Cabaser 1 mg & 2 mg Tablets

1. Name Of The Medicinal Product

Cabaser® Tablets 1 mg

Cabaser® Tablets 2 mg

2. Qualitative And Quantitative Composition

Cabergoline INN 1 mg, 2 mg,

For excipients, see 6.1

3. Pharmaceutical Form

Tablet

Cabaser 1 mg tablets are white, oval, 3.8 x 7.4mm and concave with one side scored and engraved '7' on the left and '01' on the right

Cabaser 2 mg tablets are white, oval, 5.1 x 10mm and concave with one side scored and engraved '7' on the left and '02' on the right

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of Parkinson's disease

If treatment with a dopamine agonist is being considered, cabergoline is indicated as second line therapy in patients who are intolerant or fail treatment with a non-ergot compound, as monotherapy, or as adjunctive treatment to levodopa plus dopa-decarboxylase inhibitor, in the management of the signs and symptoms of Parkinson's disease.

Treatment should be initiated under specialist supervision. The benefit of continued treatment should be regularly reassessed taking into account the risk of fibrotic reactions and valvulopathy (see sections 4.3, 4.4 & 4.8)

4.2 Posology And Method Of Administration

The tablets are for oral administration.

Since the tolerability of dopaminergic agents is improved when administered with food, it is recommended that Cabaser be taken with meals.

Cabaser is intended for chronic, long term treatment.

Adults and elderly patients

As expected for dopamine agonists, dose response for both efficacy and side effects appears to be linked to individual sensitivity. Optimization of dose should be obtained through slow initial dose titration, from starting doses of 1 mg daily. The dosage of concurrent levodopa may be gradually decreased, while the dosage of Cabaser is increased, until the optimum balance is determined. In view of the long half-life of the compound, increments of the daily dose of 0.5-1 mg should be done at weekly (initial weeks) or bi-weekly intervals, up to optimal doses.

The recommended therapeutic dosage is 2 to 3 mg/day for patients with signs and symptoms of Parkinson's disease. Cabaser should be given as a single daily dose.

Use in children

The safety and efficacy of Cabaser have not been investigated in children as Parkinson's disease does not affect this population.

4.3 Contraindications

Hypersensitivity to Cabaser, any excipient of the product, or any ergot alkaloid.

History of pulmonary, pericardial and retroperitoneal fibrotic disorders.

For long-term treatment: Evidence of cardiac valvulopathy as determined by pre-treatment echocardiography.

(See section 4.4 Special warnings and precautions for use – Fibrosis and cardiac valvulopathy and possibly related clinical phenomena)

4.4 Special Warnings And Precautions For Use

General:

As with other ergot derivatives, Cabaser should be given with caution to patients with severe cardiovascular disease, Raynaud's syndrome, peptic ulcer or gastrointestinal bleeding, or with a history of serious, particularly psychotic, mental disorders.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Hepatic Insufficiency:

Lower doses of Cabaser should be considered in patients with severe hepatic insufficiency. Compared to normal volunteers and those with lesser degrees of hepatic insufficiency, an increase in AUC has been seen in patients with severe hepatic insufficiency (Child-Pugh Class C) who received a single 1 mg dose.

Postural Hypotension:

Postural hypotension can occur following administration of Cabaser, particularly during the first days of administration of Cabaser. Care should be exercised when administering Cabaser concomitantly with other drugs known to lower blood pressure.

Fibrosis and Cardiac Valvulopathy and Possibly Related Clinical Phenomena:

Fibrotic and serosal inflammatory disorders such as pleuritis, pleural effusion, pleural fibrosis, pulmonary fibrosis, pericarditis, pericardial effusion, cardiac valvulopathy involving one or more valves (aortic, mitral and tricuspid) or retroperitoneal fibrosis have occurred after prolonged usage of ergot derivatives with agonist activity at the serotonin 5HT_2B receptor, such as Cabaser. In some cases, symptoms or manifestations of cardiac valvulopathy improved after discontinuation of Cabaser.

Erythrocyte sedimentation rate (ESR) has been found to be abnormally increased in association with pleural effusion/fibrosis. Chest x-ray examination is recommended in cases of unexplained ESR increases to abnormal values.

Serum creatinine measurements can also be used to help in the diagnosis of fibrotic disorder. Following diagnosis of pleural effusion/pulmonary fibrosis or valvulopathy, the discontinuance of Cabaser has been reported to result in improvement of signs and symptoms. (See section 4.3 Contraindications)

Valvulopathy has been associated with cumulative doses, therefore patients should be treated with the lowest effective dose. At each visit, the risk benefit profile of Cabaser treatment for the patient should be reassessed to determine the suitability of continued treatment with Cabaser.

