Voltarol Dispersible Tablets 50mg

1. Name Of The Medicinal Product

Voltarol^® Dispersible tablets 50mg

2. Qualitative And Quantitative Composition

The active ingredient is o-[(2,6-Dichlorophenyl)amino]phenylacetic acid (diclofenac).

Each tablet contains 46.5mg of diclofenac free acid, which is equivalent to 50mg of diclofenac sodium.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

The tablets are pink, speckled with white, triangular shaped, uncoated, impressed GEIGY on one side with an embossed "V" on the other, with a blackcurrant odour.

4. Clinical Particulars

4.1 Therapeutic Indications

Adults and Elderly:

The rapid onset of absorption of diclofenac from Voltarol Dispersible makes this preparation more suitable for short-term use in acute conditions for which treatment is required for no more than 3 months including: acute episodes of arthritic conditions, acute musculo-skeletal disorders and acute pain resulting from trauma.

There is no information on the use of Voltarol Dispersible for more than 3 months.

4.2 Posology And Method Of Administration

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

For oral administration

Adults:

100-150mg daily in two or three divided doses. The Voltarol Dispersible tablet should be dropped into a glass of water, and the liquid stirred to aid dispersion, before swallowing.

The recommended maximum daily dose of Voltarol is 150mg.

Children: Not recommended.

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

4.3 Contraindications

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

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

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

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

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

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

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

4.4 Special Warnings And Precautions For Use

General

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

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

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

As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, can also occur in rare cases with diclofenac without earlier exposure to the drug (see section 4.8 Undesirable effects).

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

Gastrointestinal effects:

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

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

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

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

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

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

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

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

Hepatic effects:

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

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

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

Hepatitis may occur with diclofenac without prodromal symptoms.

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

Renal effects:

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

Skin effects:

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

SLE and mixed connective tissue disease:

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

Cardiovascular and cerebrovascular effects:

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

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

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

Haematological effects:

Use of Voltarol dispersible tablets is recommended only for short term treatment.

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

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

Pre-existing asthma:

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

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

Female fertility:

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

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The following interactions include those observed with Voltarol dispersible tablets and/or other pharmaceutical forms of diclofenac.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

4.6 Pregnancy And Lactation

Pregnancy

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

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

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

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

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

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

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

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

- inhibition of uterine contractions resulting in delayed or prolonged labour

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

Lactation

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

Female fertility

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

See also section 4.4 Special warnings and precautions for use, regarding female fertility.

4.7 Effects On Ability To Drive And Use Machines

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

4.8 Undesirable Effects

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

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

Table 1

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

Clinical trial and epidemiological data suggest that use of diclofenac, particularly at high doses (150mg daily) and in long term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4 Special warnings and special precautions for use).

4.9 Overdose

Symptoms

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

Therapeutic measures

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

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

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

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group

Nonsteroidal anti-inflammatory drugs (NSAIDs).

Mechanism of action

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

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

5.2 Pharmacokinetic Properties

Absorption

Absorption begins immediately upon administration. Mean peak plasma concentrations of diclofenac are reached at about 1 hour 0.9 ± 0.4µg/ml (1µg/mL ≡ 3µmol/L). Ingestion of dispersible tablets together with or immediately after a meal does not delay the onset of absorption but reduces the amount absorbed by on average of about 16% and the maximum concentrations by about 50%.

Bioavailability:

The bioavailability is 82% of that of enteric-coated tablets. Ingestion with food affects the bioavailability (see above).

Pharmacokinetic behaviour does not change on repeated administration. Accumulation does not occur, provided the recommended dosage intervals are observed.

Distribution

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

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

Metabolism

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

Elimination

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

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

Characteristics in patients

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

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

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

5.3 Preclinical Safety Data

None stated.

6. Pharmaceutical Particulars

6.1 List Of Excipients

The dispersible tablets also contain avicel PH 101, croscarmellose sodium type A, sodium starch glycollate, sodium saccharin, hydrogenated caster oil, purified talc special, aerosil 200 standard, blackcurrant and F.D. and C. red No. 3.

6.2 Incompatibilities

None known.

6.3 Shelf Life

Five years.

6.4 Special Precautions For Storage

Protect from heat (store below 30°C) and moisture.

Medicines should be kept out of the reach of children.

6.5 Nature And Contents Of Container

The tablets come in aluminium blister packs of 3 and 21.

6.6 Special Precautions For Disposal And Other Handling

The dispersible tablets should be dissolved in water.

7. Marketing Authorisation Holder

Novartis Pharmaceuticals UK Ltd.

Trading as Geigy Pharmaceuticals,

Frimley Business Park

Frimley

Camberley

Surrey

GU16 7SR.

8. Marketing Authorisation Number(S)

PL 00101/0467

9. Date Of First Authorisation/Renewal Of The Authorisation

11 July 1997

10. Date Of Revision Of The Text

01 July 2011

LEGAL CATEGORY

POM

Contrin

Generic Name: multivitamin with iron (MUL tee VYE ta mins with i ron)

Brand Names:

What is Contrin (multivitamin with iron)?

Multivitamin are a combination of many different vitamins that are normally found in foods and other natural sources.

Iron is normally found in foods like red meat. In the body, iron becomes a part of your hemoglobin (HEEM o glo bin) and myoglobin (MY o glo bin). Hemoglobin carries oxygen through your blood to tissues and organs. Myoglobin helps your muscle cells store oxygen.

Multivitamin and iron are used to provide vitamins and iron that are not taken in through the diet. They are also used to treat iron or vitamin deficiencies caused by illness, pregnancy, poor nutrition, digestive disorders, and many other conditions.

Multivitamin and iron may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about Contrin (multivitamin with iron)?

Never take more than the recommended dose of a multivitamin. Avoid taking any other multivitamin product within 2 hours before or after you take multivitamin with iron. Taking similar vitamin products together at the same time can result in a vitamin overdose or serious side effects. Seek emergency medical attention if you think you have used too much of this medicine. An overdose of vitamins A, D, E, or K can cause serious or life-threatening side effects. Iron and other minerals contained in a multivitamin can also cause serious overdose symptoms if you take too much.

Overdose symptoms may include severe stomach pain, vomiting, bloody diarrhea, coughing up blood, constipation, loss of appetite, hair loss, peeling skin, warmth or tingly feeling, changes in menstrual periods, weight loss, severe headache, muscle or joint pain, severe back pain, blood in your urine or stools, black and tarry stools, pale skin, easy bruising or bleeding, weakness, shallow breathing, weak and rapid pulse, pale skin, blue lips, and seizure (convulsions).

Do not take this medication with milk, other dairy products, calcium supplements, or antacids that contain calcium. Calcium may make it harder for your body to absorb certain ingredients of the multivitamin with iron.

What should I discuss with my healthcare provider before taking Contrin (multivitamin with iron)?

Iron and certain vitamins can cause serious or life-threatening side effects if taken in large doses. Do not take more of this medication than directed on the label or prescribed by your doctor.

If you have any medical conditions, ask your doctor before taking a multivitamin with iron. If you have certain conditions, you may need a certain vitamin formulation or special tests while taking this product.

Do not take multivitamin with iron without telling your doctor if you are pregnant or plan to become pregnant. Some vitamins and minerals can harm an unborn baby if taken in large doses. You may need to use a prenatal vitamin specially formulated for pregnant women. Multivitamin can pass into breast milk and may harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I take Contrin (multivitamin with iron)?

Use this medication as directed on the label, or as your doctor has prescribed. Do not use the medication in larger amounts or for longer than recommended.

Never take more than the recommended dose of multivitamin with iron. Avoid taking any other multivitamin product within 2 hours before or after you take multivitamin with iron. Taking similar vitamin products together at the same time can result in a vitamin overdose or serious side effects.

