Methotrexate 10 mg Tablets (Hospira UK Ltd)

1. Name Of The Medicinal Product

Methotrexate 10 mg Tablets

2. Qualitative And Quantitative Composition

Methotrexate 10 mg per tablet.

For excipients see 6.1.

3. Pharmaceutical Form

Tablet for oral administration.

4. Clinical Particulars

4.1 Therapeutic Indications

Methotrexate is indicated in the treatment of neoplastic disease, such as trophoblastic neoplasms and leukaemia and in the control of severe recalcitrant psoriasis which is not responsive to other forms of therapy.

4.2 Posology And Method Of Administration

Adults and Children

Antineoplastic Chemotherapy

Methotrexate is active orally and parenterally. Methotrexate Injection B.P. may be given by the intramuscular, intravenous, intra-arterial or intrathecal routes. Dosage is related to the patient's body weight or surface area. Methotrexate has been used with beneficial effect in a wide variety of neoplastic diseases, alone and in combination with other cytotoxic agents.

Choriocarcinoma and Similar Trophoblastic Diseases

Methotrexate is administered orally or intramuscularly in doses of 15-30 mg daily for a 5-day course. Such courses may be repeated 3-5 times as required, with rest periods of one or more weeks interposed between courses until any manifesting toxic symptoms subside.

The effectiveness of therapy can be evaluated by 24 hour quantitative analysis of urinary chorionic gonadotrophin hormone (HCG). Combination therapy with other cytotoxic drugs, has also been reported as useful.

Hydatidiform mole may precede or be followed by choriocarcinoma, and methotrexate has been used in similar doses for the treatment of hydatidiform mole and chorioadenoma destruens.

Breast Carcinoma

Prolonged cyclic combination with Cyclophosphamide, methotrexate and Fluorouracil has given good results when used as adjuvant treatment to radical mastectomy in primary breast cancer with positive axillary lymph nodes. Methotrexate dosage was 40 mg/m² intravenously on the first and eighth days.

Leukaemia

Acute granulocytic leukaemia is rare in children but common in adults and this form of leukaemia responds poorly to chemotherapy.

Methotrexate is not generally a drug of choice for induction of remission of lymphoblastic leukaemia. Oral methotrexate 3.3 mg/m² daily, and Prednisolone 40-60 mg/m² daily for 4-6 weeks has been used. After a remission is attained, methotrexate in a maintenance dosage of 20-30 mg/m² orally or by I.M. injection has been administered twice weekly. Twice weekly doses appear to be more effective than daily drug administration. Alternatively, 2.5 mg/kg has been administered I.V. every 14 days.

Meningeal Leukaemia

Some patients with leukaemia are subject to leukaemic invasions of the central nervous system and the CSF should be examined in all leukaemia patients.

Passage of methotrexate from blood to the cerebrospinal fluid is minimal and for adequate therapy the drug should be administered intrathecally. Methotrexate may be given in a prophylactic regimen in all cases of lymphocytic leukaemia. Methotrexate is administered by intrathecal injection in doses of 200-500 microgram/kg body weight. The administration is at intervals of 2 to 5 days and is usually repeated until the cell count of cerebrospinal fluid returns to normal. At this point one additional dose is advised. Alternatively, methotrexate 12 mg/m² can be given once weekly for 2 weeks, and then once monthly. Large doses may cause convulsions and untoward side effects may occur as with any intrathecal injection, and are commonly neurological in character.

Lymphomas

In Burkitt's Tumour, stages 1-2, methotrexate has prolonged remissions in some cases. Recommended dosage is 10-25 mg per day orally for 4 to 8 days. In stage 3, methotrexate is commonly given concomitantly with other antitumour agents. Treatment in all stages usually consists of several courses of the drug interposed with 7 to 10 day rest periods, and in stage 3 they respond to combined drug therapy with methotrexate given in doses of 0.625 mg to 2.5 mg/kg daily. Hodgkin's Disease responds poorly to methotrexate and to most types of chemotherapy.

Mycosis Fungoides

Therapy with methotrexate appears to produce clinical remissions in one half of the cases treated. Recommended dosage is usually 2.5 to 10 mg daily by mouth for weeks or months and dosage should be adjusted according to the patient's response and haematological monitoring. Methotrexate has also been given intramuscularly in doses of 50 mg once weekly or 25 mg twice weekly.

Psoriasis Chemotherapy

Cases of severe uncontrolled psoriasis, unresponsive to conventional therapy, have responded to weekly single, oral, I.M. or I.V. doses of 10-25 mg per week, adjusted according to the patient's response. An initial test dose one week prior to initiation of therapy is recommended to detect any idiosyncrasy. A suggested dose range is 5-10 mg.

An alternative dosage schedule consists of 2.5 to 5 mg of methotrexate administered orally at 12 hour intervals for 3 doses each week or at 8-hour intervals for 4 doses each week; weekly dosages should not exceed 30 mg.

A daily oral dosage schedule of 2 to 5 mg administered orally for 5 days followed by a rest period of at least 2 days may also be used. The daily dose should not exceed 6.25 mg.

The patient should be fully informed of the risks involved and the clinician should pay particular attention to the appearance of liver toxicity by carrying out liver function tests before starting methotrexate treatment, and repeating these at 2 to 4 month intervals during therapy. The aim of therapy should be to reduce the dose to the lowest possible level with the longest possible rest period. The use of methotrexate may permit the return to conventional topical therapy which should be encouraged.

4.3 Contraindications

Significantly impaired renal function.

Significantly impaired hepatic function

Pre-existing blood dyscrasias, such as significant marrow hypoplasia, leukopenia, thrombocytopenia or anaemia.

Methotrexate is contraindicated in pregnancy.

Due to the potential for serious adverse reactions from methotrexate in breast fed infants, breast feeding is contra-indicated in women taking methotrexate.

Patients with a known allergic hypersensitivity to methotrexate should not receive methotrexate.

4.4 Special Warnings And Precautions For Use

Warnings

Methotrexate must be used only by physicians experienced in antimetabolite chemotherapy.

Concomittant administration of hepatotoxic or haematotoxic DMARDs (e.g. leflunomide) is not advisable.

Due to the possibility of fatal or severe toxic reactions, the patient should be fully informed by the physician of the risks involved and be under his constant supervision.

Acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported. Symptoms typically include dyspnoea, cough (especially a dry non-productive cough) and fever for which patients should be monitored at each follow-up visit. Patients should be informed of the risk of pneumonitis and advised to contact their doctor immediately should they develop persistent cough or dyspnoea.

Methotrexate should be withdrawn from patients with pulmonary symptoms and a thorough investigation should be made to exclude infection. If methotrexate induced lung disease is suspected treatment with corticosteroids should be initiated and treatment with methotrexate should not be restarted.

The carton and bottle label will state: “Check dose and frequency – methotrexate is usually taken once a week.”

Deaths have been reported with the use of methotrexate in the treatment of psoriasis.

In the treatment of psoriasis, methotrexate should be restricted to severe recalcitrant, disabling psoriasis which is not adequately responsive to other forms of therapy, but only when the diagnosis has been established by biopsy and/or after dermatological consultation.

1. Full blood counts should be closely monitored before, during and after treatment. If a clinically significant drop in white-cell or platelet count develops, methotrexate should be withdrawn immediately. Patients should be advised to report all symptoms or signs suggestive of infection.

2. Methotrexate may be hepatotoxic, particularly at high dosage or with prolonged therapy. Liver atrophy, necrosis, cirrhosis, fatty changes, and periportal fibrosis have been reported. Since changes may occur without previous signs of gastrointestinal or haematological toxicity, it is imperative that hepatic function be determined prior to initiation of treatment and monitored regularly throughout therapy. If substantial hepatic function abnormalities develop, methotrexate dosing should be suspended for at least 2 weeks.Special caution is indicated in the presence of pre-existing liver damage or impaired hepatic function. Concomitant use of other drugs with hepatotoxic potential (including alcohol) should be avoided.

3. Methotrexate has been shown to be teratogenic; it has caused foetal death and/or congenital anomalies. Therefore it is not recommended in women of childbearing potential unless there is appropriate medical evidence that the benefits can be expected to outweigh the considered risks. Pregnant psoriatic patients should not receive methotrexate.

4. Renal function should be closely monitored before, during and after treatment. Caution should be exercised if significant renal impairment is disclosed. Reduce dose of methotrexate in patients with renal impairment. High doses may cause the precipitation of methotrexate or its metabolites in the renal tubules. A high fluid throughput and alkalinisation of the urine to pH 6.5 – 7.0, by oral or intravenous administration of sodium bicarbonate (5 x 625 mg tablets every three hours) or acetazolamide (500 mg orally four times a day) is recommended as a preventative measure. Methotrexate is excreted primarily by the kidneys. Its use in the presence of impaired renal function may result in accumulation of toxic amounts or even additional renal damage.

