Mesalazine

Wha is Asacol Foam Enema (Mesalazine)?

Asacol Foam Enema contains the active substance mesalazine (also known as 5-aminosalicylic acid) which is an anti-inflammatory drug used in the treatment of Ulcerative colitis.

Ulcerative colitis is a disease of the large bowel (colon) and back passage (rectum) in which the lining of the bowel becomes inflamed (red and swollen). Symptoms can include rectal bleeding, frequent diarrhoea and abdominal pain. The enema acts locally in the lower part of the colon to reduce the inflammation.

Drug Approvals

(British Approved Name, rINN)

Note. Distinguish from 4-aminosalicylic acid (Aminosalicylic Acid) which is used in the treatment of tuberculosis.

Pharmacopoeias. In Europe and US.

European Pharmacopoeia, 6th ed. (Mesalazine). An almost white or light grey or light pink powder or crystals. Very slightly soluble in water practically insoluble in alcohol. It dissolves in dilute solutions of alkali hydroxides and in dilute hydrochloric acid. Store in airtight containers. Protect from light.

The United States Pharmacopeia 31, 2008 (Mesalamine). Light tan to pink needle-shaped crystals, odourless or with a slight characteristic odour. The colour may darken on exposure to air. Slightly soluble in water very slightly soluble in dehydrated alcohol, in acetone, and in methyl alcohol practically insoluble in butyl alcohol, in chloroform, in dichloromethane, in ether, in ethyl acetate, in n-hexane, and in propyl alcohol soluble in dilute hydrochloric acid and in dilute alkali hydroxides. A 2.5% suspension in water has a pH of 3.5 to 4.5. Store in airtight containers. Protect from light.

What Asacol Foam Enema contains

The active substance is mesalazine (5-aminosalicylic acid). Each metered dose contains 1 g of mesalazine. The other ingredients are sorbitan mono-oblate, polysorbate 20, emulsifying wax, colloidal anhydrous silica, sodium metabisulphite (E223), disodium edetate, methylhydroxybenzoate (E218), propylhydroxybenzoate (E216), sodium phosphate dodecahydrate or heptahydrate, sodium acid phosphate, glycerol (E422), macrogol 300, purified water, propane, iso-butane, n-butane (see also end of Section 2 on ‘Important information about some of the ingredients of Asacol Foam Enema’).

What Asacol Foam Enema looks like and contents of the pack

Asacol Foam Enema is a white foam. It is supplied in an aerosol can containing 14 metered doses with 14 disposable applicators and 14 disposable plastic bags.

HOW TO USE ASACOL FOAM ENEMA

Please read these instructions carefully, even if you have used Asacol Foam Enema before, as these instructions have recently changed.

Asacol Foam Enema should not be swallowed.

Please use the product with care as it may cause staining to clothing and household articles.

DOSE FOR ADULTS AND THE ELDERLY: Please read the pharmacist’s label carefully as your doctor will have instructed you whether to use one or two doses each day.

This medicine should be delivered to the back passage (rectum) as described below:

1. Before using the enema for the first time, thoroughly mix the contents by shaking the can vigorously for 15 seconds. Rest for about 30 seconds, and then shake the can vigorously for another 15 seconds.
2. Also, before using the enema for the first time, remove the safety tag from under the dome.
3. Push the plastic applicator firmly onto the spout of the can and align the notch beneath the dome with the spout.
4. Hold the can in the palm of one hand with the dome pointing downwards.This product must only be dispensed when the can is upside down, with the dome nearest the ground (if the can is not upside down, the foam will not come out properly).
5. You may find the easiest way to use the enema is to raise one foot onto a firm surface such as a stool or chair, and insert the applicator into the rectum as far as is comfortable. You can apply a lubricating jelly to the tip of the applicator for comfort if you wish.
6. To administer one dose, fully push the dome down once and release it. The foam will not come out of the can until you release the dome. To administer a second dose, press  and release the dome again. Wait for 15 seconds before withdrawing the applicator. Note, the can will only work properly when held with the dome pointing downwards.
7. Remove the applicator and dispose of it in one of the plastic bags provided. Do not  flush it down the toilet. Wash your hands.
8. Before using the enema again, mix the contents of the can by shaking vigorously for 5 seconds only, before continuing to use the enema as instructed above.