Many multivitamin products also contain minerals such as calcium, magnesium, potassium, and zinc. Minerals (especially taken in large doses) can cause side effects such as tooth staining, increased urination, stomach bleeding, uneven heart rate, confusion, and muscle weakness or limp feeling. Read the label of any multivitamin product you take to make sure you are aware of what it contains.

Take your multivitamin with a full glass of water. You may take the multivitamin with food if it upsets your stomach.

The chewable tablet must be chewed or allowed to dissolve in the mouth before swallowing.

Measure the liquid form of this multivitamin using a special dose-measuring spoon or cup, not a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist where you can get one.

Liquid multivitamin may sometimes be mixed with water, fruit juice, or infant formula (but not milk or other dairy products). Follow the directions on the medicine label.

Do not crush, chew, break, or open an extended-release tablet or capsule. Swallow the pill whole. Breaking or opening the pill may cause too much of the drug to be released at one time.

It is important to take multivitamin with iron regularly to get the most benefit.

Store this medication at room temperature away from moisture and heat. Keep the liquid medicine from freezing.

Store multivitamin in their original container. Storing multivitamin in a glass container can ruin the medication.

What happens if I miss a dose?

Take the missed dose as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at the next regularly scheduled time. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine. An overdose of vitamins A, D, E, or K can cause serious or life-threatening side effects. Iron and other minerals contained in a multivitamin can also cause serious overdose symptoms.

Overdose symptoms may include severe stomach pain, vomiting, bloody diarrhea, coughing up blood, constipation, loss of appetite, hair loss, peeling skin, warmth or tingly feeling, changes in menstrual periods, weight loss, severe headache, muscle or joint pain, severe back pain, blood in your urine or stools, black and tarry stools, pale skin, easy bruising or bleeding, weakness, shallow breathing, weak and rapid pulse, pale skin, blue lips, and seizure (convulsions).

What should I avoid while taking Contrin (multivitamin with iron)?

Avoid taking any other multivitamin product within 2 hours before or after you take multivitamin with iron. Taking similar vitamin products together at the same time can result in a vitamin overdose or serious side effects.

Avoid the regular use of salt substitutes in your diet if your multivitamin contains potassium. If you are on a low-salt diet, ask your doctor before taking a vitamin or mineral supplement.

Avoid taking an antibiotic medicine within 2 hours before or after you take multivitamin with iron. This is especially important if you are taking an antibiotic such as ciprofloxacin (Cipro), demeclocycline (Declomycin), doxycycline (Adoxa, Doryx, Oracea, Vibramycin), levofloxacin (Levaquin), lomefloxacin (Maxaquin), minocycline (Dynacin, Minocin, Solodyn, Vectrin), norfloxacin (Noroxin), ofloxacin (Floxin), or tetracycline (Brodspec, Panmycin, Sumycin, Tetracap).

Certain foods can also make it harder for your body to absorb iron. Avoid taking this multivitamin within 1 hour before or 2 hours after eating fish, meat, liver, and whole grain or "fortified" breads or cereals.

Do not take this medication with milk, other dairy products, calcium supplements, or antacids that contain calcium. Calcium may make it harder for your body to absorb certain ingredients of the multivitamin.

Contrin (multivitamin with iron) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor if you have serious side effects such as:

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  bright red blood in your stools; or

  
  


• 
  

  pain in your chest or throat when swallowing a ferrous fumarate tablet.

  
  

When taken as directed, multivitamin are not expected to cause serious side effects. Less serious side effects may include:

• 
  

  constipation, diarrhea;

  
  


• 
  

  nausea, vomiting, heartburn;

  
  


• 
  

  stomach pain, upset stomach;

  
  


• 
  

  black or dark-colored stools or urine;

  
  


• 
  

  temporary staining of the teeth;

  
  


• 
  

  headache; or

  
  


• 
  

  unusual or unpleasant taste in your mouth.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Contrin (multivitamin with iron)?

Vitamin and mineral supplements can interact with certain medications, or affect how medications work in your body. Before taking multivitamin with iron, tell your doctor if you also use:

• 
  

  acetohydroxamic acid (Lithostat);

  
  


• 
  

  cimetidine (Tagamet);

  
  


• 
  

  deferoxamine (Desferal);

  
  


• 
  

  etidronate (Didronel);

  
  


• 
  

  diuretics (water pills);

  
  


• 
  

  heart or blood pressure medications;

  
  


• 
  

  tretinoin (Vesanoid);

  
  


• 
  

  isotretinoin (Accutane, Amnesteen, Clavaris, Sotret);

  
  


• 
  

  dimercaprol (an injection used to treat poisoning by arsenic, lead, or mercury);

  
  


• 
  

  penicillamine (Cuprimine);

  
  


• 
  

  pancrelipase (Cotazym, Creon, Ilozyme, Pancrease, Ultrase);

  
  


• 
  

  trimethoprim and sulfamethoxazole (Cotrim, Bactrim, Septra, TMP/SMX); or

  
  


• 
  

  an NSAID (non-steroidal anti-inflammatory drug) such as ibuprofen (Motrin, Advil), naproxen (Aleve, Naprosyn), diclofenac (Cataflam, Voltaren), etodolac (Lodine), indomethacin (Indocin), ketoprofen (Orudis), and others.

  
  

This list is not complete and there may be other medications that can interact with or be affected by multivitamin with iron. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

More Contrin resources

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

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Compare Contrin with other medications

• Anemia
• Vitamin/Mineral Supplementation and Deficiency

Where can I get more information?

• Your pharmacist can provide more information about multivitamin with iron.

See also: Contrin side effects (in more detail)

Eryc

erythromycin

Dosage Form: Delayed-Release Capsules, USP

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Eryc® and other antibacterial drugs, Eryc should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

Eryc Description

Eryc capsules contain enteric-coated pellets of erythromycin base for oral administration. Each Eryc capsule contains 250 mg of erythromycin base. Also contains: lactose NF, povidone USP, FD&C Yellow #6 and other ingredients. The capsule shell contains gelatin NF, titanium dioxide USP, FD&C Yellow #6.

Erythromycin is produced by a strain of Saccharopolyspora erythraea (formerly Streptomyces erythraeus) and belongs to the macrolide group of antibiotics. It is basic and readily forms salts with acids but it is the base which is microbiologically active. Erythromycin base is (3R *, 4S *, 5S *, 6R *, 7R *, 9R *, 11R *, 12R *, 13S *, 14R *)-4-[(2,6-Dideoxy-3-C-methyl- 3 - O - methyl - α - L - ribo - hexopyranosyl)oxy] - 14 - ethyl - 7,12,13 - trihydroxy - 3,5,7,9,11,13 - hexamethyl - 6 - [[3,4,6 - trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-oxacyclo-tetradecane-2,10-dione.

ERYTHROMYCIN

Eryc - Clinical Pharmacology

Orally administered erythromycin base and its salts are readily absorbed in the microbiologically active form. Interindividual variations in the absorption of erythromycin are, however, observed, and some patients do not achieve acceptable serum levels. Erythromycin is largely bound to plasma proteins, and the freely dissociating bound fraction after administration of erythromycin base represents 90% of the total erythromycin absorbed. After absorption, erythromycin diffuses readily into most body fluids. In the absence of meningeal inflammation, low concentrations are normally achieved in the spinal fluid, but the passage of the drug across the blood-brain barrier increases in meningitis. The drug is excreted in human milk. The drug crosses the placental barrier, but fetal plasma levels are low. Erythromycin is not removed by peritoneal dialysis or hemodialysis.

In the presence of normal hepatic function erythromycin is concentrated in the liver and is excreted in the bile; the effect of hepatic dysfunction on biliary excretion of erythromycin is not known. After oral administration, less than 5% of the administered dose can be recovered in the active form in the urine.