5. Diarrhoea and ulcerative stomatitis are frequent toxic effects and require interruption of therapy, otherwise haemorrhagic enteritis and death from intestinal perforation may occur.

6. Methotrexate affects gametogenesis during the period of its administration and may result in decreased fertility which is thought to be reversible on discontinuation of therapy. Conception should be avoided during the period of methotrexate administration and for at least 6 months thereafter. Patients and their partners should be advised to this effect.

7. Methotrexate has some immunosuppressive activity and immunological responses to concurrent vaccination may be decreased. The immunosuppressive effect of methotrexate should be taken into account when immune responses of patients are important or essential.

8. Pleural effusions and ascites should be drained prior to initiation of methotrexate therapy.

9. Deaths have been reported with the use of methotrexate. Serious adverse reactions including deaths have been reported with concomitant administration of methotrexate (usually in high doses) along with some non-steroidal anti-inflammatory drugs (NSAIDs).

10. Concomitant administration of folate antagonists such as trimethoprim/sulphamethoxazole has been reported to cause an acute megaloblastic pancytopenia in rare instances.

11. Systemic toxicity may occur following intrathecal administration. Blood counts should be monitored closely.

12 A chest X-ray is recommended prior to initiation of methotrexate therapy.

13 If acute methotrexate toxicity occurs, patients may require folinic acid.

Precautions

Methotrexate has a high potential toxicity, usually dose related, and should be used only by physicians experienced in antimetabolite chemotherapy, in patients under their constant supervision. The physician should be familiar with the various characteristics of the drug and its established clinical usage.

Before beginning methotrexate therapy or reinstituting methotrexate after a rest period, assessment of renal function, liver function and blood elements should be made by history, physical examination and laboratory tests.

It should be noted that intrathecal doses are transported into the cardiovascular system and may give rise to systemic toxicity. Systemic toxicity of methotrexate may also be enhanced in patients with renal dysfunction, ascites, or other effusions due to prolongation of serum half-life.

Malignant Lymphomas may occur in patients receiving low dose methotrexate, in which case therapy must be discontinued. Failure of the Lymphoma to show signs of spontaneous regression requires the initiation of cytotoxic therapy.

Carcinogenesis, mutagenesis, and impairment of fertility: Animal carcinogenicity studies have demonstrated methotrexate to be free of carcinogenic potential. Although methotrexate has been reported to cause chromosomal damage to animal somatic cells and bone marrow cells in humans, these effects are transient and reversible. In patients treated with methotrexate, evidence is insufficient to permit conclusive evaluation of any increased risk of neoplasia.

Methotrexate has been reported to cause impairment of fertility, oligospermia, menstrual dysfunction and amenorrhoea in humans, during and for a short period after cessation of therapy. In addition, methotrexate causes, embryotoxicity, abortion and foetal defects in humans. Therefore the possible risks of effects on reproduction should be discussed with patients of childbearing potential (see 'Warnings').

Patients undergoing therapy should be subject to appropriate supervision so that signs or symptoms of possible toxic effects or adverse reactions may be detected and evaluated with minimal delay. Pretreatment and periodic haematological studies are essential to the use of methotrexate in chemotherapy because of its common effect of haematopoietic suppression. This may occur abruptly and on apparent safe dosage, and any profound drop in blood cell count indicates immediate stopping of the drug and appropriate therapy. In patients with malignant disease who have pre-existing bone marrow aplasia, leukopenia, thrombocytopenia or anaemia, methotrexate should be used with caution, if at all.

In general, the following laboratory tests are recommended as part of essential clinical evaluation and appropriate monitoring of patients chosen for or receiving methotrexate therapy: complete haemogram; haematocrit; urinalysis; renal function tests; liver function tests and chest X-ray.

The purpose is to determine any existing organ dysfunction or system impairment. The tests should be performed prior to therapy, at appropriate periods during therapy and after termination of therapy.

Liver biopsy may be considered after cumulative doses > 1.5g have been given, if hepatic impairment is suspected.

Methotrexate is bound in part to serum albumin after absorption, and toxicity may be increased because of displacement by certain drugs such as salicylates, sulphonamides, phenytoin, and some antibacterials such as tetracycline, chloramphenicol and para-aminobenzoic acid. These drugs, especially salicylates and sulphonamides, whether antibacterial, hypoglycaemic or diuretic, should not be given concurrently until the significance of these findings is established.

Vitamin preparations containing folic acid or its derivatives may alter response to methotrexate.

Methotrexate should be used with extreme caution in the presence of infection, peptic ulcer, ulcerative colitis, debility, and in extreme youth and old age. If profound leukopenia occurs during therapy, bacterial infection may occur or become a threat. Cessation of the drug and appropriate antibiotic therapy is usually indicated. In severe bone marrow depression, blood or platelet transfusions may be necessary.

Since it is reported that methotrexate may have an immunosuppressive action, this factor must be taken into consideration in evaluating the use of the drug where immune responses in a patient may be important or essential.

In all instances where the use of methotrexate is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risks of toxic effects or adverse reactions. Most such adverse reactions are reversible if detected early. When such effects or reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken according to the clinical judgement of the physician. Reinstitution of methotrexate therapy should be carried out with caution, with adequate consideration of further need for the drug and alertness as to the possible recurrence of toxicity.

Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Methotrexate is extensively protein bound and may be displaced by certain drugs such as salicylates, hypoglycaemics, diuretics, sulphonamides, diphenylhydantoins, tetracyclines, chloramphenicol and p-aminobenzoic acid, and the acidic anti-inflammatory agents, so causing a potential for increased toxicity when used concurrently.

Concomitant use of other drugs with nephrotoxic,myelotoxic or hepatotoxic potential such as leflunomide, azathioprine, sulphasalazine, retinoids and alcohol should be avoided.

Vitamin preparations containing folic acid or its derivatives may decrease the effectiveness of methotrexate.

Caution should be used when NSAIDs and salicylates are administered concomitantly with methotrexate. These drugs have been reported to reduce the tubular secretion of methotrexate and thereby may enhance its toxicity. Concomitant use of NSAIDs and salicylates has been associated with fatal methotrexate toxicity.

However, patients using constant dosage regimens of NSAIDs have received concurrent doses of methotrexate without problems observed.

Renal tubular transport is also diminished by probenecid and penicillins; use of these with methotrexate should be carefully monitored.

Omeprazole may inhibit methotrexate clearance resulting in potentially toxic methotrexate levels.

Severe bone marrow depression has been reported following the concurrent use of methotrexate and co-trimoxazole or trimethoprim. Concurrent use should probably be avoided.

Methotrexate-induced stomatitis and other toxic effects may be increased by the use of nitrous oxide.

An increased risk of hepatitis has been reported following the use of methotrexate and the acitretin metabolite, etretinate. Consequently, the concomitant use of methotrexate and acitretin should be avoided.

4.6 Pregnancy And Lactation

Abortion, foetal death, and/or congenital anomalies have occurred in pregnant women receiving methotrexate, especially during the first trimester of pregnancy. Methotrexate is contraindicated in the management of psoriasis or rheumatoid arthritis in pregnant women. Women of childbearing potential should not receive methotrexate until pregnancy is excluded. For the management of psoriasis or rheumatoid arthritis, methotrexate therapy in women should be started immediately following a menstrual period and appropriate measures should be taken in men or women to avoid conception during and for at least 6 months following cessation of methotrexate therapy.

Both men and women receiving methotrexate should be informed of the potential risk of adverse effects on reproduction. Women of childbearing potential should be fully informed of the potential hazard to the foetus should they become pregnant during methotrexate therapy. In cancer chemotherapy, methotrexate should not be used in pregnant women or women of childbearing potential who might become pregnant unless the potential benefits to the mother outweigh the possible risks to the foetus.

Defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, and infertility have been reported in patients receiving methotrexate.

Methotrexate is distributed into breast milk. Because of the potential for serious adverse reactions to methotrexate in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

4.7 Effects On Ability To Drive And Use Machines

Not applicable

4.8 Undesirable Effects

The most common adverse reactions include ulcerative stomatitis, leukopenia, vasculitis, eye-irritation and loss of libido/impotence, nausea and abdominal distress. Although very rare, anaphylactic reactions to methotrexate have occurred. Others reported are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection. In general, the incidence and severity of side effects are considered to be dose-related. Adverse reactions as reported for the various systems are as follows:

Skin: Stevens-Johnson syndrome, epidermal necrolysis, erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis. Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation. Skin ulceration in psoriatic patients and rarely painful erosion of psoriatic plaques have been reported. The recall phenomenon has been reported in both radiation and solar damaged skin.

Blood: Bone marrow depression, leukopenia, thrombocytopenia, anaemia, hypogammaglobulinaemia, haemorrhage from various sites, septicaemia.

