Alpharma, Moore
		20 mg/5 mL with Guaifenesin 200 mg/5 mL and Pseudoephedrine Hydrochloride 60 mg/5 mL	Cycofed Expectorant ( C-III)	Cypress
			KG-Fed Expectorant Syrup ( C-III)	King
			Nucofed Expectorant ( C-III)	Monarch
			Nucotuss Expectorant ( C-III)	Alpharma
		20 mg/5 mL with Pseudoephedrine Hydrochloride 60 mg/5 mL	KG-Fed Syrup ( C-III)	King
			Nucofed Syrup ( C-III)	Monarch
	Tablets	16 mg with Aspirin 325 mg and Carisoprodol 200 mg*	Soma Compound with Codeine ( C-III)	Wallace

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

Codeine Sulfate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Bulk	Powder*
Oral	Tablets	15 mg*	Codeine Sulfate Tablets ( C-II)
		30 mg*	Codeine Sulfate Tablets ( C-II)
		60 mg*	Codeine Sulfate Tablets ( C-II)

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 05/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Acetaminophen-Codeine 120-12MG/5ML Solution (MORTON GROVE PHARMACEUTICALS): 240/$19.99 or 720/$35.97

Acetaminophen-Codeine #2 300-15MG Tablets (TEVA PHARMACEUTICALS USA): 30/$14.99 or 60/$19.97

Acetaminophen-Codeine #3 300-30MG Tablets (MALLINCKRODT PHARM): 30/$15.99 or 60/$20.98

Acetaminophen-Codeine #4 300-60MG Tablets (MALLINCKRODT PHARM): 30/$17.99 or 90/$33.97

Carisoprodol-Aspirin-Codeine 200-325-16MG Tablets (SANDOZ): 30/$83.37 or 90/$240.03

Cheratussin AC 100-10MG/5ML Syrup (QUALITEST): 480/$15.99 or 1440/$25.97

Cheratussin AC 100-10MG/5ML Syrup (QUALITEST): 118/$11.99 or 354/$19.97

Cheratussin DAC 30-10-100MG/5ML Solution (QUALITEST): 480/$35.99 or 960/$60.97

Codeine Sulfate 30MG Tablets (ROXANE): 20/$19.99 or 30/$26.98

Mytussin DAC 30-10-100MG/5ML Solution (MORTON GROVE PHARMACEUTICALS): 473/$39.66 or 1419/$118.98

Promethazine-Codeine 6.25-10MG/5ML Syrup (QUALITEST): 473/$29.99 or 1419/$83.38

Tylenol with Codeine #4 300-60MG Tablets (MCNEIL): 30/$45.99 or 90/$119.97

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 February 01, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

Only references cited for selected revisions after 1984 are available electronically.

100. Food and Drug Administration. Cold, cough, allergy, bronchodilator, and antiasthmatic drug products for over-the-counter human use; tentative final monograph for OTC antitussive drug products. [21 CFR Part 341] Fed Regist. 1983; 43:48576-95.

101. Committee on Drugs, American Academy of Pediatrics. Use of codeine- and dextromethorphan-containing cough syrups in pediatrics. Pediatrics. 1978; 62:118-22. [IDIS 112027] [PubMed 683771]

102. von Muhlendahl KE, Krienke EG, Scherf-Rahne B et al. Codeine intoxication in childhood. Lancet. 1976; 2:303-5. [PubMed 59870]

103. Food and Drug Administration. Cold, cough, allergy, bronchodilator, and antiasthmatic drug products for over-the-counter human use; final monograph for OTC antitussive drug products [21 CFR Parts 310, 341, and 369] Fed Regist. 1987; 52:30042-57.

104. Food and Drug Administration. FDA public health advisory: use of codeine by some breastfeeding mothers may lead to life-threatening side effects in nursing babies. Rockville, MD; 2007 Aug 17. From FDA website.