The enteric coating of pellets in Eryc capsules protects the erythromycin base from inactivation by gastric acidity. Because of their small size and enteric coating, the pellets readily pass intact from the stomach to the small intestine and dissolve efficiently to allow absorption of erythromycin in a uniform manner. After administration of a single dose of a 250 mg Eryc capsules, peak serum levels in the range of 1.13 to 1.68 mcg/mL are attained in approximately 3 hours and decline to 0.30-0.42 mcg/mL in 6 hours. Optimal conditions for stability in the presence of gastric secretion and for complete absorption are attained when Erythromycin is taken on an empty stomach.

Microbiology: Erythromycin acts by inhibition of protein synthesis by binding 50 S ribosomal subunits of susceptible organisms. It does not affect nucleic acid synthesis. Antagonism has been demonstrated in vitro between erythromycin and clindamycin, lincomycin, and chloramphenicol.

Many strains of Haemophilus influenzae are resistant to erythromycin alone but are susceptible to erythromycin and sulfonamides used concomitantly.

Staphylococci resistant to erythromycin may emerge during a course of therapy.

Erythromycin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the  INDICATIONS AND USAGE section.

Gram-positive Organisms:

Corynebacterium diphtheriae

Corynebacterium minutissimum

Listeria monocytogenes

Staphylococcus aureus (resistant organisms may

emerge during treatment.)

Streptococcus pneumoniae

Streptococcus pyogenes

Gram-negative Organisms:

Bordetella pertussis

Haemophilus influenzae

Legionella pneumophila

Neisseria gonorrhoeae

Other Microorganisms:

Chlamydia trachomatis

Entamoeba histolytica

Mycoplasma pneumoniae

Treponema pallidum

Ureaplasma urealyticum

Susceptibility Tests:

Dilution techniques:

Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MIC’s). These MIC’s provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MIC’s should be determined using a standardized procedure. Standardized procedures are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of erythromycin powder. The MIC values should be interpreted according to the following criteria:

MIC (μg/mL)	Interpretation
≤0.5	Susceptible (S)
1-4	Intermediate (I)
≥8	Resistant (R)

 

A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard erythromycin powder should provide the following MIC values:

Microorganism	MIC (μg/mL)
S. aureus ATCC 29213	0.12-0.5

 

Diffusion techniques:

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 15-μg erythromycin to test the susceptibility of microorganisms to erythromycin.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 15-μg erythromycin disk should be interpreted according to the following criteria:

Zone diameter (mm)	Interpretation
≤23	Susceptible (S)
14-22	Intermediate (I)
≥13	Resistant (R)

 

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for erythromycin.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 15-μg erythromycin disk should provide the following zone diameters in these laboratory test quality control strains:

Microorganism	Zone Diameter (mm)
S. aureus ATCC 25923	22-30

 

Indications and Usage for Eryc

Erythromycin is indicated in the treatment of infections caused by susceptible strains of the designated organisms in the diseases listed below:

Upper respiratory tract infections of mild to moderate degree caused by Streptococcus pyogenes, Streptococcus pneumoniae, or Haemophilus influenzae (when used concomitantly with adequate doses of sulfonamides, since many strains of H. influenzae are not susceptible to the erythromycin concentrations ordinarily achieved). (See appropriate sulfonamide labeling for prescribing information).

Lower respiratory tract infections of mild to moderate severity caused by Streptococcus pneumoniae or Streptococcus pyogenes.

Listeriosis caused by Listeria monocytogenes.

Pertussis (whooping cough) caused by Bordetella pertussis. Erythromycin is effective in eliminating the organism from the nasopharynx of infected individuals rendering them noninfectious. Some clinical studies suggest that erythromycin may be helpful in the pro-phylaxis of pertussis in exposed susceptible individuals. Respiratory tract infections due to Mycoplasma pneumoniae.

Skin and skin structure infections of mild to moderate severity caused by Streptococcus pyogenes or Staphylococcus aureus (resistant staphylococci may emerge during treatment).

Diphtheria: Infections due to Corynebacterium diphtheriae, as an adjunct to antitoxin, to prevent establishment of carriers and to eradicate the organism in carriers.

Erythrasma: In the treatment of infections due to Corynebacterium minutissimum.

Syphilis caused by Treponema pallidum: Erythromycin is an alternate choice of treatment for primary syphilis in penicillin-allergic patients. In primary syphilis, spinal fluid examinations should be done before treatment and as part of follow-up after therapy.

Intestinal amebiasis caused by Entamoeba histolytica (oral erythromycins only). Extraenteric amebiasis requires treatment with other agents.

Acute pelvic inflammatory disease caused by Neisseria gonorrhoeae: Erythromycin lactobionate for injection, USP followed by erythromycin base orally, as an alternative drug in treatment of acute pelvic inflammatory disease caused by N. gonorrhoeae in female patients with a history of sensitivity to penicillin. Patients should have a serologic test for syphilis before receiving erythromycin as treatment of gonorrhea and a follow-up serologic test for syphilis after 3 months.

Erythromycins are indicated for the treatment of the following infections caused by Chlamydia trachomatis: conjunctivitis of the newborn, pneumonia of infancy, and urogenital infections during pregnancy. When tetracyclines are contraindicated or not tolerated, erythromycin is indicated for the treatment of uncomplicated urethral, endocervical, or rectal infections in adults due to Chlamydia trachomatis.

When tetracyclines are contraindicated or not tolerated, erythromycin is indicated for the treatment of nongono-coccal urethritis caused by Ureaplasma urealyticum.

Legionnaires’ Disease caused by Legionella pneumophila. Although no controlled clinical efficacy studies have been conducted, in vitro and limited preliminary clinical data suggest that erythromycin may be effective in treating Legionnaires’ Disease.

Prophylaxis:

Prevention of Initial Attacks of Rheumatic Fever: Penicillin is considered by the American Heart Association to be the drug of choice in the prevention of initial attacks of rheumatic fever (treatment of Streptococcus pyogenes infections of the upper respiratory tract, e.g., tonsillitis or pharyngitis). Erythromycin is indicated for the treatment of penicillin-allergic patients.3 The therapeutic dose should be administered for ten days.

Prevention of Recurrent Attacks of Rheumatic Fever: Penicillin or sulfonamides are considered by the American Heart Association to be the drugs of choice in the prevention of recurrent attacks of rheumatic fever. In patients who are allergic to penicillin and sulfonamides, oral erythromycin is recommended by the American Heart Association in the long-term prophylaxis of streptococcal pharyngitis (for the prevention of recurrent attacks of rheumatic fever).3

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Eryc and other antibacterial drugs, Eryc should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Contraindications

Erythromycin is contraindicated in patients with known hypersensitivity to this antibiotic.

Erythromycin is contraindicated in patients taking terfenadine or astemizole. (SeePRECAUTIONS, Drug interactions).

Warnings

There have been reports of prolonged QT syndrome in geriatric patients receiving oral erythromycin products.

There have been reports of hepatic dysfunction, with or without jaundice, occurring in patients receiving oral erythromycin products.

There have been reports suggesting that erythromycin does not reach the fetus in adequate concentration to prevent congenital syphilis. Infants born to women treated during pregnancy with oral erythromycin for early syphilis should be treated with an appropriate penicillin regimen.

Rhabdomyolysis with or without renal impairment has been reported in seriously ill patients receiving erythromycin concomitantly with lovastatin. Therefore, patients receiving concomitant lovastatin and erythromycin should be carefully monitored for creatine kinase (CK) and serum transaminase levels. (See package insert for lovastatin.)