Before initiating long-term treatment:

All patients must undergo a cardiovascular evaluation, including echocardiogram, to assess the potential presence of asymptomatic valvular disease. It is also appropriate to perform baseline investigations of erythrocyte sedimentation rate or other inflammatory markers, lung function/chest x-ray and renal function prior to initiation of therapy. In patients with valvular regurgitation, it is not known whether Cabaser treatment might worsen the underlying disease. If fibrotic valvular disease is detected, the patient should not be treated with Cabaser (See section 4.3 contraindications).

During long-term treatment:

Fibrotic disorders can have an insidious onset and patients should be regularly monitored for possible manifestations of progressive fibrosis. Therefore during treatment, attention should be paid to the signs and symptoms of:

• Pleuro-pulmonary disease such as dyspnoea, shortness of breath, persistent cough, or chest pain.

• Renal insufficiency or ureteral/abdominal vascular obstruction that may occur with pain in the loin/flank, and lower limb oedema, as well as any possible abdominal masses or tenderness that may indicate retroperitoneal fibrosis.

• Cardiac failure: cases of valvular and pericardial fibrosis have often manifested as cardiac failure. Therefore, valvular fibrosis (and constrictive pericarditis) should be excluded if such symptoms occur.

Clinical diagnostic monitoring for development of fibrotic disorders, as appropriate, is essential. Following treatment initiation, the first echocardiogram should occur within 3-6 months, thereafter, the frequency of echocardiographic monitoring should be determined by appropriate individual clinical assessment with particular emphasis on the above-mentioned signs and symptoms, but must occur at least every 6 to 12 months.

Cabaser should be discontinued if an echocardiogram reveals new or worsened valvular regurgitation, valvular restriction or valve leaflet thickening. (See Section 4.3 Contraindications)

The need for other clinical monitoring (e.g., physical examination including, cardiac auscultation, X-ray, CT scan) should be determined on an individual basis.

Additional appropriate investigations such as erythrocyte sedimentation rate, and serum creatinine measurements should be performed if necessary to support a diagnosis of a fibrotic disorder.

Somnolence/Sudden Sleep Onset:

Cabaser has been associated with somnolence and episodes of sudden sleep onset in patients with Parkinson's disease. Sudden onset of sleep during activities, in some cases without awareness or warning signs, has been reported. Patients must be informed of this and advised to exercise caution while driving or operating machines during treatment with cabergoline. Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines. A reduction of dosage or termination of therapy may be considered. (See section 4.7 Effects on ability to drive and use machines)

The effects of alcohol on overall tolerability of Cabaser are currently unknown.

Psychiatric:

Pathological gambling, increased libido, and hypersexuality have been reported in patients treated with dopamine agonists including Cabaser. This has been generally reversible upon reduction of the dose or treatment discontinuation.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The concomitant use of antiparkinson non-dopamine agonists (eg, selegiline, amantadine, biperiden, trihexyphenidyl) was allowed in clinical studies for patients receiving CABASER. In studies where the pharmacokinetic interactions of CABASER with L-dopa or selegiline were evaluated, no interactions were observed.

No information is available about interaction between Cabaser and other ergot alkaloids: therefore the concomitant use of these medications during long-term treatment with Cabaser is not recommended.

Since Cabaser exerts its therapeutic effect by direct stimulation of dopamine receptors, it should not be concurrently administered with drugs which have dopamine-antagonist activity (such as phenothiazines, butyrophenones, thioxanthenes, metoclopramide) since these might reduce the therapeutic effect of Cabaser.

As with other ergot derivatives, Cabaser should not be used in association with macrolide antibiotics (e.g. erythromycin) due to increased systemic bioavailability.

4.6 Pregnancy And Lactation

In a twelve year observational study on pregnancy outcomes following cabergoline therapy, information is available on 256 pregnancies. Seventeen of these 256 pregnancies (6.6%) eventuated in major congenital malformations or abortion. Information is available on 23/258 infants who had a total of 27 neonatal abnormalities, both major and minor. Musculoskeletal malformations were the most common neonatal abnormality (10), followed by cardio-pulmonary abnormalities (5). There is no information on perinatal disorders or long-term development of infants exposed to intra-uterine cabergoline. Based on recent published literature, the prevalence of major congenital malformations in the general population has been reported to be 6.9% or greater. Rates of congenital abnormality vary between different populations. It is not possible to accurately determine if there is an increased risk as no control group was included.

It is recommended that contraception is used whilst on treatment with Cabaser.