105. Food and Drug Administration. FDA Alert: Use of codeine products in nursing mothers. 2007 Aug 17. From FDA website.

106. Food and Drug Administration. Codeine products used by nursing mothers. Medwatch alert. Rockville, MD; 2007 Aug 17. From FDA website.

107. Koren G, Cairns J, Chitayat D et al. Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother. Lancet. 2006; 368:704. [PubMed 16920476]

108. Kirchheiner J, Schmidt H, Tzvetkov M et al. Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. Pharmacogenomics J. 2007; 7:257-65. [PubMed 16819548]

109. Meyer UA. Pharmacogenetics and adverse drug reactions. Lancet. 2000; 356:1667-71. [PubMed 11089838]

110. Gasche Y, Daali Y, Fathi M et al. Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med. 2004; 351:2827-31. [PubMed 15625333]

111. Roche Molecular Systems, Inc. AmpliChip CYP450 Test for in vitro diagnostic use. Branchburg, NJ; 2007 July.

112. Voronov P, Przybylo HJ, Jagannathan N. Apnea in a child after oral codeine: a genetic variant-an ultra-rapid metabolizer. Paediatr Anaesth. 2007; 17: 684-7. [PubMed 17564651]

113. Food and Drug Administration. FDA warning on codeine use by nursing mothers. FDA News. Rockville, MD; 2007 Aug 17. From FDA website.

114. Weinshilboum R. Inheritance and drug response. N Engl J Med. 2003; 348:529-37. [PubMed 12571261]

115. Srinivasan A, Budnitz D, Shehab N et al. Infant deaths associated with cough and cold medications—two states, 2005. MMWR Morb Mortal Wkly Rep. 2007; 56:1-4. [PubMed 17218934]

116. Food and Drug Administration. Cough and cold medications in children less than two years of age. Rockville, MD; 2007 Jan 12. From FDA website.

117. Jackson KC II, Lipman AG. Nonopioid analgesics. In: Lipman AG, ed. Pain management for primary care clinicians. Bethesda, MD: American Society of Health-System Pharmacists; 2004:43-58.

118. Cranmer KW, Mason M. Special considerations in geriatric pain management. In: Lipman AG, ed. Pain management for primary care clinicians. Bethesda, MD: American Society of Health-System Pharmacists; 2004:219-232.

119. Fakata KL, Miaskowski C, Lipman AG. Chronic malignant pain. In: Lipman AG, ed. Pain management for primary care clinicians. Bethesda, MD: American Society of Health-System Pharmacists; 2004:139-52.

120. McNicol E, Carr DB. Pharmacological treatment of pain. In: McCarberg B, Passik SD, eds. Expert guide to pain management. Philadelphia: American College of Physicians; 2005:145-78.

121. American Pain Society. Principles of analgesic use in the treatment of acute pain and cancer pain. 5th edition. Glenview, IL; 2003:3,9,13,14.

a. AHFS Drug Information 2003. McEvoy GK, ed. Codeine. Bethesda, MD: American Society of Health-System Pharmacists; 2003:2570-2.

b. AHFS Drug Information 2003. McEvoy GK, ed. Codeine. Bethesda, MD; American Society of Health-System Pharmacists; 2003:2027-8.

c. AHFS drug information 2003. McEvoy GK, ed. Opiate agonists general statement. Bethesda, MD: American Society of Hospital Pharmacists; 2002:2022-7.

d. Roxane Laboratories. Codeine sulfate tablets prescribing information. Columbus, OH. 2001 Jul.

e. Roxane Laboratories. Codeine sulfate oral solution prescribing information. Columbus, OH. 2000 Dec.

f. Ortho-McNeil. Tylenol with Codeine (acetaminophen and codeine phosphate) tablets prescribing information. In: Physicians’ desk reference. 56th ed. Montvale, NJ: Medical Economics Company Inc; 2002: 2595-6.

g. Novartis. Fioricet with Codeine (butalbital, acetaminophen, caffeine, and codeine phosphate) capsules prescribing information. East Hanover, NJ. 2002 Oct.

h. USPDI: Drug information for the health care professional. Johnson KW, ed. 23th ed. Greenwood Village CO: Micromedex; 2003;2068-70.

i. Monarch Pharmaceuticals. Nucofed (codeine phosphate, pseudoephedrine hydrochloride, and guaifenesin) expectorant syrup. Bristol, TN; 1998 Sep.