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Eryc®Capsules, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Precautions

General

Prescribing Eryc in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Since erythromycin is principally excreted by the liver, caution should be exercised when erythromycin is administered to patients with impaired hepatic function. (See CLINICAL PHARMACOLOGY and WARNINGS).

There have been reports that erythromycin may aggravate the weakness of patients with myasthenia gravis.

Prolonged or repeated use of erythromycin may result in an overgrowth of nonsusceptible bacteria or fungi. If superinfection occurs, erythromycin should be discontinued and appropriate therapy instituted.

When indicated, incision and drainage or other surgical procedures should be performed in conjunction with antibiotic therapy.

Information for patients

Patients should be counseled that antibacterial drugs including Eryc should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Eryc is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Eryc or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

Interactions

Drug interactions

Erythromycin has been reported to significantly alter the metabolism of the nonsedating anti-histamines terfenadine and astemizole when taken concomitantly. Rare cases of serious cardiovascular adverse events, including electrocardiographic QT/QTc interval prolongation, cardiac arrest, torsades de pointes, and other ventricular arrhythmias, have been observed. (See CONTRAINDICATIONS). In addition, deaths have been reported rarely with concomitant administration of terfenadine and erythromycin.

There have been postmarketing reports of drug interactions when erythromycin is coadministered with cisapride, resulting in cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes) most likely due to the inhibition of hepatic metabolism of cisapride by erythromycin.

There has been an isolated report of drug interaction occurring with the concomitant administration of erythromycin and quinidine in their usual oral forms, resulting in QT prolongation, torsades de pointes and cardiac arrest. Caution and close monitoring is recommended when the drugs are administered concomitantly.

Erythromycin use in patients who are receiving high doses of theophylline may be associated with an increase of serum theophylline levels and potential theophylline toxicity. In case of theophylline toxicity and/or elevated serum theophylline levels, the dose of theophylline should be reduced while the patient is receiving concomitant erythromycin therapy.

Concomitant administration of erythromycin and digoxin has been reported to result in elevated digoxin serum levels.

There have been reports of increased anticoagulant effects when erythromycin and oral anticoagulants were used concomitantly. Increased anticoagulation effects due to this drug may be more pronounced in the elderly.

Concurrent use of erythromycin and ergotamine or dihydroergotamine has been associated in some patients with acute ergot toxicity characterized by severe peripheral vasospasm and dysethesia.

Erythromycin has been reported to decrease the clearance of triazolam and midazolam and, thus, may increase the pharmacologic effect of these benzodiazepines.

The use of erythromycin in patients concurrently taking drugs metabolized by the cytochrome P450 system may be associated with elevations in serum levels of these other drugs. There have been reports of interactions of erythromycin with carbamazepine, cyclosporine, hexobarbital, phenytoin, alfentanil, disopyramide, lovastatin, bromocriptine, valproate, terfenadine and astemizole. Serum concentrations of drugs metabolized by the cytochrome P450 system should be monitored closely in patients concurrently receiving erythromycin.

Drug/laboratory test interactions

Erythromycin interferes with the fluorometric determination of urinary catecholamines.

Carcinogenesis, mutagenesis, impairment of fertility

Long-term (2-year) oral studies conducted in rats with erythromycin base did not provide evidence of tumorigenicity. Mutagenicity studies have not been conducted. There was no apparent effect on male or female fertility in rats fed erythromycin (base) at levels up to 0.25 percent of diet.

Pregnancy

Pregnancy Category B Teratogenic effects

There was no evidence of teratogenicity or any other adverse effect on reproduction in female rats fed ery-thromycin base (up to 0.25 percent of diet) prior to and during mating, during gestation, and through weaning of two successive litters. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Labor and delivery

The effect of erythromycin on labor and delivery is unknown.

Nursing mothers

Erythromycin is excreted in human milk. Caution should be exercised when erythromycin is administered to a nursing woman.

Pediatric use

See INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION.

Geriatric use

Clinical studies with Eryc did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of the decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

See WARNINGS with regard to prolongation of QT syndrome in geriatric patients with erythromycin products.

Elderly patients may experience increased effects of oral anticoagulant therapy while undergoing treatment with erythromycin. (See PRECAUTIONS, Drug interactions).

Eryc 250 mg capsules do not contain sodium.

Adverse Reactions

The most frequent side effects of oral erythromycin preparations are gastrointestinal and are dose-related. They include nausea, vomiting, abdominal pain, diarrhea and anorexia. Onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment. (See WARNINGS). Symptoms of hepatic dysfunction and/or abnormal liver function test results may occur (see WARNINGS).

Rarely, erythromycin has been associated with the production of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, in individuals with prolonged QTc intervals.

Allergic reactions ranging from urticaria to anaphylaxis have occurred. Skin reactions ranging from mild eruptions to erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported rarely.

Overdosage

In case of overdosage, erythromycin should be discontinued. Overdosage should be handled with the prompt elimination of unabsorbed drug and all other appropriate measures.

Erythromycin is not removed by peritoneal dialysis or hemodialysis.

Eryc Dosage and Administration

Erythromycin is well absorbed and may be given without regard to meals. Optimum blood levels are obtained in a fasting state (administration at least one half hour and preferably two hours before or after a meal); however, blood levels obtained upon administration of enteric-coated erythromycin products in the presence of food are still above minimal inhibitory concentrations (MICs) of most organisms for which erythromycin is indicated.

ADULTS: The usual dose is 250 mg every 6 hours taken one hour before meals. If twice-a-day dosage is desired, the recommended dose is 500 mg every 12 hours. Dosage may be increased up to 4 grams per day, according to the severity of the infection. Twice-a-day dosing is not recommended when doses larger than 1 gram daily are administered.

CHILDREN: Age, weight, and severity of the infection are important factors in determining the proper dosage. The usual dosage is 30 to 50 mg/kg/day in divided doses. For the treatment of more severe infections, this dose may be doubled.

Streptococcal infections: A therapeutic dosage of oral erythromycin should be administered for at least 10 days. For continuous prophylaxis against recurrences of streptococcal infections in persons with a history of rheumatic heart disease, the dose is 250 mg twice a day.

Primary syphilis: 30-40 grams given in divided doses over a period of 10-15 days.

Intestinal amebiasis: 250 mg four times daily for 10 to 14 days for adults; 30 to 50 mg/kg/day in divided doses for 10 to 14 days for children.

Legionnaires’ disease:Although optimal doses have not been established, doses utilized in reported clinical data were those recommended above (1 to 4 grams daily in divided doses).

Urogenital infections during pregnancy due to Chlamydia trachomatis: Although the optimal dose and duration of therapy have not been established, the suggested treatment is erythromycin 500 mg, by mouth, 4 times a day on an empty stomach for at least 7 days. For women who cannot tolerate this regimen, a decreased dose of 250 mg, by mouth, 4 times a day should be used for at least 14 days.

For adults with uncomplicated urethral, endocervical, or rectal infections caused by Chlamydia trachomatis in whom tetracyclines are contraindicated or not tolerated: 500 mg, by mouth, 4 times a day for at least 7 days.

Pertussis: Although optimum dosage and duration of therapy have not been established, doses of erythromycin utilized in reported clinical studies were 40-50 mg/kg/day, given in divided doses for 5 to 14 days.

Nongonococcal urethritis due to Ureaplasma urealyticum: When tetracycline is contraindicated or not tolerated: 500 mg of erythromycin, orally, four times daily for at least 7 days.

Acute pelvic inflammatory disease due to N gonorrhoeae: 500 mg IV of erythromycin lactobionate for injection, USP every 6 hours for 3 days followed by 250 mg of erythromycin, orally every six hours for 7 days.

How is Eryc Supplied

Each clear and orange opaque capsule imprinted Eryc WC 696 contains 250 mg erythromycin as enteric-coated pellets. The pellets are colored white and orange. Capsules are supplied in bulk containers of 75,000 (NDC 50546-300-01).