DO NOT use Asacol Foam Enema more than twice in 12 hours.

Do not use this medicine in children under 2 years of age.

Keep using the foam until your prescribed course is finished. Your symptoms may come back if you stop treatment too early. Your doctor will normally recommend that you take treatment for between 4 and 6 weeks.

If you use more Asacol Foam Enema than you should

Do not exceed the recommended dose. You should only use as much enema as your doctor has instructed on the pharmacist’s label. If you use too much, tell your doctor immediately or go to your nearest Accident & Emergency Department (take the foam enema pack with you if possible).

If you forget to use Asacol Foam Enema

If you forget to use your enema at the required time, take the dose as soon as you remember and continue using the foam as before. Do not use Asacol Foam Enema more than twice in 12 hours.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

Adverse Effects and Precautions

Mesalazine may cause headache and gastrointestinal disturbances, such as nausea, diarrhoea, and abdominal pain. Hyper sensitivity reactions may occasionally occur. Some patients may experience exacerbation of symptoms of colitis. There are some reports of myocarditis, pericarditis, pancreatitis, interstitial nephritis, nephrotic syndrome, allergic lung reaction, increased liver enzyme values, hepatitis, lupus-like syndrome, skin reactions, alopecia, peripheral neuropathy, myalgia, and arthralgia. There have been rare reports of blood disorders including aplastic anaemia, agranulocytosis, leucopenia, neutropenia, thrombocytopenia, and methaemoglobinaemia.

Mesalazine should not be given to patients with severe renal or hepatic impairment, or salicylate hypersensi-tivity. It should be used with caution in the elderly, and in mild to moderate renal or hepatic impairment, active peptic ulceration, or sulfasalazine allergy.

If a blood dyscrasia is suspected treatment should be stopped immediately and a blood count performed. Patients or their carers should be told how to recognise signs of blood toxicity and should be advised to seek immediate medical attention if symptoms such as fever, sore throat, mouth ulcers, bruising, or bleeding develop. It is recommended that renal function is monitored before and during therapy (see Effects on the Kidneys).

Many of the adverse effects associated with sulfasalazine (sul-fapyridine linked to mesalazine) therapy have been attributed to the sulfapyridine moiety and most patients unable to tolerate sulfasalazine because of hypersensitivity or adverse reactions can be transferred to mesalazine without adverse effects occurring. However, a small number of patients also have adverse effects while taking mesalazine and these are often very similar to those seen with sulfasalazine. They may include nausea, abdominal discomfort or pain, exacerbation of diarrhoea, headache, fever, and rashes.

Mesalazine is not generally associated with sulfasalazine‘s adverse effects on sperm (although there has been a case of reversible male infertility attributed to mesalazine — see under Sulfasalazine). An analysis of adverse reactions reported to the UK CSM between 1991 and 1998 found no evidence of a significant difference in the frequency of serious adverse effects for mesalazine and sulfasalazine in the treatment of inflammatory bowel disease. Reports of pancreatitis and interstitial nephritis (see Effects on the Kidneys), were more common with mesalazine. However, it has been pointed out that 80% of patients intolerant to sulfasalazine will tolerate mesalazine without problems.

Mesalazine therapy should be started cautiously in patients with a history of sulfasalazine hypersensitivity and it should be withdrawn if signs of sensitivity develop or if there is diarrhoea or rectal bleeding. It has been suggested that patients with a history of sulfasalazine hypersensitivity should be given test doses of mesalazine before starting a full course.

Breast feeding

The concentrations of mesalazine in maternal plasma and breast milk in a woman taking 500 mg three times daily, were 410 and 110 nanograms/mL respectively Although it was considered that the amount of mesalazine distributed into breast milk was small and that it was safe during breast feeding, maternal use of mesalazine 500 mg suppositories twice daily has been associated with watery diarrhoea in a breast-fed infant and for this reason the American Academy of Pediatrics considers that mesalazine should be given with caution to breastfeeding mothers.

Effects on the blood

Although uncommon, mesalazine-asso-ciated adverse effects on the blood have been reported, including thrombocytopenia, neutropenia, severe aplastic anaemia, and pancytopenia. In July 1995 the UK CSM stated that it had been notified of 49 haemato logical reactions suspected of being associated with mesalazine, including 5 reports of aplastic anaemia, 1 of agranulocytosis, 11 of leucopenia, and 17 of thrombocytopenia. There had been 3 fatalities. They recommended a blood count and immediate withdrawal of the drug if a dyscrasia was suspected. Intensive immunosuppressive treatment has been used in the management of mesalazine-associated aplastic anaemia.