In rats, Cabaser and/or its metabolites are excreted in milk. No information is available on excretion in breast milk in humans; however, lactation is expected to be inhibited/suppressed by Cabaser, in view of its dopamine agonist properties. Mothers should be advised not to breast-feed while being treated with Cabaser.

4.7 Effects On Ability To Drive And Use Machines

Patients being treated with Cabaser and presenting with somnolence and/or sudden sleep onset episodes must be informed to refrain from driving or engaging in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g. operating machines) until such episodes and somnolence have resolved (see section 4.4 Special warnings and precautions for use – Somnolence/Sudden Sleep Onset).

4.8 Undesirable Effects

The following undesirable effects have been observed and reported during treatment with Cabaser with the following frequencies: Very common (

Newly Diagnosed Parkinson's Patients
MedDRA System Organ Class	Frequency	Undesirable Effects
Psychiatric disorders	Common	Hallucinations, sleep disturbances
Nervous system disorders	Common	Dizziness, dyskinesias
Vascular disorders	Common	Postural hypotension
Gastrointestinal disorders	Very common	Nausea
Common	Constipation, dyspepsia, gastritis, vomiting
General disorders and administration site conditions	Very common	Peripheral edema
Patients on Adjunct Levodopa Therapy
MedDRA System Organ Class	Frequency	Undesirable Effects
Psychiatric disorders	Common	Confusion, hallucinations
Nervous system disorders	Common	Dizziness, dyskinesia
Uncommon	Hyperkinesia
Cardiac disorders	Common	Angina
Vascular disorders	Common	Postural hypotension
Uncommon	Erythromelalgia
Respiratory, thoracic and mediastinal disorders	Uncommon	Pleural effusion, pulmonary fibrosis
Gastrointestinal disorders	Very common	Nausea
Common	Dyspepsia, gastritis, vomiting
General disorders and administration site conditions	Common	Peripheral edema
Investigations	Common	Decreased hemoglobin, hematocrit, and/or red blood cell (>15% vs baseline)
Post-marketing Surveillance
MedDRA System Organ Class	Frequency	Undesirable Effects
Immune system disorders	Uncommon	Hypersensitivity reaction
Psychiatric disorders	Common	Increased libido
Uncommon	Delusions, psychotic disorder
Not Known	Aggression, hypersexuality, pathological gambling
Nervous system disorders	Common	Headache, somnolence
Not Known	Sudden sleep onset, syncope
Cardiac disorders	Very Common	Valvulopathy (including regurgitation) and related disorders (pericarditis and pericardial effusion)
Vascular disorders	Not Known	Digital vasospasm
Respiratory, thoracic and mediastinal disorders	Common	Dyspnea
Very rare	Fibrosis
Not Known	Respiratory disorder, respiratory failure
Hepato-biliary disorders	Uncommon	Hepatic function abnormal
Skin and subcutaneous tissue disorders	Uncommon	Rash
Not Known	Alopecia
Musculoskeletal and connective tissue disorders	Not Known	Leg cramps
General disorders and administration site conditions	Common	Asthenia
Uncommon	Edema, fatigue
Investigations	Common	Liver function tests abnormal
Not Known	Blood creatinine phosphokinase increased

4.9 Overdose

Symptoms of overdose would likely be those of over-stimulation of dopamine receptors, e.g. nausea, vomiting, gastric complaints, postural hypotension, confusion/psychosis or hallucinations.

Supportive measures should be taken to remove unabsorbed drug and maintain blood pressure, if necessary. In addition, the administration of dopamine antagonist drugs may be advisable.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Cabaser is a dopaminergic ergoline derivative endowed with potent and long-lasting dopamine D2 receptor agonist properties. In rats the compound, acting at D2 dopamine receptors on pituitary lactotrophic cells, decreases PRL secretion at oral doses of 3-25 mcg/kg, and in vitro at a concentration of 45 pg/ml. In addition, Cabaser exerts a central dopaminergic effect via D2 receptor stimulation at doses higher than those effective in lowering serum PRL levels. Improvement of motor deficit in animal models of parkinson's disease was present at oral daily doses of 1-2.5 mg/kg in rats and at s.c. doses of 0.5-1 mg/kg in monkeys.

In healthy volunteers the administration of Cabaser at single oral doses of 0.3-2.5 mg was associated with a significant decrease in serum PRL levels. The effect is prompt (within 3 hours of administration) and persistent (up to 7-28 days). The PRL-lowering effect is dose-related both in terms of degree of effect and duration of action.

The pharmacodynamic actions of Cabaser not linked to the therapeutic effect relate only to blood pressure decrease. The maximal hypotensive effect of Cabaser as a single dose usually occurs during the first 6 hours after drug intake and is dose-dependent both in terms of maximal decrease and frequency.