STORAGE CONDITIONS

Store at controlled room temperature 15°C to 30°C (59°F to 86°F).

REFERENCES

1. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically — Third Edition. Approved Standard NCCLS Document M7-A3, Vol. 13, No. 25, NCCLS, Villanova, PA, December 1993.

2. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests — Fifth Edition. Approved Standard NCCLS Document M2-A5, Vol. 13, No. 24, NCCLS, Villanova, PA, December 1993.

3. Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young, The American Heart Association: Prevention of Rheumatic Fever. Special Report Circulation 78 (4): 1082-1086, October 1988.

RX Only

Manufactured by:

Mayne Pharma International Pty Ltd

1538 Main North Road

Salisbury South, SA 5106

South Australia

Marketed by:

Warner Chilcott (US), Inc.

100 Enterprise Drive

Rockaway, NJ 07866 USA

Revised - March 2007

443263/6

Eryc  erythromycin  capsule, delayed release pellets

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 50546-300 Route of Administration ORAL DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength erythromycin (erythromycin) Active 250 MILLIGRAM  In 1 CAPSULE FD&C Yellow #6 Inactive   lactose Inactive   other ingredients Inactive   povidone Inactive

Product Characteristics Color ORANGE (ORANGE) Score no score Shape CAPSULE (CAPSULE) Size 22mm Flavor Imprint Code Eryc;WC;696 Contains          Coating false Symbol false

Packaging # NDC Package Description Multilevel Packaging 1 50546-300-01 75000 CAPSULE In 1 CONTAINER None

Revised: 04/2007Warner Chilcott (US), Inc.

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• Eryc Side Effects (in more detail)
• Eryc Dosage
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• Drug Images
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• Eryc Support Group
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• Bacterial Endocarditis Prevention
• Bartonellosis
• Bowel Preparation
• Bronchitis
• Bullous Pemphigoid
• Campylobacter Gastroenteritis
• Chancroid
• Chlamydia Infection
• Dental Abscess
• Legionella Pneumonia
• Lyme Disease
• Lymphogranuloma Venereum
• Mycoplasma Pneumonia
• Nongonococcal Urethritis
• Ocular Rosacea
• Otitis Media
• Pemphigoid
• Pertussis
• Pharyngitis
• Pneumonia
• Rheumatic Fever Prophylaxis
• Skin Infection
• Strep Throat
• Syphilis, Early
• Upper Respiratory Tract Infection

Topiramate 100mg Film-Coated Tablets

1. Name Of The Medicinal Product

Topiramate 100mg Film-Coated Tablets

2. Qualitative And Quantitative Composition

Each tablet contains 100mg of Topiramate.

Excipient: Also contains 0.53mg soya lecithin (E322).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-Coated Tablets

Topiramate 100mg Film-Coated Tablets are yellow, round, biconvex tablets with 10mm diameter and engraved with the marking “V4”.

4. Clinical Particulars

4.1 Therapeutic Indications

Monotherapy in adults, adolescents and children over 6 years of age with partial seizures with or without secondary generalised seizures, and primary generalised tonic-clonic seizures.

Adjunctive therapy in children aged 2 years and above, adolescents and adults with partial onset seizures with or without secondary generalization or primary generalized tonic-clonic seizures and for the treatment of seizures associated with Lennox-Gastaut syndrome.

Topiramate is indicated in adults for the prophylaxis of migraine headache after careful evaluation of possible alternative treatment options. Topiramate is not intended for acute treatment.

4.2 Posology And Method Of Administration

General

It is recommended that therapy be initiated at a low dose followed by titration to an effective dose. Dose and titration rate should be guided by clinical response.

Topiramate is available in film-coated tablets and it is recommended that the film-coated tablets not be broken.

It is not necessary to monitor topiramate plasma concentrations to optimize therapy with topiramate. On rare occasions, the addition of topiramate to phenytoin may require an adjustment of the dose of phenytoin to achieve optimal clinical outcome. Addition or withdrawal of phenytoin and carbamazepine to adjunctive therapy with topiramate may require adjustment of the dose of topiramate.

Topiramate can be taken without regard to meals.

In patients with or without a history of seizures or epilepsy, antiepileptic drugs including topiramate should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency. In clinical trials, daily dosages were decreased in weekly intervals by 50-100 mg in adults with epilepsy and by 25-50 mg in adults receiving topiramate at doses up to 100 mg/day for migraine prophylaxis. In paediatric clinical trials, topiramate was gradually withdrawn over a 2-8 week period.

Monotherapy epilepsy

General

When concomitant antiepileptic drugs (AEDs) are withdrawn to achieve monotherapy with topiramate, consideration should be given to the effects this may have on seizure control. Unless safety concerns require an abrupt withdrawal of the concomitant AED, a gradual discontinuation at the rate of approximately one-third of the concomitant AED dose every 2 weeks is recommended.

When enzyme inducing medicinal products are withdrawn, topiramate levels will increase. A decrease in topiramate dosage may be required if clinically indicated.

Adults

Dose and titration should be guided by clinical response. Titration should begin at 25 mg nightly for 1 week. The dosage should then be increased at 1- or 2-week intervals by increments of 25 or 50 mg/day, administered in two divided doses. If the patient is unable to tolerate the titration regimen, smaller increments or longer intervals between increments can be used.

The recommended initial target dose for topiramate monotherapy in adults is 100 mg/day to 200 mg/day in 2 divided doses. The maximum recommended daily dose is 500 mg/day in 2 divided doses. Some patients with refractory forms of epilepsy have tolerated topiramate monotherapy at doses of 1,000 mg/day. These dosing recommendations apply to all adults including the elderly in the absence of underlying renal disease.

Paediatric population (children over 6 years of age)

Dose and titration rate in children should be guided by clinical outcome. Treatment of children over 6 years of age should begin at 0.5 to 1 mg/kg nightly for the first week. The dosage should then be increased at 1 or 2 week intervals by increments of 0.5 to 1 mg/kg/day, administered in two divided doses. If the child is unable to tolerate the titration regimen, smaller increments or longer intervals between dose increments can be used.

The recommended initial target dose range for topiramate monotherapy in children over 6 years of age is 100 mg/day depending on clinical response, (this is about 2.0 mg/kg/day in children 6-16 years).

Adjunctive therapy epilepsy (partial onset seizures with or without secondary generalization, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome)

Adults

Therapy should begin at 25-50 mg nightly for one week. Use of lower initial doses has been reported, but has not been studied systematically. Subsequently, at weekly or bi-weekly intervals, the dose should be increased by 25-50 mg/day and taken in two divided doses. Some patients may achieve efficacy with once-a-day dosing.

In clinical trials as adjunctive therapy, 200 mg was the lowest effective dose. The usual daily dose is 200-400 mg in two divided doses.

These dosing recommendations apply to all adults, including the elderly, in the absence of underlying renal disease (see section 4.4).

Paediatric population (children aged 2 years and above)

The recommended total daily dose of topiramate as adjunctive therapy is approximately 5 to 9 mg/kg/day in two divided doses. Titration should begin at 25 mg (or less, based on a range of 1 to 3 mg/kg/day) nightly for the first week. The dosage should then be increased at 1- or 2-week intervals by increments of 1 to 3 mg/kg/day (administered in two divided doses), to achieve optimal clinical response.

Daily doses up to 30 mg/kg/day have been studied and were generally well tolerated.

Migraine

Adults

The recommended total daily dose of topiramate for prophylaxis of migraine headache is 100 mg/day administered in two divided doses. Titration should begin at 25 mg nightly for 1 week. The dosage should then be increased in increments of 25 mg/day administered at 1-week intervals. If the patient is unable to tolerate the titration regimen, longer intervals between dose adjustments can be used.