Alimentary System: Gingivitis, pharyngitis, stomatitis, anorexia, vomiting, diarrhoea, haematemesis, melaena, gastrointestinal ulceration and bleeding, enteritis, hepatic toxicity resulting in active liver atrophy, necrosis, fatty metamorphosis, periportal fibrosis, or hepatic cirrhosis. In rare cases the effect of methotrexate on the intestinal mucosa has led to malabsorption or toxic megacolon.

Hepatic: Hepatic toxicity resulting in significant elevations of liver enzymes, acute liver atrophy, necrosis, fatty metamorphosis, periportal fibrosis or cirrhosis or death may occur, usually following chronic administration.

Urogenital System: Renal failure, azotaemia, cystitis, haematuria, defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, infertility, abortion, foetal defects, severe nephropathy. Vaginitis, vaginal ulcers, cystitis, haematuria and nephropathy have also been reported.

Pulmonary System: Acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported (see Section 4.4 Special warnings and special precautions for use). Acute pulmonary oedema has also been reported after oral and intrathecal use. Pulmonary fibrosis is rare. A syndrome consisting of pleuritic pain and pleural thickening has been reported following high doses.

Central Nervous System: Headaches, drowsiness, blurred vision, aphasia, hemiparesis and convulsions have occurred possibly related to haemorrhage or to complications from intra-arterial catheterization. Convulsion, paresis, Guillain-Barre syndrome and increased cerebrospinal fluid pressure have followed intrathecal administration.

Other reactions related to, or attributed to the use of methotrexate such as pneumonitis, metabolic changes, precipitation of diabetes, osteoporotic effects, abnormal changes in tissue cells and even sudden death have been reported.

There have been reports of leukoencephalopathy following intravenous methotrexate in high doses, or low doses following cranial-spinal radiation.

Adverse reactions following intrathecal methotrexate are generally classified into three groups, acute, subacute, and chronic. The acute form is a chemical arachnoiditis manifested by headache, back or shoulder pain, nuchal rigidity, and fever. The subacute form may include paresis, usually transient, paraplegia, nerve palsies, and cerebellar dysfunction. The chronic form is a leukoencephalopathy manifested by irritability, confusion, ataxia, spasticity, occasionally convulsions, dementia, somnolence, coma, and rarely, death. There is evidence that the combined use of cranial radiation and intrathecal methotrexate increases the incidence of leukoencephalopathy.

Additional reactions related to or attributed to the use of methotrexate such as osteoporosis, abnormal (usually 'megaloblastic') red cell morphology, precipitation of diabetes, other metabolic changes, and sudden death have been reported.

A small number of cases of accelerated nodulosis have been reported in the literature it is unclear whether the development of accelerated nodulosis during methotrexate therapy is a drug-related side effect or is part of the natural history of the rheumatoid disease.

4.9 Overdose

Calcium folinate (Calcium Leucovorin) is a potent agent for neutralizing the immediate toxic effects of methotrexate on the haematopoietic system. Where large doses or overdoses are given, calcium folinate may be administered by intravenous infusion in doses up to 75 mg within 12 hours, followed by 12 mg intramuscularly every 6 hours for 4 doses. Where average doses of methotrexate appear to have an adverse effect 6-12 mg of calcium folinate may be given intramuscularly every 6 hours for 4 doses. In general, where overdosage is suspected, the dose of calcium folinate should be equal to or higher than, the offending dose of methotrexate and should be administered as soon as possible; preferably within the first hour and certainly within 4 hours after which it may not be effective.

Other supporting therapy such as blood transfusion and renal dialysis may be required. In cases of massive overdose, hydration and urinary alkalisation may be necessary to prevent precipitation of methotrexate and/or its metabolites in the renal tubules. Neither haemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination. Effective clearance of methotrexate has been reported with acute, intermittent haemodialysis using a high flux dialyser.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Methotrexate is an antimetabolite which acts principally by competitively inhibiting the enzyme, dihydrofolate reductase. In the process of DNA synthesis and cellular replication, folic acid must be reduced to tetrahydrofolic acid by this enzyme, and inhibition by methotrexate interferes with tissue cell reproduction. Actively proliferating tissues such as malignant cells are generally more sensitive to this effect of methotrexate. It also inhibits antibody synthesis.

Methotrexate also has immunosuppressive activity, in part possibly as a result of inhibition of lymphocyte multiplication. The mechanism(s) of action in the management of rheumatoid arthritis of the drug is not known, although suggested mechanisms have included immunosuppressive and/or anti-inflammatory effect.

5.2 Pharmacokinetic Properties

In doses of 0.1 mg (of methotrexate) per kg, methotrexate is completely absorbed from the G.I. tract; larger oral doses may be incompletely absorbed. Peak serum concentrations are achieved within 0.5 - 2 hours following I.V. / I.M. or intra-arterial administration. Serum concentrations following oral administration of methotrexate may be slightly lower than those following I.V. injection.

Methotrexate is actively transported across cell membranes. The drug is widely distributed into body tissues with highest concentrations in the kidneys, gall bladder, spleen, liver and skin. Methotrexate is retained for several weeks in the kidneys and for months in the liver. Sustained serum concentrations and tissue accumulation may result from repeated daily doses. Methotrexate crosses the placental barrier and is distributed into breast milk. Approximately 50% of the drug in the blood is bound to serum proteins.

In one study, methotrexate had a serum half-life of 2-4 hours following I.M. administration. Following oral doses of 0.06 mg/kg or more, the drug had a serum half-life of 2-4 hours, but the serum half-life was reported to be increased to 8-10 hours when oral doses of 0.037 mg/kg were given.

Methotrexate does not appear to be appreciably metabolised. The drug is excreted primarily by the kidneys via glomerular filtration and active transport. Small amounts are excreted in the faeces, probably via the bile. Methotrexate has a biphasic excretion pattern. If methotrexate excretion is impaired accumulation will occur more rapidly in patients with impaired renal function. In addition, simultaneous administration of other weak organic acids such as salicylates may suppress methotrexate clearance.

5.3 Preclinical Safety Data

Not applicable

6. Pharmaceutical Particulars

6.1 List Of Excipients

Other Constituents

Maize Starch
Lactose
Pre gelatinized Starch (Prejel PA5)
Polysorbate 80
Microcrystalline Cellulose (AVICEL 101)
Magnesium Stearate

There is no overage included in the formulation.

6.2 Incompatibilities

Immediate precipitation or turbidity results when combined with certain concentrations of Droperidol, Heparin Sodium, Metoclopramide Hydrochloride, Ranitidine Hydrochloride in Syringe.

6.3 Shelf Life

60 months

6.4 Special Precautions For Storage

There are no specific storage requirements.

6.5 Nature And Contents Of Container

White polyethylene bottle with high density polyethylene screw closure containing 100 tablets.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Hospira UK Limited

Queensway

Royal Leamington Spa

Warwickshire, CV31 3RW

8. Marketing Authorisation Number(S)

PL 04515/0005

9. Date Of First Authorisation/Renewal Of The Authorisation

9^th March 2003

10. Date Of Revision Of The Text

January 2008

Minims Cyclopentolate Hydrochloride

Minims* Cyclopentolate Hydrochloride

0.5% and 1% w/v cyclopentolate hydrochloride

About Minims Cyclopentolate

The name of this medicine is Minims Cyclopentolate. Minims Cyclopentolate eye drops are available in two strengths. Each Minims unit contains either 0.5% or 1% w/v cyclopentolate hydrochloride solution. It also contains purified water and a small amount of hydrochloric acid. Each Minims unit is a sterile, single-use container which holds approximately 0.5ml of solution. Each carton contains 20 units. Cyclopentolate is a mydriatic and cycloplegic drug. These drugs are used to enlarge the pupil of the eye and to paralyse the lens temporarily.

Who makes Minims Cyclopentolate?

Minims Cyclopentolate Hydrochloride 0.5% and 1% are manufactured by

Laboratoire Chauvin S.A. ZI Ripotier

07200/Aubenas

France

The Marketing Authorisations for Minims Cyclopentolate Hydrochloride 0.5% (PL 0033/5005R and PA 118/12/2) and Minims Cyclopentolate Hydrochloride 1% (PL 0033/5006R and PA 118/12/3) are held by

Chauvin Pharmaceuticals Ltd

106 London Road

Kingston-Upon-Thames

KT2 6TN

England

What is it for?

Minims Cyclopentolate is used to enlarge the pupil of the eye and to paralyse the lens temporarily so that a doctor or eye specialist can examine it closely. These eye drops are also used to treat some types of inflammation of the eye.

Before using Minims Cyclopentolate

You should not use this product if you are allergic to any of the ingredients listed in the section ‘About Minims Cyclopentolate’ above.

This product is not intended for use in neonates (babies less than 28 days old), however, your doctor or eye specialist can use it if he or she decides that it is necessary.

Cyclopentolate should not be used in eyes which are likely to develop increased internal pressure when the pupil becomes enlarged. The doctor or eye specialist will check to make sure that this problem does not affect you.