More Codeine Phosphate resources

• Codeine Phosphate Side Effects (in more detail)
• Codeine Phosphate Dosage
• Codeine Phosphate Use in Pregnancy & Breastfeeding
• Drug Images
• Codeine Phosphate Drug Interactions
• Codeine Phosphate Support Group
• 19 Reviews for Codeine Phosphate - Add your own review/rating

• Codeine Professional Patient Advice (Wolters Kluwer)


• codeine Concise Consumer Information (Cerner Multum)


• codeine Advanced Consumer (Micromedex) - Includes Dosage Information

Compare Codeine Phosphate with other medications

• Cough
• Diarrhea
• Pain

Voltarol SR and Retard Tablets

1. Name Of The Medicinal Product

Voltarol 75mg SR and Retard tablets 100mg

2. Qualitative And Quantitative Composition

The active substance is sodium-[o-[(2,6-dichlorophenyl)-amino]-phenyl]-acetate (diclofenac sodium).

Each slow/sustained release tablet contains 75mg or 100mg diclofenac sodium Ph.Eur.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Slow/sustained release, film-coated tablet.

4. Clinical Particulars

4.1 Therapeutic Indications

Adults and Elderly:

Relief of all grades of pain and inflammation in a wide range of conditions, including:

(i) arthritic conditions: rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute gout,

(ii) acute musculo-skeletal disorders such as periarthritis (for example frozen shoulder), tendinitis, tenosynovitis, bursitis,

(iii) other painful conditions resulting from trauma, including fracture, low back pain, sprains, strains, dislocations, orthopaedic, dental and other minor surgery.

Children: Voltarol 75mg SR tablets and Retard tablets 100mg are not suitable for children.

4.2 Posology And Method Of Administration

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4 Special warnings and precautions for use).

For oral administration

Adults:

Voltarol 75mg SR: One tablet once or twice daily, taken whole with liquid, preferably at meal times.

Voltarol Retard tablets 100mg: One tablet daily, taken whole with liquid, preferably at meal times.

The recommended maximum daily dose of Voltarol is 150mg.

Children: Voltarol 75mg SR tablets and Voltarol Retard 100mg are not suitable for children.

Elderly: Although the pharmacokinetics of Voltarol are not impaired to any clinically relevant extent in elderly patients, nonsteroidal anti-inflammatory drugs should be used with particular caution in such patients who generally are more prone to adverse reactions. In particular it is recommended that the lowest effective dosage be used in frail elderly patients or those with a low body weight (see also Precautions) and the patient should be monitored for GI bleeding during NSAID therapy.

4.3 Contraindications

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

• Active, gastric or intestinal ulcer, bleeding or perforation.

• History of gastrointestinal bleeding or perforation, relating to previous NSAID therapy

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

• Last trimester of pregnancy (see section 4.6 Pregnancy and lactation).

• Severe hepatic, renal or cardiac failure (see section 4.4 Special warnings and precautions for use).

• Like other non-steroidal anti-inflammatory drugs (NSAIDs), diclofenac is also contraindicated in patients in whom attacks of asthma, angioedema, urticaria or acute rhinitis are precipitated by ibuprofen, acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs.

4.4 Special Warnings And Precautions For Use

General

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2 Posology and method of administration and GI and cardiovascular risks below).

The concomitant use of Voltarol with systemic NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided due to the absence of any evidence demonstrating synergistic benefits and the potential for additive undesirable effects (see section 4.5 Interactions with other medicaments and other forms of interaction).

Caution is indicated in the elderly on basic medical grounds. In particular, it is recommended that the lowest effective dose be used in frail elderly patients or those with a low body weight (see section 4.2 Posology and Method of administration)

As with other nonsteroidal anti-inflammatory drugs including diclofenac , allergic reactions, including anaphylactic/anaphylactoid reactions, can also occur without earlier exposure to the drug (see section 4.8 Undesirable effects).