Some patients may experience a benefit at a total daily dose of 50 mg/day. Patients have received a total daily dose up to 200 mg/day. This dose may be benefit in some patients, nevertheless, caution is advised due to an increase incidence of side effects

Paediatric population

Topiramate is not recommended for treatment or prevention of migraine in children due to insufficient data on safety and efficacy.

General dosing recommendations for topiramate in special patient populations

Renal impairment

In patients with impaired renal function (CL_CR

In patients with end-stage renal failure, since topiramate is removed from plasma by haemodialysis, a supplemental dose of topiramate equal to approximately one-half the daily dose should be administered on haemodialysis days. The supplemental dose should be administered in divided doses at the beginning and completion of the haemodialysis procedure. The supplemental dose may differ based on the characteristics of the dialysis equipment being used.

Hepatic impairment

In patients with moderate to severe hepatic impairment topiramate should be administered with caution as the clearance of topiramate is decreased.

Elderly

No dose adjustment is required in the elderly population providing renal function is intact.

4.3 Contraindications

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

Migraine prophylaxis in pregnancy and in women of childbearing potential if not using effective methods of contraception

4.4 Special Warnings And Precautions For Use

In situations where rapid withdrawal of topiramate is medically required, appropriate monitoring is recommended (see section 4.2 for further details).

As with other anti-epileptic drugs, some patients may experience an increase in seizure frequency or the onset of new types of seizures with topiramate. These phenomena may be the consequence of an overdose, a decrease in plasma concentrations of concomitantly used anti-epileptics, progress of the disease, or a paradoxical effect.

Adequate hydration while using topiramate is very important. Hydration can reduce the risk of nephrolithiasis (see below). Proper hydration prior to and during activities such as exercise or exposure to warm temperatures may reduce the risk of heat-related adverse reactions (see section 4.8).

Oligohydrosis (decreased sweating) has been reported in association with the use of topiramate. Decreased sweating and rise in body temperature may occur especially in young children exposed to high ambient temperature.

Mood disturbances/depression

An increased incidence of mood disturbances and depression has been observed during topiramate treatment.

Suicide/suicide ideation

Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo-controlled trials of anti-epileptic drugs has shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for topiramate.

In double blind clinical trials, suicide related events (SREs) (suicidal ideation, suicide attempts and suicide) occurred at a frequency of 0.5 % in topiramate treated patients (46 out of 8,652 patients treated) and at a nearly 3 fold higher incidence than those treated with placebo (0.2 %; 8 out of 4,045 patients treated).

Patients therefore should be monitored for signs of suicidal ideation and behaviour and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

Nephrolithiasis

Some patients, especially those with a predisposition to nephrolithiasis, may be at increased risk for renal stone formation and associated signs and symptoms such as renal colic, renal pain or flank pain.

Risk factors for nephrolithiasis include prior stone formation, a family history of nephrolithiasis and hypercalciuria. None of these risk factors can reliably predict stone formation during topiramate treatment. In addition, patients taking other medicinal products associated with nephrolithiasis may be at increased risk.

Decreased hepatic function

In hepatically-impaired patients, topiramate should be administered with caution as the clearance of topiramate may be decreased.

Acute myopia and secondary angle closure glaucoma

A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving topiramate. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber shallowing, ocular hyperaemia (redness) and increased intraocular pressure. Mydriasis may or may not be present. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating topiramate therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in paediatric patients as well as adults. Treatment includes discontinuation of topiramate, as rapidly as possible in the judgment of the treating physician, and appropriate measures to reduce intraocular pressure. These measures generally result in a decrease in intraocular pressure.

Elevated intraocular pressure of any aetiology, if left untreated, can lead to serious sequelae including permanent vision loss.

A determination should be made whether patients with history of eye disorders should be treated with topiramate.

Metabolic acidosis

Hyperchloremic, non-anion gap, metabolic acidosis (i.e. decreased serum bicarbonate below the normal reference range in the absence of respiratory alkalosis) is associated with topiramate treatment. Depending on underlying conditions, appropriate evaluation including measurement of serum bicarbonate levels is recommended with topiramate therapy. If signs or symptoms are present (e.g. Kussmaul's deep breathing, dyspnoea, anorexia, nausea, vomiting, excessive tiredness, tachycardia or arrhythmia), indicative of metabolic acidosis, measurement of serum bicarbonate is recommended. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing topiramate (using dose tapering).

This decrease in serum bicarbonate is due to the inhibitory effect of topiramate on renal carbonic anhydrase. Generally, the decrease in bicarbonate occurs early in treatment although it can occur at any time during treatment. These decreases are usually mild to moderate (average decrease of 4 mmol/l at doses of 100 mg/day or above in adults and at approximately 6 mg/kg/day in paediatric patients). Rarely, patients have experienced decreases to values below 10 mmol/l. Conditions or therapies that predispose to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhoea, surgery, ketogenic diet, or certain medicinal products) may be additive to the bicarbonate lowering effects of topiramate.

Chronic metabolic acidosis increases the risk of renal stone formation and may potentially lead to osteopenia.

Chronic metabolic acidosis in paediatric patients can reduce growth rates. The effect of topiramate on bone-related sequelae has not been systematically investigated in paediatric or adult populations.

Depending on underlying conditions, appropriate evaluation including serum bicarbonate levels is recommended with topiramate therapy. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing topiramate (using dose tapering).

Topiramate should be used with caution in patients with conditions or treatments that represent a risk factor for the appearance of metabolic acidosis.

Nutritional supplementation

Some patients may experience weight loss whilst on treatment with topiramate. It is recommended that patients on topiramate treatment should be monitored for weight loss. A dietary supplement or increased food intake may be considered if the patient is losing weight while on topiramate.

Lecithin

Topiramate 50 mg, 100 mg and 200 mg film-coated tablets contain lecithin (contains soya oil). Patients that are allergic to peanuts or soya should not use this medicinal product.

Impairment of cognitive function

Cognitive impairment in epilepsy is multifactorial and may be due to the underlying aetiology, due to the epilepsy or due to the anti epileptic treatment.

There have been reports in the literature of impairment of cognitive function in adults on topiramate therapy which required reduction in dosage or discontinuation of treatment. However, studies regarding cognitive outcomes in children treated with topiramate are insufficient and its effect in this regard still needs to be elucidated.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Effects of topiramate on other antiepileptic medicinal products

The addition of topiramate to other antiepileptic drugs (phenytoin, carbamazepine, valproic acid, phenobarbital, primidone) has no effect on their steady-state plasma concentrations, except in the occasional patient, where the addition of topiramate to phenytoin may result in an increase of plasma concentrations of phenytoin. This is possibly due to inhibition of a specific enzyme polymorphic isoform (CYP2C19). Consequently, any patient on phenytoin showing clinical signs or symptoms of toxicity should have phenytoin levels monitored.

A pharmacokinetic interaction study of patients with epilepsy indicated the addition of topiramate to lamotrigine had no effect on steady state plasma concentration of lamotrigine at topiramate doses of 100 to 400 mg/day. In addition, there was no change in steady state plasma concentration of topiramate during or after removal of lamotrigine treatment (mean dose of 327 mg/day).

Topiramate inhibits the enzyme CYP 2C19 and may interfere with other substances metabolized via this enzyme (e.g., diazepam, imipramin, moclobemide, proguanil, omeprazol).