If you are pregnant you should tell the doctor or eye specialist before Minims Cyclopentolate is used. It is possible that you will still receive it, but it is also possible that an alternative may be used.

These eye drops may cause temporary blurring of your eyesight. You should not, therefore, drive or operate hazardous machinery until it has returned to normal.

This product should be used with care in eyes that are inflamed (red and painful). It should also be used with care in very young, very ill or in elderly patients.

Using Minims Cyclopentolate

In order to examine your eyes closely, the doctor or eye specialist may put 1 - 2 drops of cyclopentolate into your eye.

If cyclopentolate has been prescribed to you because your eye is inflamed (red and painful) you will usually be asked to put 1 - 2 drops into your eye every 6 to 8 hours, however, this may vary. Your doctor or pharmacist will give you more detailed instructions, which you should follow carefully.

The dose for children depends on their size, age and the effect of the first drop. The doctor or eye specialist will decide how much to use.

If you are putting in your own eye drops then follow these instructions carefully:

• 1. Wash your hands thoroughly, peel the overwrap apart and take out the Minims unit.


• 2. Twist off the cap.


• 3. Look upwards and gently pull down the lower eyelid.


• 4. Hold the Minims unit just above your eye and gently squeeze until a drop of liquid falls into the gap between your eyeball and lower eyelid. Make sure the dropper does not touch any part of your eye.


• 5. Release the lower eyelid and then press gently on the inner corner of your eye for a minute or so. This will help to stop the solution draining away into your nose and throat. This is especially advisable in children.


• 6. Throw away the rest of the Minims unit when you have finished, even if there is some solution left.

It is very unlikely that you will suffer an overdose if you follow these instructions carefully, but if you suddenly feel unwell after using Minims Cyclopentolate, contact a doctor or the nearest casualty department as soon as possible.

After using Minims Cyclopentolate

Most people who are treated with this product do not suffer form any unwanted side effects, however, temporary irritation may occur following the instillation of this product into your eyes. This product can also increase the pressure within your eyes and can, rarely, produce an allergic reaction.

Other side effects which are possible, but which are unlikely following the normal dosage, include a temporary effect on your balance, vision and sense of touch. Children are more susceptible to such reactions occurring.

If you experience any unpleasant effects after using this product, please contact your doctor or eye specialist.

Storing Minims Cyclopentolate

• The expiry date is printed on each Minims unit overwrap and printed on the carton label. Do not use it after this date.


• Minims Cyclopentolate should be stored below 25ºC and protected from strong light. Do not allow to freeze.

This leaflet applies only to Minims Cyclopentolate, but it does not contain all the information known about it. If you have any questions or are not sure about anything, ask a doctor or pharmacist.

Date of Partial Revision: August 2002

* Trade Mark

Minocin MR 100mg Modified Release Capsules (Meda Pharmaceuticals )

1. Name Of The Medicinal Product

MINOCIN MR 100mg Modified Release Capsules

2. Qualitative And Quantitative Composition

MINOCIN MR Capsules contain 100mg of the active ingredient minocycline (equivalent to 116 mg of minocycline hydrochloride as the dehydrate salt).

For a full list of excipients see 6.1

3. Pharmaceutical Form

Modified release capsule.

Two piece, hard shell, size 2 capsules with an orange opaque body and a brown opaque cap.

4. Clinical Particulars

4.1 Therapeutic Indications

MINOCIN MR Capsules are indicated for the treatment of acne.

4.2 Posology And Method Of Administration

Dosage:

Adults: One 100mg capsule every 24 hours.

Children over 12 years: One 100mg capsule every 24 hours.

Children under 12 years: MINOCIN is not recommended.

Elderly: No special dosing requirements.

Administration:

To reduce the risk of oesophageal irritation and ulceration, the capsules should be swallowed whole with plenty of fluid, while sitting or standing. Unlike earlier tetracyclines, absorption of Minocin MR is not significantly impaired by food or moderate amounts of milk.

Treatment of acne should be continued for a minimum of 6 weeks. If, after six months, there is no satisfactory response Minocin MR should be discontinued and other therapies considered. If Minocin MR is to be continued for longer than six months, patients should be monitored at least three monthly thereafter for signs and symptoms of hepatitis or SLE or unusual pigmentation (see Special Warnings and Precautions).

4.3 Contraindications

Known hypersensitivity to tetracyclines, or to any of the components of Minocin MR. Use in pregnancy, lactation, children under the age of 12 years, complete renal failure.

4.4 Special Warnings And Precautions For Use

Minocin MR should be used with caution in patients with hepatic dysfunction and in conjunction with alcohol and other hepatotoxic drugs. It is recommended that alcohol consumption should remain within the Government's recommended limits.

Rare cases of auto-immune hepatotoxicity and isolated cases of systemic lupus erythematosus (SLE) and also exacerbation of pre-existing SLE have been reported. If patients develop signs or symptoms of SLE or hepatotoxicity, or suffer exacerbation of pre-existing SLE, minocycline should be discontinued.

Clinical studies have shown that there is no significant drug accumulation in patients with renal impairment when they are treated with Minocin MR in the recommended doses. In cases of severe renal insufficiency, reduction of dosage and monitoring of renal function may be required. The anti-anabolic action of the tetracyclines may cause an increase in serum urea. In patients with significantly impaired renal function, higher serum levels of tetracyclines may lead to uraemia, hyperphosphataemia and acidosis. If renal impairment exists, even usual oral and parenteral doses may lead to excessive systemic accumulations of the drug and possible liver toxicity.

Caution is advised in patients with myasthenia gravis as tetracyclines can cause weak neuromuscular blockade.

Cross-resistance between tetracyclines may develop in micro-organisms and cross-sensitisation in patients. Minocin MR should be discontinued if there are signs/symptoms of overgrowth of resistant organisms, e.g. enteritis, glossitis, stomatitis, vaginitis, pruritus ani or Staphylococcal enteritis.

Patients taking oral contraceptives should be warned that if diarrhoea or breakthrough bleeding occur there is a possibility of contraceptive failure.

Minocycline may cause hyperpigmentation at various body sites (see Administration and 4.8 Undesirable Effects). Hyperpigmentation may present regardless of dose or duration of therapy but develops more commonly during long term treatment. Patients should be advised to report any unusual pigmentation without delay and Minocin should be discontinued.

If a photosensitivity reaction occurs, patients should be warned to avoid direct exposure to natural or artificial light and to discontinue therapy at the first signs of skin discomfort.

As with other tetracyclines, bulging fontanelleles in infants and benign intracranial hypertension in juveniles and adults have been reported. Presenting features were headache and visual disturbances including blurring of vision, scotoma and diplopia. Permanent vision loss has been reported. Treatment should cease if evidence of raised intracranial pressure develops.

Use in the elderly:

Dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Use in children:

The use of tetracyclines during tooth development in children under the age of 12 years may cause permanent discolouration. Enamel hypoplasia has also been reported.

Laboratory monitoring:

Periodic laboratory evaluations of organ system function, including haematopoietic, renal and hepatic should be conducted.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Tetracyclines depress plasma prothrombin activity and reduced doses of concomitant anticoagulants may be necessary.

Diuretics may aggravate nephrotoxicity by volume depletion.

Bacteriostatic drugs may interfere with the bactericidal action of penicillin. Avoid giving tetracycline-class drugs in conjunction with penicillin. Absorption of Minocin MR is impaired by the concomitant administration of antacids, iron, calcium, magnesium, aluminium bismuth and zinc salts (interactions with specific salts, antacids, bismuth containing ulcer – healing drugs, quinapril which contains a magnesium carbonate excipient). It is recommended that any indigestion remedies, vitamins, or other supplements containing these salts are taken at least 3 hours before or after a dose of Minocin MR. Unlike earlier tetracyclines, absorption of Minocin MR is not significantly impaired by food or moderate amounts of milk.

There is an increased risk of ergotism when ergot alkaloids or their derivatives are given with tetracyclines.

The concomitant use of tetracyclines may reduce the efficacy of oral contraceptives.

Administration of isotretinoin or other systemic retinoids or retinol should be avoided shortly before, during and shortly after minocycline therapy. Each of these agents alone has been associated with pseudotumor cerebri (benign intracranial hypertension) (see 4.4 Special warnings and precautions).

Interference with laboratory and other diagnostic tests:

False elevations of urinary catecholamine levels may occur due to interference with the fluorescence test.

4.6 Pregnancy And Lactation

Use in pregnancy:

Minocin MR should not be used in pregnancy unless considered essential.

Results of animal studies indicate that tetracyclines cross the placenta, are found in foetal tissues and can have toxic effects on the developing foetus (often related to retardation of skeletal development). Evidence of embryotoxicity has also been noted in animals treated early in pregnancy. Minocin MR therefore, should not be used in pregnancy unless considered essential

In humans, Minocin, like other tetracycline-class antibiotics, crosses the placenta and may cause foetal harm when administered to a pregnant woman. In addition, there have been post marketing reports of congenital abnormalities including limb reduction. If Minocin is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to the foetus.