5.2 Pharmacokinetic Properties

The pharmacokinetic and metabolic profiles of Cabaser have been studied in healthy volunteers of both sexes, in female hyperprolactinemic patients and in parkinsonian patients. After oral administration of the labelled compound, radioactivity was rapidly absorbed from the gastrointestinal tract as the peak of radioactivity in plasma was between 0.5 and 4 hours. Ten days after administration about 18/20% and 55/72% of the radioactive dose (³H-cabergoline/¹⁴C-cabergoline) was recovered in urine and faeces, respectively. Unchanged drug in urine accounted for 2-3% of the dose.

In urine, the main metabolite identified was 6-allyl-8b-carboxy-ergoline, which accounted for 4-6% of the dose. Three additional metabolites were identified in urine, which accounted overall for less than 3% of the dose. The metabolites have been found to be much less potent than Cabaser as D₂ dopamine receptor agonists "in vitro".

The low urinary excretion of unchanged Cabaser has been confirmed also in studies with non-radioactive product. The elimination half-life of Cabaser, estimated from urinary excretion rates, is long (63-68 hours in healthy volunteers, 79-115 hours in hyperprolactinemic patients).

The pharmacokinetics of Cabaser seem to be dose-independent both in healthy volunteers (doses of 0.5-1.5 mg) and parkinsonian patients (steady state of daily doses up to 7 mg/day).

On the basis of the elimination half-life, steady state conditions should be achieved after 4 weeks, as confirmed by the mean peak plasma levels of Cabaser obtained after a single dose (37+8 pg/ml) and after a 4 week multiple-regimen (101+43 pg/ml). "In vitro" experiments showed that the drug at concentrations of 0.1-10 ng/ml is 41-42% bound to plasma proteins.

Food does not appear to affect absorption and disposition of Cabaser.

While renal insufficiency has been shown not to modify cabergoline kinetics, hepatic insufficiency of severe degree (> 10 Child-Pugh score, maximum score 12) has been shown to be associated with an increase of AUC.

5.3 Preclinical Safety Data

Almost all the findings noted throughout the series of preclinical safety studies are a consequence of the central dopaminergic effects or the long-lasting inhibition of PRL in rodents with a specific hormonal physiology different to man.

Preclinical safety studies of Cabaser indicate a consistent safety margin for this compound in rodents and in monkeys, as well as a lack of teratogenic, genotoxic or carcinogenic potential.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose anhydrous NF, USP

Leucine Ph Eur

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

24 months at room temperature (25^oC).

6.4 Special Precautions For Storage

There are no special precautions for storage.

6.5 Nature And Contents Of Container

The tablets are contained in Type I amber glass bottles with tamper resistant screw caps which contain silica gel desiccant.

Each bottle contains 20 or 30 tablets and is enclosed in an outer cardboard carton.

6.6 Special Precautions For Disposal And Other Handling

Bottles of Cabaser are supplied with desiccant in the caps. This desiccant must not be removed.

Administrative Data

7. Marketing Authorisation Holder

Pharmacia Laboratories Limited

Ramsgate Road

Sandwich

Kent

CT13 9NJ

United Kingdom

8. Marketing Authorisation Number(S)

1mg: PL 00022/0169

2mg: PL 00022/0170

9. Date Of First Authorisation/Renewal Of The Authorisation

14 February 1996

10. Date Of Revision Of The Text

August 2010

Company Ref: CA10_0

PURI-NETHOL 50 mg Tablets

1. Name Of The Medicinal Product

Puri-Nethol^® 50 mg tablets

2. Qualitative And Quantitative Composition

Each tablet contains 50 mg of 6-mercaptopurine.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Tablets

Pale yellow, round tablets, biconvex, scored on one side, engraved GX above the score and EX2 below the score and plain on the other side

4. Clinical Particulars

4.1 Therapeutic Indications

Cytotoxic agent.

Puri-Nethol is indicated for the treatment of acute leukaemia. It may be utilised in remission induction and it is particularly indicated for maintenance therapy in: acute lymphoblastic leukaemia; acute myelogenous leukaemia. Puri-Nethol may be used in the treatment of chronic granulocytic leukaemia.

4.2 Posology And Method Of Administration

For oral administration

Dosage in adults and children:

For adults and children the usual starting dose is 2.5 mg/kg bodyweight per day, or 50-75 mg/m² body surface area per day, but the dose and duration of administration depend on the nature and dosage of other cytotoxic agents given in conjunction with Puri-Nethol.

The dosage should be carefully adjusted to suit the individual patient.