Effects of other antiepileptic medicinal products on topiramate

Phenytoin and carbamazepine decrease the plasma concentration of topimarate. The addition or withdrawal of phenytoin or carbamazepine to topiramate therapy may require an adjustment in dosage of the latter. This should be done by titrating to clinical effect. The addition or withdrawal of valproic acid does not produce clinically significant changes in plasma concentrations of topiramate and, therefore, does not warrant dosage adjustment of topiramate. The results of these interactions are summarized below:

AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	↔**
Carbamazepine (CBZ)	↔
Valproic acid	↔	↔
Lamotrigine	↔	↔
Phenobarbital	↔	NS
Primidone	↔	NS
↔ = No effect on plasma concentration ( ** = Plasma concentrations increase in individual patients NS = Not studied AED = antiepileptic drug

Other medicinal product interactions

Digoxin

In a single-dose study, serum digoxin area under plasma concentration curve (AUC) decreased 12 % due to concomitant administration of topiramate. The clinical relevance of this observation has not been established. When topiramate is added or withdrawn in patients on digoxin therapy, careful attention should be given to the routine monitoring of serum digoxin.

CNS depressants

Concomitant administration of topiramate and alcohol or other CNS depressant medicinal products has not been evaluated in clinical studies. It is recommended that topiramate not be used concomitantly with alcohol or other CNS depressant medicinal products.

St John's Wort (Hypericum perforatum)

A risk of decreased plasma concentrations resulting in a loss of efficacy could be observed with co-administration of topiramate and St John's Wort. There have been no clinical studies evaluating this potential interaction.

Oral contraceptives

In a pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 μg ethinyl estradiol (EE), topiramate given in the absence of other medications at doses of 50 to 200 mg/day was not associated with statistically significant changes in mean exposure (AUC) to either component of the oral contraceptive. In another study, exposure to EE was statistically significantly decreased at doses of 200, 400, and 800 mg/day (18 %, 21 %, and 30 %, respectively) when given as adjunctive therapy in epilepsy patients taking valproic acid. In both studies, topiramate (50-200 mg/day in healthy volunteers and 200-800 mg/day in epilepsy patients) did not significantly affect exposure to NET. Although there was a dose dependent decrease in EE exposure for doses between 200-800 mg/day (in epilepsy patients), there was no significant dose dependent change in EE exposure for doses of 50-200 mg/day (in healthy volunteers). The clinical significance of the changes observed is not known. The possibility of decreased contraceptive efficacy and increased breakthrough bleeding should be considered in patients taking combination oral contraceptive products with topiramate. Patients taking estrogen containing contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding.

Lithium

In healthy volunteers, there was an observed reduction (18 % for AUC) in systemic exposure for lithium during concomitant administration with topiramate 200 mg/day. In patients with bipolar disorder, the pharmacokinetics of lithium were unaffected during treatment with topiramate at doses of 200 mg/day; however, there was an observed increase in systemic exposure (26 % for AUC) following topiramate doses of up to 600 mg/day. Lithium levels should be monitored when co-administered with topiramate.

Risperidone

Drug-drug interaction studies conducted under single dose conditions in healthy volunteers and multiple dose conditions in patients with bipolar disorder, yielded similar results. When administered concomitantly with topiramate at escalating doses of 100, 250 and 400 mg/day there was a reduction in risperidone (administered at doses ranging from 1 to 6 mg/day) systemic exposure (16 % and 33 % for steady-state AUC at the 250 and 400 mg/day doses, respectively). However, differences in AUC for the total active moiety between treatment with risperidone alone and combination treatment with topiramate were not statistically significant. Minimal alterations in the pharmacokinetics of the total active moiety (risperidone plus 9-hydroxyrisperidone) and no alterations for 9-hydroxyrisperidone were observed. There were no significant changes in the systemic exposure of the risperidone total active moiety or of topiramate. When topiramate was added to existing risperidone (1-6 mg/day) treatment, adverse events were reported more frequently than prior to topiramate (250-400 mg/day) introduction (90 % and 54 % respectively). The most frequently reported AE's when topiramate was added to risperidone treatment were: somnolence (27 % and 12 %), paraesthesia (22 % and 0 %) and nausea (18 % and 9 % respectively).

Hydrochlorothiazide (HCTZ)

A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of HCTZ (25 mg q24h) and topiramate (96 mg q12h) when administered alone and concomitantly. The results of this study indicate that topiramate C_max increased by 27 % and AUC increased by 29 % when HCTZ was added to topiramate. The clinical significance of this change is unknown. The addition of HCTZ to topiramate therapy may require an adjustment of the topiramate dose. The steady-state pharmacokinetics of HCTZ were not significantly influenced by the concomitant administration of topiramate. Clinical laboratory results indicated decreases in serum potassium after topiramate or HCTZ administration, which were greater when HCTZ and topiramate were administered in combination.

Metformin

A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of metformin and topiramate in plasma when metformin was given alone and when metformin and topiramate were given simultaneously. The results of this study indicated that metformin mean C_max and mean AUC0-12h increased by 18 % and 25 %, respectively, while mean CL/F decreased 20 % when metformin was co-administered with topiramate. Topiramate did not affect metformin tmax. The clinical significance of the effect of topiramate on metformin pharmacokinetics is unclear. Oral plasma clearance of topiramate appears to be reduced when administered with metformin. The extent of change in the clearance is unknown. The clinical significance of the effect of metformin on topiramate pharmacokinetics is unclear.

When topiramate is added or withdrawn in patients on metformin therapy, careful attention should be given to the routine monitoring for adequate control of their diabetic disease state.

Pioglitazone

A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of topiramate and pioglitazone when administered alone and concomitantly. A 15 % decrease in the AUC_max,ss was observed. This finding was not statistically significant. In addition, a 13 % and 16 % decrease in C_max,ss and AUC_max,ss and AUC

Glyburide

A drug-drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state pharmacokinetics of glyburide (5 mg/day) alone and concomitantly with topiramate (150 mg/day). There was a 25 % reduction in glyburide AUC₂₄ during topiramate administration. Systemic exposure of the active metabolites, 4-trans-hydroxy-glyburide (M1) and 3-cis-hydroxyglyburide (M2), were also reduced by 13 % and 15 %, respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide.

When topiramate is added to glyburide therapy or glyburide is added to topiramate therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.

Other forms of interactions

Agents predisposing to nephrolithiasis

Topiramate, when used concomitantly with other agents predisposing to nephrolithiasis, may increase the risk of nephrolithiasis. While using topiramate, agents like these should be avoided since they may create a physiological environment that increases the risk of renal stone formation.

Valproic acid

Concomitant administration of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either medicinal product alone. In most cases, symptoms and signs abated with discontinuation of either medicinal product. This adverse reaction is not due to a pharmacokinetic interaction. An association of hyperammonemia with topiramate monotherapy or concomitant treatment with other anti-epileptics has not been established.

Additional pharmacokinetic drug interaction studies

Clinical studies have been conducted to assess the potential pharmacokinetic drug interaction between topiramate and other agents. The changes in C_max or AUC as a result of the interactions are summarized below. The second column (concomitant drug concentration) describes what happens to the concentration of the concomitant drug listed in the first column when topiramate is added. The third column (topiramate concentration) describes how the coadministration of a drug listed in the first column modifies the concentration of topiramate.

Summary of Results from Additional Clinical Pharmacokinetic Drug Interaction Studies
Concomitant Drug	Concomitant Drug Concentrationa	Topiramate Concentrationa
Amitriptyline	↔ 20 % increase in Cmax and AUC of nortriptyline metabolite	NS
Dihydroergotamine (Oral and Subcutaneous)	↔	↔
Haloperidol	↔ 31 % increase in AUC of the reduced metabolite	NS
Propranolol	↔ 17 % increase in Cmax for 4-OH propranolol (TPM 50 mg q12h)	9 % and 16 % increase in Cmax, 9 % and17 % increase in AUC (40 and 80 mg propranolol q12h respectively)
Sumatriptan (Oral and Subcutaneous)	↔	NS
Pizotifen	↔	↔
Diltiazem	25 % decrease in AUC of diltiazem and 18 % decrease in DEA, and ↔ for DEM*	20 % increase in AUC
Venlafaxine	↔	↔
Flunarizine	16 % increase in AUC (TPM 50 mg q12h)b	↔
a % values are the changes in treatment mean Cmax or AUC with respect to monotherapy ↔ = No effect on Cmax and AUC ( NS = Not studied *DEA = des acetyl diltiazem, DEM = N-demethyl diltiazem b Flunarizine AUC increased 14 % in subjects taking flunarizine alone. Increase in exposure may be attributed to accumulation during achievement of steady state.