Like other NSAIDs, diclofenac may mask the signs and symptoms of the infection due to its pharmacodynamic properties.

Voltarol 75mg SR tablets and Voltarol Retard tablets 100mg contain sucrose and therefore are not recommended for patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency.

Gastrointestinal effects:

Gastrointestinal bleeding (haematemesis, melaena) ulceration or perforation which can be fatal has been reported with all NSAIDs including diclofenac and may occur at any time during treatment, with or without warning symptoms or a previous history of serious GI events. They generally have more serious consequences in the elderly. If gastrointestinal bleeding or ulceration occurs in patients receiving diclofenac, the drug should be withdrawn.

As with all NSAIDs, including diclofenac close medical surveillance is imperative and particular caution should be excised when prescribing diclofenac in patients with symptoms indicative of gastrointestinal disorders, or with a history suggestive of gastric or intestinal ulceration, bleeding or perforation (see section 4.8 Undesirable effects). The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses including diclofenac, and in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation.

The elderly have increased frequency of adverse reactions to NSAIDs especially gastro intestinal bleeding and perforation which may be fatal (see section 4.2 Posology and method of administration).

To reduce the risk of GI toxicity in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation, and in the elderly, the treatment should be initiated and maintained at the lowest effective dose.

Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant use of medicinal products containing low dose acetylsalicylic acid (ASA/aspirin or medicinal products likely to increase gastrointestinal risk. (See section 4.5 Interactions with other medicaments and other forms of interaction).

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

Caution is recommended in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors (SSRIs) or anti-platelet agents such as acetylsalicylic acid (see section 4.5 Interaction with other medicaments and other forms of interaction).

Close medical surveillance and caution should be exercised in patients with ulcerative colitis, or with Crohn's disease as these conditions may be exacerbated (see section 4.8 Undesirable effects).

Hepatic effects:

Close medical surveillance is required when prescribing Voltarol to patients with impairment of hepatic function as their condition may be exacerbated.

As with other NSAIDs, including diclofenac, values of one or more liver enzymes may increase. During prolonged treatment with Diclofenac, regular monitoring of hepatic function is indicated as a precautionary measure.

If abnormal liver function tests persist or worsen, clinical signs or symptoms consistent with liver disease develop or if other manifestations occur (eosinophilia, rash), Voltarol should be discontinued.

Hepatitis may occur with diclofenac without prodromal symptoms.

Caution is called for when using diclofenac in patients with hepatic porphyria, since it may trigger an attack.

Renal effects:

As fluid retention and oedema have been reported in association with NSAIDs therapy, including diclofenac, particular caution is called for in patients with impaired cardiac or renal function, history of hypertension, the elderly, patients receiving concomitant treatment with diuretics or medicinal products that can significantly impact renal function, and those patients with substantial extracellular volume depletion from any cause, e.g. before or after major surgery (see section 4.3 Contraindications). Monitoring of renal function is recommended as a precautionary measure when using diclofenac in such cases. Discontinuation therapy is usually followed by recovery to the pre-treatment state.

Skin effects:

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 NSAIDs, including Voltarol (see section 4.8 Undesirable effects). Patients appear to be at the highest risk of 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. Voltarol should be discontinued at the first appearance of skin rash, mucosal lesions or any other signs of hypersensitivity.

SLE and mixed connective tissue disease:

In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis (see section 4.8 Undesirable effects).

Cardiovascular and cerebrovascular effects:

Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy including diclofenac.

Clinical trial and epidemiological data suggest that use of diclofenac, particularly at high dose (150mg daily) and in long term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke).

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with diclofenac after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, and smoking).

Haematological effects:

During prolonged treatment with diclofenac, as with other NSAIDs, monitoring of the blood count is recommended.