Effects on the cardiovascular system

Myocarditis associated with chest pain and ECG abnormalities has been reported in 2 patients taking mesalazine 1 patient died in cardiogenic shock. It has been suggested that mesalazine or sulfasalazine should be replaced by glucocorticoids if cardiac symptoms arise during treatment. Pericarditis with fever, rash, dyspnoea, pleural and pericardial effusions, and arthritis, has been described, and is considered to constitute a drug-induced lupus-like syndrome.

Constrictive pericarditis with an absence of other lupus-like symptoms developed in a patient taking mesalazine for inflammatory bowel disease. Based on reported cases of mesalazine-induced pericarditis, symptoms of this potentially life-threatening adverse effect have tended to arise 2 to 4 weeks after starting mesalazine, although symptom onset may be delayed by concurrent corticosteroid treatment. Mesalazine cardiotoxicity presenting as an acute coronary syndrome, without myocarditis or pericarditis, has also been reported.

Effects on fertility

For a report of reversible male infertility occurring with mesalazine, see under Sulfasalazine.

Effects on the hair

For a report of accelerated loss of scalp hair in 2 patients receiving mesalazine enemas, see under Sulfasalazine.

Effects on the kidneys

Between February 1988 and December 1990 the UK CSM received 9 reports of serious nephrotoxic reactions associated with the use of Asacol, a modified-release mesalazine preparation. The reactions included 4 cases of interstitial nephritis, 3 of severe renal failure, and 2 cases of nephrotic syndrome. A subsequent case report indicated that by September 1998 the number of such reports for mesalazine totalled 104, including 35 cases of interstitial nephritis. The authors considered that monitoring of renal function was required in patients receiving mesalazine. A protocol for such monitoring was subsequently suggested, and a similar protocol has been adopted in UK licensing information for mesalazine, with serum creatinine being estimated:

• before treatment
• every 3 months for the first year
• every 6 months for the next 4 years
• annually thereafter

The nephrotic syndrome and interstitial nephritis have also been reported with sulfasalazine, and interstitial nephritis with olsalazine. A large UK epidemiologic study found no difference in risk of renal disease between mesalazine and sulfasalazine. The study also concluded that the risk of renal disease associated with mesalazine and related compounds is low and may be partly attributable to the underlying disease. Overall nephrotoxicity has been estimated to occur in about 1 in 4000 UK patients per year taking aminosalicylate-based therapy.

Effects on the liver

A case of chronic hepatitis and liver fibro-sis has been reported after prolonged use of mesalazine. The authors considered that mesalazine should be stopped when liver dysfunction occurred.

Effects on the nervous system

Peripheral neuropathy, mainly affecting the legs, has occurred during mesalazine treatment. The symptoms resolved on stopping the drug. Mononeuri-tis multiplex was part of the presentation of an eosinophilic reaction attributed to mesalazine in an asthmatic patient Churg-Strauss syndrome developed after withdrawal of mesalazine, but the patient subsequently recovered without sequelae.

Effects on the pancreas

Pancreatitis has been reported as an adverse effect of mesalazine. In 2 patients, with abdominal pain and raised amylase activity, this reaction to mesalazine was confirmed by rechallenge and symptoms resolved on mesalazine withdrawal. By February 1994 the UK CSM had received 15 reports of pancreatitis associated with mesalazine therapy. However, a case control study suggested that inflammatory bowel disease, rather than the use of mesalazine, may be associated with an increased risk of acute pancreatitis (see under Sulfasalazine)

Effects on the respiratory system

Pulmonary complications have been rarely reported with mesalazine. There have though been cases of interstitial lung disease, with features of hy-persensitivity pneumonia. Symptoms have included dyspnoea, cough, fever, and pleuritic chest pain, with the onset of symptoms varying from a few days to several years after starting mesalazine therapy. Although pulmonary complications can also be associated with inflammatory bowel disease itself, there has been a report of eosinophilic pleural effusion in a patient who was given mesalazine in the absence of an established diagnosis of inflammatory bowel disease.