4.6 Pregnancy And Lactation

Topiramate was teratogenic in mice, rats and rabbits. In rats, topiramate crosses the placental barrier.

There are no adequate and well-controlled studies with topiramate in pregnant women.

Pregnancy registry data suggest that there may be an association between the use of topiramate during pregnancy and congenital malformations (e.g., craniofacial defects, such as cleft lip/palate, hypospadias, and anomalies involving various body systems). This has been reported with topiramate monotherapy and topiramate as part of a polytherapy regimen. This data should be interpreted with caution, as more data is needed to identify increased risks for malformations.

In addition, data from these registries and other studies suggest that, compared with monotherapy, there may be an increased risk of teratogenic effects associated with the use of anti-epileptic drugs in combination therapy.

It is recommended that women of child bearing potential use adequate contraception.

Animal studies have shown excretion of topiramate in milk. The excretion of topiramate in human milk has not been evaluated in controlled studies. Limited observations in patients suggest an extensive excretion of topiramate into breast milk. Since many medicinal products are excreted into human milk, a decision must be made whether to suspend breast-feeding or to discontinue/ abstain from topiramate therapy taking into account the importance of the medicinal product to the mother (section 4.4).

Indication Epilepsy

During pregnancy, topiramate should be prescribed after fully informing the woman of the known risks of uncontrolled epilepsy to the pregnancy and the potential risks of the medicinal product to the foetus.

Indication Migraine Prophylaxis

Topiramate is contraindicated in pregnancy, and in women of childbearing potential if an effective method of contraception is not used (see section 4.3 and 4.5 Interactions with oral contraceptives).

4.7 Effects On Ability To Drive And Use Machines

Topiramate acts on the central nervous system and may produce drowsiness, dizziness or other related symptoms. It may also cause visual disturbances and/or blurred vision. These adverse reactions could potentially be dangerous in patients driving a vehicle or operating machinery, particularly until such time as the individual patient's experience with the medicinal products established.

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable Effects

The safety of topiramate was evaluated from a clinical trial database consisting of 4,111 patients (3,182 on topiramate and 929 on placebo) who participated in 20 double-blind trials and 2,847 patients who participated in 34 open-label trials, respectively, for topiramate as adjunctive treatment of primary generalized tonic-clonic seizures, partial onset seizures, seizures associated with Lennox-Gastaut syndrome, monotherapy for newly or recently diagnosed epilepsy or migraine prophylaxis. The majority of ADRs were mild to moderate in severity. ADRs identified in clinical trials, and during post-marketing experience (as indicated by “*”) are listed by their incidence in clinical trials in Table 1. Assigned frequencies are as follows:

Very common

Common

Uncommon

Rare

Not known cannot be estimated from the available data

The most common ADRs (those with an incidence of >5 % and greater than that observed in placebo in at least 1 indication in double-blind controlled studies with topiramate) include: anorexia, decreased appetite, bradyphrenia, depression, expressive language disorder, insomnia, coordination abnormal, disturbance in attention, dizziness, dysarthria, dysgeusia, hypoesthesia, lethargy, memory impairment, nystagmus, paresthesia, somnolence, tremor, diplopia, vision blurred, diarrhoea, nausea, fatigue, irritability, and weight decreased.

Paediatric population

ADRs reported more frequently (

• decreased appetite

• increased appetite

• acidosis hyperchloraemic

• hypokalaemia

• abnormal behaviour

• aggression

• apathy

• initial insomnia

• suicidal ideation

• disturbance in attention

• lethargy

• circadian rhythm sleep disorder

• poor quality sleep

• lacrimation increased

• sinus bradycardia

• feeling abnormal

• gait disturbance.

ADRs that were reported in children but not in adults in double-blind controlled studies include:

• eosinophilia

• psychomotor hyperactivity

• vertigo

• vomiting

• hyperthermia

• pyrexia

• learning disability.

Table 1: Topiramate Adverse Drug Reactions
System Organ Class	Very common	Common	Uncommon	Rare	Not known
Investigations	Weight decreased	Weight increased*	Crystal urine present, tandem gait test abnormal, white blood cell count decreased	Blood bicarbonate decreased
Cardiac disorders			Bradycardia, sinus bradycardia, palpitations
Blood and lymphatic system disorders		Anaemia	Leucopenia, thrombocytopenia lymphadenopathy, eosinophilia	Neutropenia*
Nervous system disorders	Paraesthesia, somnolence Dizziness	Disturbance in attention, memory impairment, amnesia, cognitive disorder, mental impairment, psychomotor skills impaired, convulsion, coordination abnormal, tremor, lethargy, hypoaesthesia, nystagmus, dysgeusia, balance disorder, dysarthria, intention tremor, sedation	Depressed level of consciousness, grand mal convulsion, visual field defect, complex partial seizures, speech disorder, psychomotor hyperactivity, syncope, sensory disturbance, drooling, hypersomnia, aphasia, repetitive speech, hypokinesia, dyskinesia, dizziness postural, poor quality sleep, burning sensation, sensory loss, parosmia, cerebellar syndrome, dysaesthesia, hypogeusia, stupor, clumsiness, aura, ageusia, dysgraphia, dysphasia, neuropathy peripheral, presyncope, dystonia, formication	Apraxia, circadian rhythm sleep disorder, hyperaesthesia, hyposmia, anosmia, essential tremor, akinesia, unresponsive to stimuli
Eye disorders		Vision blurred, diplopia, visual disturbance	Visual acuity reduced, scotoma, myopia*, abnormal sensation in eye*, dry eye, photophobia, blepharospasm, lacrimation increased, photopsia, mydriasis, presbyopia	Blindness unilateral, blindness transient, glaucoma, accommodation disorder, altered visual depth perception, scintillating scotoma, eyelid oedema*, night blindness, amblyopia	Angle closure glaucoma*, Maculopathy*, eye movement disorder*
Ear and labyrinth disorders		Vertigo, tinnitus, ear pain	Deafness, deafness unilateral, deafness neurosensory, ear discomfort, hearing impaired
Respiratory, thoracic and mediastinal disorders		Dyspnoea , epistaxis, nasal congestion, rhinorrhoea	Dyspnoea exertional, Paranasal sinus hypersecretion, dysphonia
Gastrointestinal disorders	Nausea, diarrhoea	Vomiting, constipation, abdominal pain upper, dyspepsia, abdominal pain, dry mouth, stomach discomfort, paraesthesia oral, gastritis, abdominal discomfort	Pancreatitis, flatulence, gastrooesophageal reflux disease, abdominal pain lower, hypoaesthesia oral, gingival bleeding, abdominal distension, epigastric discomfort, abdominal tenderness, salivary hypersecretion, oral pain, breath odour, glossodynia
Renal and urinary disorders		Nephrolithiasis, pollakiuria, dysuria	Calculus urinary, urinary incontinence, haematuria, incontinence, micturition urgency, renal colic, renal pain	Calculus ureteric, renal tubular acidosis*
Skin and subcutaneous tissue disorders		Alopecia, rash, pruritus	Anhidrosis, hypoaesthesia facial, urtic