Voltarol may reversibly inhibit platelet aggregation (see anticoagulants in section 4.5 Interaction with other medicaments and other forms of interactions). Patients with defects of haemostasis, bleeding diathesis or haematological abnormalities should be carefully monitored.

Pre-existing asthma:

In patients with asthma, seasonal allergic rhinitis, swelling of the nasal mucosa (i.e. nasal polyps), chronic obstructive pulmonary diseases or chronic infections of the respiratory tract (especially if linked to allergic rhinitis-like symptoms), reactions on NSAIDs like asthma exacerbations (so called intolerance to analgesics / analgesics asthma), Quincke's oedema or urticaria are more frequent than in other patients. Therefore, special precaution is recommended in such patients (readiness for emergency). This is applicable as well for patients who are allergic to other substances, e.g. with skin reactions, pruritus or urticaria.

Like other drugs that inhibit prostaglandin synthetase activity, diclofenac sodium and other NSAIDs can precipitate bronchospasm if administered to patients suffering from, or with a previous history of bronchial asthma.

Female fertility:

The use of Voltarol may impair female fertility and is not recommended in women attempting to conceive. In women who may have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of Voltarol should be considered (see section 4.6 Pregnancy and Lactation).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The following interactions include those observed with diclofenac gastro-resistant tablets and/or other pharmaceutical forms of diclofenac.

Lithium: If used concomitantly, Voltarol may increase plasma concentrations of lithium. Monitoring of the serum lithium level is recommended.

Digoxin: If used concomitantly, Voltarol may raise plasma concentrations of digoxin. Monitoring of the serum digoxin level is recommended.

Diuretics and antihypertensive agents: Like other NSAIDs, concomitant use of Voltarol with diuretics and antihypertensive agents (e.g. beta-blockers, angiotensin converting enzyme (ACE) inhibitors may cause a decrease in their antihypertensive effect via inhibition of vasodilatory prostaglandin synthesis.

Therefore, the combination should be administered with caution and patients, especially the elderly, should have their blood pressure periodically monitored. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy periodically thereafter, particularly for diuretics and ACE inhibitors due to the increased risk of nephrotoxicity. Concomitant treatment with potassium-sparing diuretics may be associated with increased serum potassium levels, which should therefore be monitored frequently (see section 4.4 Special warnings and precautions for use).

Anticoagulants and anti-platelet agents: Caution is recommended since concomitant administration could increase the risk of bleeding (see section 4.4 Special warnings and precautions for use). Although clinical investigations do not appear to indicate that Voltarol has an influence on the effect of anticoagulants, there are isolated reports of an increased risk of haemorrhage in patients receiving diclofenac and anticoagulant concomitantly (see section 4.4 Special warnings and precautions for use). Therefore, to be certain that no change in anticoagulant dosage is required, close monitoring of such patients is required. As with other nonsteroidal anti-inflammatory agents, diclofenac in a high dose can reversibly inhibit platelet aggregation.

Other NSAIDs including cyclooxygenase-2 selective inhibitors and corticosteroids: Co-administration of diclofenac with other systemic NSAIDs or corticosteroids may increase the risk of gastrointestinal bleeding or ulceration. Avoid concomitant use of two or more NSAIDs (see section 4.4 Special warnings and precautions for use).

Antidiabetic: Clinical studies have shown that Voltarol can be given together with oral antidiabetic agents without influencing their clinical effect. However there have been isolated reports of hypoglycaemic and hyperglycaemic effects necessitating changes in the dosage of the antidiabetic agents during treatment with diclofenac. For this reason, monitoring of the blood glucose level is recommended as a precautionary measure during concomitant therapy.

Methotrexate: Diclofenac can inhibit the tubular renal clearance of methotrexate hereby increasing methotrexate levels. Caution is recommended when NSAIDs, including diclofenac, are administered less than 24 hours before treatment with methotrexate, since blood concentrations of methotrexate may rise and the toxicity of this substance be increase. Cases of serious toxicity have been reported when methotrexate and NSAIDs including diclofenac are given within 24 hours of each other. This interaction is mediated through accumulation of methotrexate resulting from impairment of renal excretion in the presence of the NSAID.