The use of drugs of the tetracycline class during tooth development (last half of pregnancy) may cause permanent discolouration of the teeth (yellow-grey-brown). This adverse reaction is more common during long term use of the drugs but has been observed following repeated short term courses. Enamel hypoplasia has also been reported.

Tetracyclines administered during the last trimester form a stable calcium complex throughout the human skeleton. A decrease in fibula growth rate has been observed in premature human infants given oral tetracyclines in doses up to 25mg/kg every 6 hours. Changes in fibula growth rate were shown to be reversible when the drug was discontinued.

Use in lactation:

Tetracyclines have been found in the milk of lactating women who are taking a drug in this class. Permanent tooth discolouration may occur in the developing infant and enamel hypoplasia has been reported.

4.7 Effects On Ability To Drive And Use Machines

Headache, light-headedness, dizziness, tinnitus and vertigo (more common in women) and, rarely, impaired hearing have occurred with Minocin MR. Patients should be warned about the possible hazards of driving or operating machinery during treatment. These symptoms may disappear during therapy and usually disappear when the drug is discontinued.

4.8 Undesirable Effects

Adverse reactions are listed in the Table in CIOMS frequency categories under MedDRA system/organ classes:

Common:

Uncommon:

Rare:

Very Rare: < 0.01%

Infections and Infestations

Very Rare: Oral and anogenital candidiasis, vulvovaginitis.

Blood and Lymphatic System Disorders

Rare: Eosinophilia, leucopenia, neutropenia, thrombocytopenia.

Very Rare: Haemolytic anaemia, pancytopenia.

There are also reports of: Agranulocytosis

Immune System Disorders

Rare: Anaphylaxis /anaphylactoid reaction (including shock), including fatalities.

There are also reports of: Hypersensitivity, pulmonary infiltrates, anaphylactoid purpura.

Endocrine Disorders

Very Rare: Abnormal thyroid function, brown-black discolouration of the thyroid.

Metabolism and Nutrition Disorders

Rare: Anorexia.

Nervous System Disorders

Common: Dizziness (light-headedness).

Rare: Headache, hypaesthesia, paraesthesia, intracranial hypertension, vertigo.

Very Rare: Bulging fontanelle.

There are also reports of: convulsions, sedation.

Ear and Labyrinth Disorders

Rare: Impaired hearing, tinnitus.

Cardiac Disorders

Rare: Myocarditis, pericarditis.

Respiratory, Thoracic and Mediastinal Disorders

Rare: Cough, dyspnoea.

Very Rare: Bronchospasm, exacerbation of asthma, pulmonary eosinophilia.

There are also reports of: Pneumonitis.

Gastrointestinal Disorders

Rare: Diarrhoea, nausea, stomatitis, discolouration of teeth (including adult tooth discolouration), vomiting.

Very Rare: Dyspepsia, dysphagia, enamel hypoplasia, enterocolitis, oesophagitis, oesophageal ulceration, glossitis, pancreatitis, pseudomembranous colitis.

There are also reports of: Oral cavity discolouration (including tongue, lip and gum).

Hepatobiliary Disorders

Rare: Increased liver enzymes, hepatitis, autoimmune hepatoxicity. (See Section 4.4 Special warnings and precautions for use).

Very Rare: Hepatic cholestatis, hepatic failure (including fatalities), hyperbilirubinaemia, jaundice.

There are also reports of: Autoimmune hepatitis.

Skin and Subcutaneous Tissue Disorders

Rare: Alopecia, erythema multiforme, erythema nodosum, fixed drug eruption, hyperpigmentation of skin, photosensitivity, pruritis, rash, urticaria, vasculitis.

Very Rare: Angioedema, exfoliative dermatitis, hyperpigmentation of nails, Stevens-Johnson Syndrome, toxic epidermal necrolysis.

Musculoskeletal, Connective Tissue and Bone Disorders

Rare: Arthralgia, lupus-like syndrome, myalgia.

Very Rare: Arthritis, bone discolouration, cases of or exacerbation of systemic lupus erythematosus (SLE) (See Section 4.4 Special warnings and precautions for use), joint stiffness, joint swelling.

Renal and Urinary Disorders

Rare: Increased serum urea, acute renal failure, interstitial nephritis.

Reproductive System and Breast Disorders

Very Rare: Balanitis.

General Disorders and Administration Site Conditions

Uncommon: Fever.

Very Rare: Discolouration of secretions.

The following syndromes have been reported. In some cases involving these syndromes, death has been reported. As with other serious adverse reactions, if any of these syndromes are recognised, the drug should be discontinued immediately:

• Hypersensitivity syndrome consisting of cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, and one or more of the following: hepatitis, pneumonitis, nephritis, myocarditis, pericarditis. Fever and lymphadenopathy may be present.

• Lupus-like syndrome consisting of positive antinuclear antibody, arthralgia, arthritis, joint stiffness or joint swelling, and one or more of the following: fever, myalgia, hepatitis, rash, vasculitis.

• Serum sickness-like syndrome consisting of fever, urticaria or rash, and arthralgia, arthritis, joint stiffness or joint swelling. Eosinophilia may be present.

Hyperpigmentation of various body sites including the skin, nails, teeth, oral mucosa, bones, thyroid, eyes (including sclera and conjunctiva), breast milk, lacrimal secretions and perspiration has been reported. This blue/black/grey or muddy-brown discolouration may be localised or diffuse. The most frequently reported site is in the skin. Pigmentation is often reversible on discontinuation of the drug, although it may take several months or may persist in some cases. The generalised muddy-brown skin pigmentation may persist, particularly in areas exposed to the sun.

4.9 Overdose

Dizziness, nausea and vomiting are the adverse effects most commonly seen with overdose. There is no specific antidote. In cases of overdose, discontinue medication, treat symptomatically with appropriate supportive measures. Minocin is not removed in significant quantities by haemodialysis or peritoneal dialysis.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

MINOCIN MR Capsules contain the active ingredient minocycline as minocycline hydrochloride, a semi-synthetic derivative of tetracycline.

5.2 Pharmacokinetic Properties

MINOCIN MR Capsules have been formulated as a "double pulse" delivery system in which a portion of the minocycline dose is delivered in the stomach, and a second portion of the dose is available for absorption in the duodenum and upper GI tract.

5.3 Preclinical Safety Data

None stated.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Pellets:	Microcrystalline cellulose
	Croscarmellose sodium
	Hypromellose phthalate 50
	Hypromellose (E464)
	Light liquid paraffin
	Methylene Chloride
	Methanol
	Purified Water
	Opaspray K-1-7000 (white), (containing:	Titanium dioxide
		Hydroxypropylcellulose)
Capsule shells:	Titanium dioxide (E171)
	Iron oxide yellow (E172)
	Iron oxide red (E172)
	Iron oxide black (E172)
	Gelatin
Capsule Cap:	Titaniurn Dioxide
	Iron Oxide red (E172)
	Iron Oxide black (E172)
	Iron Oxide yellow (E172)
	Gelatin

6.2 Incompatibilities

None known.

6.3 Shelf Life

18 months.

6.4 Special Precautions For Storage

Do not store above 25°C.

Blisters: Store in the original package

Keep the container in the outer carton

Bottles: Store in the original container

Keep the container tightly closed

6.5 Nature And Contents Of Container

PVC/PVDC aluminium blister packs containing 2, 49 and 56 capsules.

Polypropylene bottle with urea cap containing 100 capsules.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Meda Pharmaceuticals Ltd

249 West George Street

Glasgow

G2 4RB

Trading as:

Meda Pharmaceuticals Ltd

Skyway House

Parsonage Road

Takeley

Bishop's Stortford

CM22 6PU

8. Marketing Authorisation Number(S)

PL 15142/0101

9. Date Of First Authorisation/Renewal Of The Authorisation

14^th February 2005

10. Date Of Revision Of The Text

11^th August 2010

Mezzopram 40 mg Dispersible Gastro-resistant Tablets

1. Name Of The Medicinal Product

Mezzopram 40 mg Dispersible Gastro-resistant Tablets

2. Qualitative And Quantitative Composition

Each gastro-resistant tablet contains 40 mg omeprazole (as omeprazole magnesium)

Excipients: glucose, sucrose

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Gastro-resistant tablet

Reddish oval film-coated tablet with a score line on both sides. The tablet can be divided into equal halves.