Pulmonary complications have also been reported with sulfasalazine, and pulmonary symptoms may also manifest as part of a broader lupus-like syndrome (see Effects on the Cardiovascular System).

Lupus

A lupus-like syndrome has been reported in 4 patients receiving mesalazine who developed antinuclear antibody (ANA)-positivity with at least one clinical feature of lupus, such as arthropathy, skin rashes, or acute inflammation unrelated to the underlying condition. In all 4 cases symptoms resolved upon stopping mesalazine. For similar reports, see Effects on the Cardiovascular System, above.

Pregnancy

Renal insufficiency in a neonate whose mother received mesalazine 2 to 4 g daily by mouth during the second trimester of pregnancy was suggested to be due to the drug, although the proposed mechanism, inhibition of prostaglandin synthesis in the neonatal kidney, has been questioned. A subsequent case-control study found that use of oral mesalazine in 165 pregnant women with inflammatory bowel disease was not associated with a greater incidence of malformations. However, women treated with mesalazine were more likely to have pre-term deliveries and newborns with decreased birth-weights, although the disease may have been a factor in this finding.

A commentator on this study, considered that active inflammatory bowel disease was a greater risk to pregnancy than drug treatment. In a further cohort of 123 pregnancies, oral mesalazine at doses of 3 g daily or less did not increase the risk of fetal malformations or affect pregnancy outcome. The researchers concluded that further information was required on doses higher than 3 g daily. In another study, all of 19 pregnancies in women receiving rectal mesalazine were full-term with no fetal abnormalities.

A Danish cohort study found an increased risk of still-birth and preterm birth in women who had been prescribed mesalazine or olsalazine during pregnancy, but no significant increased risk of malformations. The risk of still-birth was greatest in women with ulcerative colitis who were prescribed corticosteroids and either mesalazine or olsalazine, and the risk of preterm birth was greatest in women with ulcerative colitis who were prescribed either mesalazine or olsalazine alone. The authors acknowledged that it was difficult to distinguish between the increase in risk due to disease state, and the increase in risk due to medication. For a discussion of sulfasalazine in pregnancy.

Interactions

Preparations formulated to release mesalazine in the colon should notbe given with drugs, such as lactulose, that lower colonic pH as they may prevent the release of mesalazine (but see Gastrointestinal Drugs).

Anticoagulants

For reference to a case of mesalazine reducing the effect of warfarin, see Gastrointestinal Drugs.

Antineoplastics

For mention of 5-aminosalicylates such as mesalazine inhibiting the metabolism of thiopurine antineoplastics, and increasing their toxicity, see Mercaptopurine.

Gastrointestinal drugs

Although it has been suggested that lactulose could delay the intestinal release of mesalazine from modified-release preparations, a study found no evidence that lactulose influenced the release or disposition of mesalazine. Similarly, omeprazole did not appear to increase the likelihood of premature mesalazine release.

Pharmacokinetics

If given orally as conventional formulations, mesalazine would be extensively absorbed from the upper gastrointestinal tract, with little of the drug reaching the colon. Oral preparations are therefore generally formulated to release the drug in the terminal ileum and colon, where it is thought to exert a mainly local action. The specific release characteristics differ somewhat between formulations and this, together with interindi-vidual variation, makes comparison of pharmacokinet-ic data between studies difficult. Even with modified-release preparations some 30 to 50% of an oral dose is thoughtto be lost to absorption in healthy subjects. Absorption from rectal dosage forms has also varied widely, with factors such as the dose, the formulation, and the pH also playing a role, but mean absorption of around 10 to 30% of a rectal dose has been reported.

The absorbed portion of mesalazine is almost completely acetylated in the gut wall and in the liver to acetyl-5-aminosalicylic acid. The rate of acetylation, and hence the concentration of parent drug and metabolite in the systemic circulation, may be dose dependent and subject to saturation. The acetylated metabolite is excreted mainly in urine by tubular secretion, with traces of the parent compound. The plasma half-life of mesalazine is reported to be about 40 minutes and it is 40 to 50% bound to plasma proteins the acetylated metabolite has a plasma half-life of 70 minutes and is about 80% bound to plasma proteins.

Only negligible quantities of mesalazine cross the placenta. Amounts distributed into breast milk are very small.