Ciclosporin: Diclofenac, like other NSAIDs, may increase the nephrotoxicity of ciclosporin due to the effect on renal prostaglandins. Therefore, it should be given at doses lower than those that would be used in patients not receiving ciclosporin.

Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus. This might be mediated through renal antiprostagladin effects of both NSAID and calcineurin inhibitor.

Quinolone antibacterials: Convulsions may occur due to an interaction between quinolones and NSAIDs. This may occur in patients with or without a previous history of epilepsy or convulsions. Therefore, caution should be exercised when considering the use of a quinolone in patients who are already receiving an NSAID.

Phenytoin: When using phenytoin concomitantly with diclofenac, monitoring of phenytoin plasma concentrations is recommended due to an expected increase in exposure to phenytoin.

Colestipol and cholestyramine: These agents can induce a delay or decrease in absorption of diclofenac. Therefore, it is recommended to administer diclofenac at least one hour before or 4 to 6 hours after administration of colestipol/cholestyramine.

Cardiac glycosides: Concomitant use of cardiac glycosides and NSAIDs in patients may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

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

Potent CYP2C9 inhibitors: Caution is recommended when co-prescribing diclofenac with potent CYP2C9 inhibitors (such as sulfinpyrazone and voriconazole), which could result in a significant increase in peak plasma concentrations and exposure to diclofenac due to inhibition of diclofenac metabolism.

4.6 Pregnancy And Lactation

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and or cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1% up to approximately 1.5%.

The risk in believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has shown to result in increased pre-and post-implantation loss and embryo-foetal lethality.

In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during organogenetic period. If Voltarol is used by a woman attempting to conceive, or during the 1st trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:

- cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension)

- renal dysfunction, which may progress to renal failure with oligo-hydroamniosis

The mother and the neonate, at the end of the pregnancy, to:

- possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses

- inhibition of uterine contractions resulting in delayed or prolonged labour

Consequently, Voltarol is contraindicated during the third trimester of pregnancy.

Lactation

Like other NSAIDs, diclofenac passes into breast milk in small amounts. Therefore Diclofenac should not be administered during breast feeding in order to avoid undesirable effects in the infant.

Female fertility

As with other NSAIDs, the use of diclofenac may impair female fertility and is not recommended in women attempting to conceive. In women who may have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of diclofenac should be considered. See also section 4.4 Special warnings and precautions for use, regarding female fertility.

4.7 Effects On Ability To Drive And Use Machines

Patients who experience visual disturbances, dizziness, vertigo, somnolence, central nervous system disturbances, drowsiness or fatigue while taking NSAIDs should refrain from driving or operating machinery.

4.8 Undesirable Effects

Adverse reactions are ranked under the heading of frequency, the most frequent first, using the following convention: very common: (>1/10); common (

The following undesirable effects include those reported with other short-term or long-term use.