4. Clinical Particulars

4.1 Therapeutic Indications

Mezzopram Dispersible gastro-resistant tablets are indicated for:

Adults

• Treatment of duodenal ulcers

• Prevention of relapse of duodenal ulcers

• Treatment of gastric ulcers

• Prevention of relapse of gastric ulcers

• In combination with appropriate antibiotics, Helicobacter pylori (H. pylori) eradication in peptic ulcer disease

• Treatment of NSAID-associated gastric and duodenal ulcers

• Prevention of NSAID-associated gastric and duodenal ulcers in patients at risk

• Treatment of reflux oesophagitis

• Long-term management of patients with healed reflux oesophagitis

• Treatment of symptomatic gastro-oesophageal reflux disease

• Treatment of Zollinger-Ellison syndrome

Paediatric use

Children over 1 year of age and

• Treatment of reflux oesophagitis

• Symptomatic treatment of heartburn and acid regurgitation in gastro-oesophageal reflux disease

Children and adolescents over 4 years of age

• In combination with antibiotics in treatment of duodenal ulcer caused by H. pylori

4.2 Posology And Method Of Administration

Posology in adults

Treatment of duodenal ulcers

The recommended dose in patients with an active duodenal ulcer is Mezzopram 20 mg once daily. In most patients healing occurs within two weeks. For those patients who may not be fully healed after the initial course, healing usually occurs during a further two weeks treatment period. In patients with poorly responsive duodenal ulcer Mezzopram 40 mg once daily is recommended and healing is usually achieved within four weeks.

Prevention of relapse of duodenal ulcers

For the prevention of relapse of duodenal ulcer in H. pylori negative patients or when H. pylori eradication is not possible the recommended dose is Mezzopram 20 mg once daily. In some patients a daily dose of 10 mg may be sufficient. In case of therapy failure, the dose can be increased to 40 mg.

Treatment of gastric ulcers

The recommended dose is Mezzopram 20 mg once daily. In most patients healing occurs within four weeks. For those patients who may not be fully healed after the initial course, healing usually occurs during a further four weeks treatment period. In patients with poorly responsive gastric ulcer Mezzopram 40 mg once daily is recommended and healing is usually achieved within eight weeks.

Prevention of relapse of gastric ulcers

For the prevention of relapse in patients with poorly responsive gastric ulcer the recommended dose is Mezzopram 20 mg once daily. If needed the dose can be increased to Mezzopram 40 mg once daily.

H. pylori eradication in peptic ulcer disease

For the eradication of H. pylori the selection of antibiotics should consider the individual patient's drug tolerance, and should be undertaken in accordance with national, regional and local resistance patterns and treatment guidelines.

• Mezzopram 20 mg + clarithromycin 500 mg + amoxicillin 1,000 mg, each twice daily for one week, or

• Mezzopram 20 mg + clarithromycin 250 mg (alternatively 500 mg) + metronidazole 400 mg (or 500 mg or tinidazole 500 mg), each twice daily for one week, or

• Mezzopram 40 mg once daily with amoxicillin 500 mg and metronidazole 400 mg (or 500 mg or tinidazole 500 mg), both three times a day for one week.

In each regimen, if the patient is still H. pylori positive, therapy may be repeated.

Treatment of NSAID-associated gastric and duodenal ulcers

For the treatment of NSAID-associated gastric and duodenal ulcers, the recommended dose is Mezzopram 20 mg once daily. In most patients healing occurs within four weeks. For those patients who may not be fully healed after the initial course, healing usually occurs during a further four weeks treatment period.

Prevention of NSAID-associated gastric and duodenal ulcers in patients at risk

For the prevention of NSAID associated gastric ulcers or duodenal ulcers in patients at risk (age> 60, previous history of gastric and duodenal ulcers, previous history of upper GI bleeding) the recommended dose is Mezzopram 20 mg once daily.

Treatment of reflux oesophagitis

The recommended dose is Mezzopram 20 mg once daily. In most patients healing occurs within four weeks. For those patients who may not be fully healed after the initial course, healing usually occurs during a further four weeks treatment period.

In patients with severe oesophagitis Mezzopram 40 mg once daily is recommended and healing is usually achieved within eight weeks.

Long-term management of patients with healed reflux oesophagitis

For the long-term management of patients with healed reflux oesophagitis the recommended dose is Mezzopram 10 mg once daily. If needed, the dose can be increased to Mezzopram 20-40 mg once daily.

Treatment of symptomatic gastro-oesophageal reflux disease

The recommended dose is Mezzopram 20 mg daily. Patients may respond adequately to 10 mg daily, and therefore individual dose adjustment should be considered.

If symptom control has not been achieved after 4 weeks treatment with Mezzopram 20 mg daily, further investigation is recommended.

Treatment of Zollinger-Ellison syndrome

In patients with Zollinger-Ellison syndrome the dose should be individually adjusted and treatment continued as long as clinically indicated. The recommended initial dose is Mezzopram 60 mg daily. All patients with severe disease and inadequate response to other therapies have been effectively controlled and more than 90% of the patients maintained on doses of Mezzopram 20–120 mg daily. When dose exceed Mezzopram 80 mg daily, the dose should be divided and given twice daily.

Posology in children

Children over 1 year of age and

Treatment of reflux oesophagitis

Symptomatic treatment of heartburn and acid regurgitation in gastro-oesophageal reflux disease

The posology recommendations are as follows:

Age	Weight	Posology
	10-20 kg	10 mg once daily. The dose can be increased to 20 mg once daily if needed
	> 20 kg	20 mg once daily. The dose can be increased to 40 mg once daily if needed

Reflux oesophagitis: The treatment time is 4–8 weeks.

Symptomatic treatment of heartburn and acid regurgitation in gastro-oesophageal reflux disease: The treatment time is 2–4 weeks. If symptom control has not been achieved after 2–4 weeks the patient should be investigated further.

Children and adolescents over 4 years of age

Treatment of duodenal ulcer caused by H. pylori

When selecting appropriate combination therapy, consideration should be given to official national, regional and local guidance regarding bacterial resistance, duration of treatment (most commonly 7 days but sometimes up to 14 days), and appropriate use of antibacterial agents.

The treatment should be supervised by a specialist.

The posology recommendations are as follows:

Weight	Posology
15-30 kg	Combination with two antibiotics: Mezzopram 10 mg, amoxicillin 25 mg/kg body weight and clarithromycin 7.5 mg/kg body weight are all administrated together two times daily for one week
31-40 kg	Combination with two antibiotics: Mezzopram 20 mg, amoxicillin 750 mg and clarithromycin 7.5 mg/kg body weight are all administrated two times daily for one week
> 40 kg	Combination with two antibiotics: Mezzopram 20 mg, amoxicillin 1 g and clarithromycin 500 mg are all administrated two times daily for one week.

Special populations

Impaired renal function

Dose adjustment is not needed in patients with impaired renal function (see section 5.2).

Impaired hepatic function

In patients with impaired hepatic function a daily dose of 10–20 mg may be sufficient (see section 5.2).

Elderly (> 65 years old)

Dose adjustment is not needed in the elderly (see section 5.2).

Method of administration

It is recommended to take Mezzopram tablets in the morning, swallowed whole with half a glass of water. The tablets must not be chewed or crushed.

For patients with swallowing difficulties and for children who can drink or swallow semi-solid food

Patients can break the tablet and disperse it in a spoonful of non-carbonated water and if so wished, mix with some fruit juices or applesauce. Patients should be advised that the dispersion should be taken immediately (or within 15 minutes)and always be stirred just before drinking and rinsed down with half a glass of water. DO NOT USE milk or carbonated water. The enteric-coated pellets must not be chewed.

4.3 Contraindications

Hypersensitivity to omeprazole, substituted benzimidazoles or to any of the excipients.

Omeprazole like other proton pump inhibitors must not be used concomitantly with nelfinavir (see section 4.5).

4.4 Special Warnings And Precautions For Use

In the presence of any alarm symptom (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis or melena) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment may alleviate symptoms and delay diagnosis.

Co-administration of atazanavir with proton pump inhibitors is not recommended (see section 4.5). If the combination of atazanavir with a proton pump inhibitor is judged unavoidable, close clinical monitoring (e.g virus load) is recommended in combination with an increase in the dose of atazanavir to 400 mg with 100 mg of ritonavir; omeprazole 20 mg should not be exceeded.

Omeprazole, as all acid-blocking medicines, may reduce the absorption of vitamin B₁₂ (cyanocobalamin) due to hypo- or achlorhydria. This should be considered in patients with reduced body stores or risk factors for reduced vitamin B₁₂ absorption on long-term therapy.

Omeprazole is a CYP2C19 inhibitor. When starting or ending treatment with omeprazole, the potential for interactions with drugs metabolised through CYP2C19 should be considered. An interaction is observed between clopidogrel and omeprazole (see section 4.5). The clinical relevance of this interaction is uncertain. As a precaution, concomitant use of omeprazole and clopidogrel should be discouraged.

Some children with chronic illnesses may require long-term treatment although it is not recommended.

Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter (see section 5.1).

As in all long-term treatments, especially when exceeding a treatment period of 1 year, patients should be kept under regular surveillance.

Mezzopram Dispersible gastro-resistant tablets contain sucrose and glucose. Patients with rare fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Effects of omeprazole on the pharmacokinetics of other active substances

Active substances with pH dependent absorption

The decreased intragastric acidity during treatment with omeprazole might increase or decrease the absorption of active substances with a gastric pH dependent absorption.