Uses and Administration

Mesalazine is an anti-inflammatory drug structurally related to the salicylates and active in inflammatory bowel disease (p. 1697) it is considered to be the active moiety of sulfasalazine (p.1773). Mesalazine is thought to act locally on the inflamed intestinal tissue, rather than systemically. Although its precise mechanism of action is uncertain, it may be due to inhibition of prostaglandin and le

UKotriene synthesis in the gastrointestinal mucosa.

Mesalazine is given orally or rectally in the treatment of acute attacks of mild to moderate ulcerative colitis, or the maintenance of remission of ulcerative colitis. Some products are also used for the maintenance of remission of Crohn’s ileo-colitis.

There are several differently formulated oral preparations of mesalazine available, and dosage recommendations vary. Recommended doses for some

UK preparations are as follows:

• Asacol 400 mg tablets (Procter and Gamble, UK), Ipocol tablets (Sandoz, UK), Mesren tablets (WAX, UK): acute attack, initially 2.4 g daily in divided doses maintenance of remission, 1.2 to 2.4 g daily in divided doses. The BNFC includes similar doses for children aged 12 to 18 years
• Asacol 800 mg tablets (Procter and Gamble, UK): mild acute exacerbations, 2.4 g daily in divided doses moderate acute exacerbations, 4.8 g daily in divided doses maintenance of remission, up to 2.4 g daily in divided doses
• Mezavant tablets (Shire, UK): acute attack, initially 2.4 to 4.8 g once daily maintenance of remission, 2.4 g once daily
• Pentasa tablets (Ferring, UK): acute attack, initially up to 4 g daily in 2 or 3 divided doses maintenance of remission, adjusted individually from an initial dose of 1.5 g daily in 2 or 3 divided doses. The BNFC includes the same doses for children aged 15 to 18 years. For children aged 5 to 15 years: acute attack, 15 to 20 mg/kg (maximum 1 g) 3 times daily maintenance of remission, 10 mg/kg (maximum 500 mg) 2 or 3 times daily
• Pentasa granules (Ferring, UK): acute attack, initially, up to 4 g daily in 2 to 4 divided doses maintenance of remission, 2 g daily in 2 divided doses. The BNFC includes the same dose for acute attack in children aged 12 to 18 years, and 0.5 to 1 g twice daily for maintenance of remission. For children aged 5 to 12 years: acute attack, 15 to 20 mg/kg (maximum 1 g) 3 times daily maintenance of remission, 10 mg/kg (maximum 500 mg) 2 or 3 times daily
• Salofalk tablets (Folk, UK): acute attack, initially 1.5 g daily in 3 divided doses maintenance of remission, 0.75 to 1.5 g daily in divided doses. The BNFC includes the same dose for acute attack in children aged 12 to 18 years, and 250 to 500 mg given 2 or 3 times daily for maintenance of remission
• Salofalk granules (Folk, UK): acute attack, initially 1.5 to 3 g daily, either once daily, or in 3 divided doses maintenance of remission, 1.5 g daily in 3 divided doses. The BNFC includes similar doses for children aged 12 to 18 years. For children aged 6 to 12 years: acute attack, 10 to 15 mg/kg (maximum 1 g) 3 times daily maintenance of remission, 7.5 to 15 mg/kg (maximum 500 mg) twice daily (or 250 mg given 3 times daily for those weighing less than 40 kg)

Mesalazine may be given rectally, particularly when disease affects the sigmoid colon and rectum. Various formulations are available and the dose is usually given at night, but preparations do vary. Recommended doses for some UK preparations are as follows (the BNFC also suggests that these doses are suitable for children aged 12 to 18 years):

• Asacol suppositories (Procter and Gamble, UK): 0.75 to 1.5 g daily in divided doses
• Asacol foam enema (Procter and Gamble, UK): 1 g daily for disease affecting the rectosigmoid region 2 g daily for disease involving the descending colon
• Pentasa suppositories and suspension enema (Ferring, UK): 1 g daily
• Salofalk suppositories (Folk, UK): 0.5 to 1 g given 2 or 3 times daily
• Salofalk foam enema and suspension enema (Folk, UK): 2 g daily

Similar preparations are available in other countries, and in the USA a suspension enema containing 4 g of mesalazine has been used.