Table 1

Blood and lymphatic system disorders
Very rare	Thrombocytopenia, leucopoenia, anaemia (including haemolytic and aplastic anaemia), agranulocytosis.
Immune system disorders
Rare Very rare	Hypersensitivity, anaphylactic and anaphylactoid reactions (including hypotension and shock). Angioneurotic oedema (including face oedema).
Psychiatric disorders
Very rare	Disorientation, depression, insomnia, nightmare, irritability, psychotic disorder.
Nervous system disorders
Common Rare Very rare Unknown	Headache, dizziness. Somnolence, tiredness. Paraesthesia, memory impairment, convulsion, anxiety, tremor, aseptic meningitis, taste disturbances, cerebrovascular accident. Confusion, hallucinations, disturbances of sensation, malaise.
Eye disorders
Very rare Unknown	Visual disturbance, vision blurred, diplopia. Optic neuritis.
Ear and labyrinth disorders
Common Very rare	Vertigo. Tinnitus, hearing impaired.
Cardiac disorders
Very rare	Palpitations, chest pain, cardiac failure, myocardial infarction.
Vascular disorders
Very rare	Hypertension, hypotension, vasculitis.
Respiratory, thoracic and mediastinal disorders
Rare Very rare	Asthma (including dyspnoea). Pneumonitis.
Gastrointestinal disorders
Common Rare Very rare	Nausea, vomiting, diarrhoea, dyspepsia, abdominal pain, flatulence, anorexia. Gastritis, gastrointestinal haemorrhage, haematemesis, diarrhoea haemorrhagic, melaena, gastrointestinal ulcer with or without bleeding or perforation (sometimes fatal particularly in the elderly). Colitis (including haemorrhagic colitis and exacerbation of ulcerative colitis or Crohn's disease), constipation, stomatitis (including ulcerative stomatitis), glossitis, oesophageal disorder, diaphragm-like intestinal strictures, pancreatitis.
Hepatobiliary disorders
Common Rare Very rare	Transaminases increased. Hepatitis, jaundice, liver disorder. Fulminant hepatitis, hepatic necrosis, hepatic failure.
Skin and subcutaneous tissue disorders
Common Rare Very rare	Rash. Urticaria. Bullous eruptions, eczema, erythema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), dermatitis exfoliative, loss of hair, photosensitivity reaction, purpura, allergic purpura, pruritus.
Renal and urinary disorders
Very rare	Acute renal failure, haematuria, proteinuria, nephrotic syndrome, interstitial nephritis, renal papillary necrosis.
General disorders and administration site conditions
Rare	Oedema
Reproductive system and breast disorders
Very rare	Impotence.

Clinical trial and epidemiological data suggest that use of diclofenac, particularly at high doses (150mg 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 Special warnings and special precautions for use).

4.9 Overdose

Symptoms

There is no typical clinical picture resulting from diclofenac over dosage. Over dosage can cause symptoms such as headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, diarrhoea, dizziness, disorientation, excitation, coma, drowsiness, tinnitus, fainting or convulsions. In the case of significant poisoning acute renal failure and liver damage are possible.

Therapeutic measures

Management of acute poisoning with NSAIDs, including diclofenac, essentially consists of supportive measures and symptomatic treatment. Supportive measures and symptomatic treatment should be given for complications such as hypotension, renal failure, convulsions, gastrointestinal disorder, and respiratory depression.

Special measures such as forced diuresis, dialysis or haemo-perfusion are probably of no help in eliminating NSAIDs, including diclofenac, due to high protein binding and extensive metabolism.

Activated charcoal may be considered after ingestion of a potentially toxic overdose, and gastric decontamination (e.g. vomiting, gastric lavage) after ingestion of a potentially life threatening overdose.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group

Nonsteroidal anti-inflammatory drugs (NSAIDs).

Mechanism of action

Voltarol is a nonsteroidal agent with marked analgesic/anti- inflammatory properties. It is an inhibitor of prostaglandin synthetase, (cyclo-oxygenase).

Diclofenac sodium in vitro does not suppress proteoglycan biosynthesis in cartilage at concentrations equivalent to the concentrations reached in human beings.

5.2 Pharmacokinetic Properties

Absorption

The same amount of active substance is released and absorbed from SR and Retard tablets as from enteric-coated tablets. Mean peak plasma concentrations of diclofenac are reached at 4 hours, 0.508 ± 0.185µg/ml (0.5µg/mL

Bioavailability:

The systemic availability of diclofenac from the SR formulations is on average 82% of that achieved with the same dose of enteric-coated tablets (possibly due to release rate dependent first-pass metabolism). As a result of the slower release of active substance, peak plasma concentrations are lower than for the equivalent enteric-coated tablets.

Pharmacokinetic behaviour does not change on repeated administration. Accumulation does not occur, provided the recommended dosage intervals are observed. Trough levels of diclofenac in the plasma after Retard 100mg daily or 75mg SR twice daily are around 22ng/ml or 25ng/ml (70nmol/l or 80nmol/l), respectively.