Nelfinavir, atazanavir

The plasma levels of nelfinavir and atazanavir are decreased in case of co-administration with omeprazole.

Concomitant administration of omeprazole with nelfinavir is contraindicated (see section 4.3). Co-administration of omeprazole (40 mg once daily) reduced mean nelfinavir exposure by ca. 40% and the mean exposure of the pharmacologically active metabolite M8 was reduced by ca. 75-90%. The interaction may also involve CYP2C19 inhibition.

Concomitant administration of omeprazole with atazanavir is not recommended (see section 4.4). Concomitant administration of omeprazole (40 mg once daily) and atazanavir 300 mg/ritonavir 100 mg to healthy volunteers resulted in a 75% decrease of the atazanavir exposure. Increasing the atazanavir dose to 400 mg did not compensate for the impact of omeprazole on atazanavir exposure. The co-administration of omeprazole (20 mg once daily) with atazanavir 400 mg/ritonavir 100 mg to healthy volunteers resulted in a decrease of approximately 30% in the atazanavir exposure as compared to atazanavir 300 mg/ritonavir 100 mg once daily.

Digoxin

Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10%. Digoxin toxicity has been rarely reported. However caution should be exercised when omeprazole is given at high doses in elderly patients. Therapeutic drug monitoring of digoxin should be then be reinforced.

Clopidogrel

In a crossover clinical study, clopidogrel (300 mg loading dose followed by 75 mg/day) alone and with omeprazole (80 mg at the same time as clopidogrel) were administered for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 46% (Day 1) and 42% (Day 5) when clopidogrel and omeprazole were administered together. Mean inhibition of platelet aggregation (IPA) was diminished by 47% (24 hours) and 30% (Day 5) when clopidogrel and omeprazole were administered together. In another study it was shown that administering clopidogrel and omeprazole at different times did not prevent their interaction that is likely to be driven by the inhibitory effect of omeprazole on CYP2C19. Inconsistent data on the clinical implications of this PK/PD interaction in terms of major cardiovascular events have been reported from observational and clinical studies.

Other active substances

The absorption of posaconazole, erlotinib, ketoconazol and itraconazol is significantly reduced and thus clinical efficacy may be impaired. For posaconazol and erlotinib concomitant use should be avoided.

Active substances metabolised by CYP2C19

Omeprazole is a moderate inhibitor of CYP2C19, the major omeprazole metabolising enzyme. Thus, the metabolism of concomitant active substances also metabolised by CYP2C19, may be decreased and the systemic exposure to these substances increased. Examples of such drugs are R-warfarin and other vitamin K antagonists, cilostazol, diazepam and phenytoin.

Cilostazol

Omeprazole, given in doses of 40 mg to healthy subjects in a cross-over study, increased C_max and AUC for cilostazol by 18% and 26% respectively, and one of its active metabolites by 29% and 69% respectively.

Phenytoin

Monitoring phenytoin plasma concentration is recommended during the first two weeks after initiating omeprazole treatment and, if a phenytoin dose adjustment is made, monitoring and a further dose adjustment should occur upon ending omeprazole treatment.

Unknown mechanism

Saquinavir

Concomitant administration of omeprazole with saquinavir/ritonavir resulted in increased plasma levels up to approximately 70% for saquinavir associated with good tolerability in HIV-infected patients.

Tacrolimus

Concomitant administration of omeprazole has been reported to increase the serum levels of tacrolimus. A reinforced monitoring of tacrolimus concentrations as well as renal function (creatinine clearance) should be performed, and dosage of tacrolimus adjusted if needed.

Effects of other active substances on the pharmacokinetics of omeprazole

Inhibitors of CYP2C19 and/or CYP3A4

Since omeprazole is metabolised by CYP2C19 and CYP3A4, active substances known to inhibit CYP2C19 or CYP3A4 (such as clarithromycin and voriconazole) may lead to increased omeprazole serum levels by decreasing omeprazole's rate of metabolism. Concomitant voriconazole treatment resulted in more than doubling of the omeprazole exposure. As high doses of omeprazole have been well-tolerated adjustment of the omeprazole dose is not generally required. However, dose adjustment should be considered in patients with severe hepatic impairment and if long-term treatment is indicated.

Inducers of CYP2C19 and/or CYP3A4

Active substances known to induce CYP2C19 or CYP3A4 or both (such as rifampicin and St John's wort) may lead to decreased omeprazole serum levels by increasing omeprazole's rate of metabolism.

4.6 Pregnancy And Lactation

Results from three prospective epidemiological studies (more than 1000 exposed outcomes) indicate no adverse effects of omeprazole on pregnancy or on the health of the foetus/newborn child. Omeprazole can be used during pregnancy.

Omeprazole is excreted in breast milk but is not likely to influence the child when therapeutic doses are used.

4.7 Effects On Ability To Drive And Use Machines

Mezzopram is not likely to affect the ability to drive or use machines. Adverse drug reactions such as dizziness and visual disturbances may occur (see section 4.8). If affected, patients should not drive or operate machinery.

4.8 Undesirable Effects

The most common side effects (1-10% of patients) are headache, abdominal pain, constipation, diarrhoea, flatulence and nausea/vomiting.

The following adverse drug reactions have been identified or suspected in the clinical trials programme for omeprazole and post-marketing. None was found to be dose-related. Adverse reactions listed below are classified according to frequency and System Organ Class (SOC). Frequency categories are defined according to the following convention: Very common (

SOC/frequency	Adverse reaction
Blood and lymphatic system disorders
Rare:	Leukopenia, thrombocytopenia
Very rare:	Agranulocytosis, pancytopenia
Immune system disorders
Rare:	Hypersensitivity reactions e.g. fever, angioedema and anaphylactic reaction/shock
Metabolism and nutrition disorders
Rare:	Hyponatraemia
Very rare:	Hypomagnesaemia
Psychiatric disorders
Uncommon:	Insomnia
Rare:	Agitation, confusion, depression
Very rare:	Aggression, hallucinations
Nervous system disorders
Common:	Headache
Uncommon:	Dizziness, paraesthesia, somnolence
Rare:	Taste disturbance
Eye disorders
Rare:	Blurred vision
Ear and labyrinth disorders
Uncommon:	Vertigo
Respiratory, thoracic and mediastinal disorders
Rare:	Bronchospasm
Gastrointestinal disorders
Common:	Abdominal pain, constipation, diarrhoea, flatulence, nausea/vomiting
Rare:	Dry mouth, stomatitis, gastrointestinal candidiasis
Hepatobiliary disorders
Uncommon:	Increased liver enzymes
Rare:	Hepatitis with or without jaundice
Very rare:	Hepatic failure, encephalopathy in patients with pre-existing liver disease
Skin and subcutaneous tissue disorders
Uncommon:	Dermatitis, pruritus, rash, urticaria
Rare:	Alopecia, photosensitivity
Very rare:	Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN)
Musculoskeletal and connective tissue disorders
Rare:	Arthralgia, myalgia
Very rare:	Muscular weakness
Renal and urinary disorders
Rare:	Interstitial nephritis
Reproductive system and breast disorders
Very rare:	Gynaecomastia
General disorders and administration site conditions
Uncommon:	Malaise, peripheral oedema
Rare:	Increased sweating

Paediatric population

The safety of omeprazole has been assessed in a total of 310 children aged 0 to 16 years with acid-related disease. There are limited long term safety data from 46 children who received maintenance therapy of omeprazole during a clinical study for severe erosive oesophagitis for up to 749 days. The adverse event profile was generally the same as for adults in short- as well as in long-term treatment. There are no long term data regarding the effects of omeprazole treatment on puberty and growth.

4.9 Overdose

There is limited information available on the effects of overdoses of omeprazole in humans. In the literature, doses of up to 560 mg have been described, and occasional reports have been received when single oral doses have reached up to 2,400 mg omeprazole (120 times the usual recommended clinical dose). Nausea, vomiting, dizziness, abdominal pain, diarrhoea and headache have been reported. Also apathy, depression and confusion have been described in single cases.

The symptoms described in connection to omeprazole overdose have been transient, and no serious outcome has been reported. The rate of elimination was unchanged (first order kinetics) with increased doses. Treatment, if needed, is symptomatic.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Proton pump inhibitors, ATC code: A02BC01

Mechanism of action

Omeprazole, a racemic mixture of two enantiomers reduces gastric acid secretion through a highly targeted mechanism of action. It is a specific inhibitor of the acid pump in the parietal cell. It is rapidly acting and provides control through reversible inhibition of gastric acid secretion with once daily dosing.

Omeprazole is a weak base and is concentrated and converted to the active form in the highly acidic environment of the intracellular canaliculi within the parietal cell, where it inhibits the enzyme H⁺ K⁺-ATPase - the acid pump. This effect on the final step of the gastric acid formation process is dose-dependent and provides for highly effective inhibition of both basal acid secretion and stimulated acid secretion, irrespective of stimulus.