Administration

Because the release characteristics of different formulations of mesalazine vary, they should not be regarded as interchangeable. This applies even to those formulations where the dosage is apparently similar. However, a study established that an oral once-daily regimen was bioequivalent to a twice-daily regimen of the same product (Pentasa (Ferring, France))

Diverticular disease

In a study involving 218 patients with a history of recurrent attacks of acute diverticulitis, half were assigned to treatment with oral rifaximin 400 mg twice daily for 7 days, and half received rifaximin plus a modified-release formulation of mesalazine 800 mg three times daily, again for 7 days. Courses were then repeated, with rifaximin at the same dose and mesalazine at 800 mg twice daily, for 7 days in each month, and patients followed for 12 months. The combination of rifaximin and mesalazine was significantly more effective in reducing symptomatic episodes and normalisation of bowel habit than rifaximin alone: 89 of 107 patients given the combination were symptom-free at 12 months, compared with 44 of 105 given just the antibacterial.

Similarly, the same group found that in patients with uncomplicated diverticular disease given 10 days of treatment with rifaximin and mesalazine (Pentacol Sofar, Italy) in the doses above, followed by mesalazine 1.6 g daily for 8 weeks, 70 of 86 completing the study were completely asymptomatic, suggesting that daily mesalazine alone was an effective maintenance therapy, although longer-term studies were needed. Mesalazine has also been investigated in combination with a probiotic preparation of lactic-acid-producing organisms.

Preparations

The United States Pharmacopeia 31, 2008: Mesalamine Delayed-Release Tablets Mesalamine Extended-Release Capsules Mesalamine Rectal Suspension.

Proprietary Preparations

Argentina: Bufexan Pentasa Salofalk Suprimal Xalazina Yolecol

Australia: Mesasal Pentasa Salofalk

Austria: Claversal Pentasa Salofalk

Belgium: Asacoll Claversal Colitofalk Pentasa

Brazil: Asalit Chron-ASA Mesacol Pentasa

Canada: Asacol Mesasal Pentasa Salofalk

Chile: Pentasa Salofalk

Czech Republic: Asacol Pentasa Salofalk Samezil

Denmark: Asacol Mesasal Pentasa

Finland: Asacol Pentasa Salofalk

France: Fivasa Pentasa Rowasa

Germany: Asacolitin Claversal Pentasa Salofalk

Greece: Asacol Asalazin Crohnezine Ectospasmol Empenox Enterin Favorat Laboxantryl Mesaginf Pentasa Prozylex Salofalk

Hong Kong: Asacol Pentasa Salofalk

Hungary: Asacol Huma-Col-Asa Pentasa Salofalk Xalazin

India: Asacol Mesacol

Indonesia: Salofalk

Ireland: Asacolon Pentasa Salofalk

Israel: Asacol Pentasa Rafassal

Italy: Asacol Asalex Asamax Asavixin Claversal Enteraproct Enterasin Lextrasa Mesaflor Pentacol Pentasa Plimage Quota Salofalk Xalazin

Japan: Pentasa

Malaysia: Pentasa Salofalk

Mexico: Asacol Kenzomyl Pentasa Salofalk Seramine

Norway: Asacol Mesasal Pentasa

New Zealand: Asacol Pentasa

Philippines: Pentasa Salofalk

Poland: Asamax Colitan Jucolon Pentasa Salofalk

Portugal: Asacol Claversal Pentasa Salofalk

Russia: Mesacol Pentasa Samezil

South Africa: Asacol Mesasal Pentasa

Singapore: Asacol Pentasa Salofalk

Spain: Claversal Lixacol Pentasa Salofalk

Sweden: Asacol Mesasal Pentasa Salofalk

Switzerland: Asacol Asazine Mesazine Pentasa Salofalk

Thailand: Asacolf Mesacol Salofalk

Turkey: Asacol Salofalk

UK: Asacol Ipocol Mesren Mezavant Pentasa Salofalk

USA: Asacol Canasa Lialda Pentasa Rowasa

Storage

Keep out of the reach and sight of children.

Store Asacol Foam Enema below 30°C (86°F).

Keep the medicine away from flames or sparks (including cigarettes) and protect from direct sunlight. Do not pierce or burn the product, even when it is empty.

Do not use the enema after the expiry date stated on the pack after ‘Exp’. 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.