Distribution

The active substance is 99.7% protein bound, mainly to albumin (99.4%).

Diclofenac enters the synovial fluid, where maximum concentrations are measured 2-4 hours after the peak plasma values have been attained. The apparent half-life for elimination from the synovial fluid is 3-6 hours. Two hours after reaching the peak plasma values, concentrations of the active substance are already higher in the synovial fluid than they are in the plasma and remain higher for up to 12 hours.

Metabolism

Biotransformation of diclofenac takes place partly by glucuronidation of the intact molecule, but mainly by single and multiple hydroxylation and methoxylation, resulting in several phenolic metabolites, most of which are converted to glucuronide conjugates. Two phenolic metabolites are biologically active, but to a much lesser extent than diclofenac.

Elimination

The total systemic clearance of diclofenac in plasma is 263 ± 56 mL/min (mean value ± SD). The terminal half-life in plasma is 1-2 hours. Four of the metabolites, including the two active ones, also have short plasma half-lives of 1-3 hours.

About 60% of the administered dose is excreted in the urine in the form of the glucuronide conjugate of the intact molecule and as metabolites, most of which are also converted to glucuronide conjugates. Less than 1% is excreted as unchanged substance. The rest of the dose is eliminated as metabolites through the bile in the faeces.

Characteristics in patients

Elderly: No relevant age-dependent differences in the drug's absorption, metabolism, or excretion have been observed, other than the finding that in five elderly patients, a 15 minute iv infusion resulted in 50% higher plasma concentrations than expected with young healthy subjects.

Patients with renal impairment: In patients suffering from renal impairment, no accumulation of the unchanged active substance can be inferred from the single-dose kinetics when applying the usual dosage schedule. At a creatinine clearance of less than 10 mL/min, the calculated steady-state plasma levels of the hydroxy metabolites are about 4 times higher than in normal subjects. However, the metabolites are ultimately cleared through the bile.

Patients with hepatic disease: In patients with chronic hepatitis or non-decompensated cirrhosis, the kinetics and metabolism of diclofenac are the same as in patients without liver disease.

5.3 Preclinical Safety Data

None stated.

6. Pharmaceutical Particulars

6.1 List Of Excipients

The 75mg SR and Retard 100mg tablets also contain colloidal anhydrous silica, cetyl alcohol, sucrose (powder), povidone, magnesium stearate, hydroxypropyl methylcellulose, polysorbate 80, purified talc, titanium dioxide (E 171), red iron oxide (E.172) and purified water.

6.2 Incompatibilities

None known.

6.3 Shelf Life

75mg SR tablets:	Three years
Retard 100mg tablets:	Five years.

6.4 Special Precautions For Storage

75mg SR tablets: Protect from moisture and heat (store below 30°C).

Retard 100mg tablets: There are no special precautions for storage.

Medicines should be kept out of the reach of children.

6.5 Nature And Contents Of Container

75mg SR tablets are pale pink, triangular film-coated tablets embossed GEIGY on one face, V 75 SR on the other, and come in PVC/PVdC blister packs of 28, 56 and 70.

The Retard 100mg tablets are pale red, round, slightly convex, film coated tablets, impressed GEIGY on one side and VOLTAROL R on the other, and come in PVC/PVdC blister packs of 28 and 70.

6.6 Special Precautions For Disposal And Other Handling

The tablets should be swallowed whole with liquid, preferably with meals.

7. Marketing Authorisation Holder

Novartis Pharmaceuticals UK Ltd.

Trading as Geigy Pharmaceuticals,

Frimley Business Park

Frimley

Camberley

Surrey

GU16 7SR.

8. Marketing Authorisation Number(S)

75mg SR tablets: PL 00101/0471

Retard 100mg tablets: PL 00101/0470

9. Date Of First Authorisation/Renewal Of The Authorisation

11 July 1997 / 29 July 2007

10. Date Of Revision Of The Text

1 July 2011

LEGAL CATEGORY

POM