Pharmacodynamic effects

All pharmacodynamic effects observed can be explained by the effect of omeprazole on acid secretion.

Effect on gastric acid secretion

Oral dosing with omeprazole once daily provides for rapid and effective inhibition of daytime and night-time gastric acid secretion with maximum effect being achieved within 4 days of treatment. With omeprazole 20 mg, a mean decrease of at least 80% in 24-hour intragastric acidity is then maintained in duodenal ulcer patients, with the mean decrease in peak acid output after pentagastrin stimulation being about 70% 24 hours after dosing.

Oral dosing with omeprazole 20 mg maintains an intragastric pH of

As a consequence of reduced acid secretion and intragastric acidity, omeprazole dose-dependently reduces/normalizes acid exposure of the oesophagus in patients with gastro-oesophageal reflux disease.

The inhibition of acid secretion is related to the area under the plasma concentration-time curve (AUC) of omeprazole and not to the actual plasma concentration at a given time.

No tachyphylaxis has been observed during treatment with omeprazole.

Effect on H. pylori

H. pylori is associated with peptic ulcer disease, including duodenal and gastric ulcer disease. H. pylori is a major factor in the development of gastritis. H. pylori together with gastric acid are major factors in the development of peptic ulcer disease. H. pylori is a major factor in the development of atrophic gastritis which is associated with an increased risk of developing gastric cancer.

Eradication of H. pylori with omeprazole and antimicrobials is associated with high rates of healing and long-term remission of peptic ulcers

Dual therapies have been tested and found to be less effective than triple therapies. They could, however, be considered in cases where known hypersensitivity precludes use of any triple combination.

Other effects related to acid inhibition

During long-term treatment gastric glandular cysts have been reported in a somewhat increased frequency. These changes are a physiological consequence of pronounced inhibition of acid secretion, are benign and appear to be reversible.

Decreased gastric acidity due to any means including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with acid-reducing drugs may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter.

Paediatric use

In a non-controlled study in children (1 to 16 years of age) with severe reflux oesophagitis, omeprazole at doses of 0.7 to 1.4 mg/kg improved oesophagitis level in 90% of the cases and significantly reduced reflux symptoms. In a single-blind study, children aged 0–24 months with clinically diagnosed gastro-oesophageal reflux disease were treated with 0.5, 1.0 or 1.5 mg omeprazole/kg. The frequency of vomiting/regurgitation episodes decreased by 50% after 8 weeks of treatment irrespective of the dose.

Eradication of H. pylori in children

A randomised, double blind clinical study (Héliot study) concluded that omeprazole, in combination with two antibiotics (amoxicillin and clarithromycin), was safe and effective in the treatment of H. pylori infection in children age 4 years old and above with gastritis: H. pylori eradication rate: 74.2% (23/31 patients) with omeprazole + amoxicillin + clarithromycin versus 9.4% (3/32 patients) with amoxicillin + clarithromycin. However, there was no evidence of any clinical benefit with respect to dyspeptic symptoms. This study does not support any information for children aged less than 4 years.

5.2 Pharmacokinetic Properties

Absorption

Omeprazole and omeprazole magnesium are acid labile and are therefore administered orally as enteric-coated granules in capsules or tablets. Absorption of omeprazole is rapid, with peak plasma levels occurring approximately 1-2 hours after dose. Absorption of omeprazole takes place in the small intestine and is usually completed within 3-6 hours. Concomitant intake of food has no influence on the bioavailability. The systemic availability (bioavailability) from a single oral dose of omeprazole is approximately 40%. After repeated once-daily administration, the bioavailability increases to about 60%.

Distribution

The apparent volume of distribution in healthy subjects is approximately 0.3 l/kg body weight. Omeprazole is 97% plasma protein bound.

Metabolism

Omeprazole is completely metabolised by the cytochrome P450 system (CYP). The major part of its metabolism is dependent on the polymorphically expressed CYP2C19, responsible for the formation of hydroxyomeprazole, the major metabolite in plasma. The remaining part is dependent on another specific isoform, CYP3A4, responsible for the formation of omeprazole sulphone. As a consequence of high affinity of omeprazole to CYP2C19, there is a potential for competitive inhibition and metabolic drug-drug interactions with other substrates for CYP2C19. However, due to low affinity to CYP3A4, omeprazole has no potential to inhibit the metabolism of other CYP3A4 substrates. In addition, omeprazole lacks an inhibitory effect on the main CYP enzymes.

Approximately 3% of the Caucasian population and 15-20% of Asian populations lack a functional CYP2C19 enzyme and are called poor metabolisers. In such individuals the metabolism of omeprazole is probably mainly catalysed by CYP3A4. After repeated once-daily administration of 20 mg omeprazole, the mean AUC was 5 to 10 times higher in poor metabolisers than in subjects having a functional CYP2C19 enzyme (extensive metabolisers). Mean peak plasma concentrations were also higher, by 3 to 5 times. These findings have no implications for the posology of omeprazole.

Excretion

The plasma elimination half-life of omeprazole is usually shorter than one hour both after single and repeated oral once-daily dosing. Omeprazole is completely eliminated from plasma between doses with no tendency for accumulation during once-daily administration. Almost 80% of an oral dose of omeprazole is excreted as metabolites in the urine, the remainder in the faeces, primarily originating from bile secretion.

The AUC of omeprazole increases with repeated administration. This increase is dose-dependent and results in a non-linear dose-AUC relationship after repeated administration. This time- and dose-dependency is due to a decrease of first pass metabolism and systemic clearance probably caused by an inhibition of the CYP2C19 enzyme by omeprazole and/or its metabolites (e.g. the sulphone).

No metabolite has been found to have any effect on gastric acid secretion.

Special populations

Impaired hepatic function

The metabolism of omeprazole in patients with liver dysfunction is impaired, resulting in an increased AUC. Omeprazole has not shown any tendency to accumulate with once-daily dosing.

Impaired renal function

The pharmacokinetics of omeprazole, including systemic bioavailability and elimination rate, are unchanged in patients with reduced renal function.

Elderly

The metabolism rate of omeprazole is somewhat reduced in elderly subjects (75-79 years of age).

Paediatric patients

During treatment with the recommended doses to children from the age of 1 year, similar plasma concentrations were obtained as compared to adults. In children younger than 6 months, clearance of omeprazole is low due to low capacity to metabolise omeprazole.

5.3 Preclinical Safety Data

Gastric ECL-cell hyperplasia and carcinoids, have been observed in life-long studies in rats treated with omeprazole. These changes are the result of sustained hypergastrinaemia secondary to acid inhibition. Similar findings have been made after treatment with H₂-receptor antagonists, proton pump inhibitors and after partial fundectomy. Thus, these changes are not from a direct effect of any individual active substance.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablet core

Sucrose

Maize starch

Glucose

Copovidone

Povidone

Talc

Titanium dioxide (E 171)

Methacrylic acid-ethyl acrylate copolymer (1:1)

Glycerol monostearate

Propylene glycol

Stearic acid

Polysorbate 80

Simeticone

Cellulose, microcrystalline

Macrogol 6000

Crospovidone

Silica colloidal anhydrous

Magnesium stearate

Tablet coating

Hypromellose

Macrogol 6000

Titanium dioxide (E 171)

Talc

Iron oxide, red (E 172)

Iron oxide, yellow (E 172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

HDPE containers:

2 years

shelf life after first opening: 6 months

Do not store above 25 °C after first opening of the container. Keep the container tightly closed, in order to protect from moisture.

Aluminium/aluminium blister:

2 years

Aclar/aluminium blister:

2 years

6.4 Special Precautions For Storage

HDPE containers:

This medicinal product does not require any special storage conditions.

For storage conditions of the medicinal product after first opening of the HDPE container, see section 6.3.

Aluminium/aluminium blister:

This medicinal product does not require any special storage conditions.

Aclar/aluminium blister:

This medicinal product does not require any special storage conditions.

6.5 Nature And Contents Of Container

HDPE container with a polypropylene screw-cap with 7, 14, 15, 28, 30, 56, 98, 100 gastro-resistant tablets

Aluminium/aluminium blister with 5, 7, 10, 14, 15, 20, 28, 30, 49, 50, 56, 60, 90, 98, 100 gastro-resistant tablets.

Aclar/aluminium blister with 5, 7, 10, 14, 15, 20, 28, 30, 49, 50, 56, 60, 90, 98, 100 gastro-resistant tablets.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Sandoz Limited

Frimley Business Park,

Frimley,

Camberley,

Surrey,

GU16 7SR.

United Kingdom

8. Marketing Authorisation Number(S)

PL 04416/1079

9. Date Of First Authorisation/Renewal Of The Authorisation

05/07/2010

10. Date Of Revision Of The Text

26/04/2011