Puri-Nethol has been used in various combination therapy schedules for acute leukaemia and the literature should be consulted for details.

Dosage in the elderly:

No specific studies have been carried out in the elderly. However, it is advisable to monitor renal and hepatic function in these patients, and if there is any impairment, consideration should be given to reducing the Puri-Nethol dosage.

Dosage in renal impairment:

Consideration should be given to reducing the dosage in patients with impaired renal function.

Dosage in hepatic function:

Consideration should be given to reducing the dosage in patients with impaired hepatic function.

In general:

When Zyloric (allopurinol) and 6-mercaptopurine are administered concomitantly it is essential that only a quarter of the usual dose of 6-mercaptopurine is given since Zyloric (allopurinol) decreases the rate of catabolism of 6-mercaptopurine.

4.3 Contraindications

Hypersensitivity to any component of the preparation.

In view of the seriousness of the indications there are no other absolute contra-indications.

4.4 Special Warnings And Precautions For Use

Puri-Nethol is an active cytotoxic agent for use only under the direction of physicians experienced in the administration of such agents.

Immunisation using a live organism vaccine has the potential to cause infection in immunocompromised hosts. Therefore, immunisations with live organism vaccines are not recommended.

Safe handling of Puri-Nethol Tablets:

See section 6.6 Instructions for Use/Handling

Monitoring:

Treatment with Puri-Nethol causes bone marrow suppression leading to leucopenia and thrombocytopenia and, less frequently, to anaemia. Full blood counts must be taken daily during remission induction and careful monitoring of haematological parameters should be conducted during maintenance therapy.

The leucocyte and platelet counts continue to fall after treatment is stopped, so at the first sign of an abnormally large fall in the counts, treatment should be interrupted immediately.

Bone marrow suppression is reversible if Puri-Nethol is withdrawn early enough.

During remission induction in acute myelogenous leukaemia the patient may frequently have to survive a period of relative bone marrow aplasia and it is important that adequate supportive facilities are available.

There are individuals with an inherited deficiency of the enzyme thiopurine methyltransferase (TPMT) who may be unusually sensitive to the myelosuppresive effect of 6-mercaptopurine and prone to developing rapid bone marrow depression following the initiation of treatment with Puri-Nethol. This problem could be exacerbated by coadministration with drugs that inhibit TPMT, such as olsalazine, mesalazine or sulfazalazine. Also a possible association between decreased TPMT activity and secondary leukaemias and myelodysplasia has been reported in individuals receiving 6–mercaptopurine in combination with other cytotoxics (see Section 4.8 Undesirable Effects). Some laboratories offer testing for TPMT deficiency, although these tests have not been shown to identify all patients at risk of severe toxicity. Therefore close monitoring of blood counts is still necessary.

Puri-Nethol is hepatotoxic and liver function tests should be monitored weekly during treatment. More frequent monitoring may be advisable in those with pre-existing liver disease or receiving other potentially hepatotoxic therapy. The patient should be instructed to discontinue Puri-Nethol immediately if jaundice becomes apparent.

During remission induction when rapid cell lysis is occurring, uric acid levels in blood and urine should be monitored as hyperuricaemia and/or hyperuricosuria may develop, with the risk of uric acid nephropathy.

Cross resistance usually exists between 6-mercaptopurine and 6-tioguanine.

The dosage of 6-mercaptopurine may need to be reduced when this agent is combined with other drugs whose primary or secondary toxicity is myelosuppression.

Mutagenicity and carcinogenicity:

Increases in chromosomal aberrations were observed in the peripheral lymphocytes of leukaemic patients, in a hypernephroma patient who received an unstated dose of 6-mercaptopurine and in patients with chronic renal disease treated at doses of 0.4 – 1.0 mg/kg/day.

In view of its action on cellular deoxyribonucleic acid (DNA) 6-mercaptopurine is potentially carcinogenic and consideration should be given to the theoretical risk of carcinogenisis with this treatment.

Two cases have been documented of the occurrence of acute nonlymphatic leukaemia in patients who received 6-mercaptopurine, in combination with other drugs, for non-neoplastic disorders. A single case has been reported where a patient was treated for pyoderma gangrenosum with 6-mercaptopurine and later developed acute nonlymphatic leukaemia, but it is not clear whether this was part of the natural history of the disease or if the 6-mercaptopurine played a causative role.

A patient with Hodgkins Disease treated with 6-mercaptopurine and multiple additional cytotoxic agents developed acute myelogenous leukaemia.

Twelve and a half years after 6-mercaptopurine treatment for myasthenia gravis a female patient developed chronic myeloid leukaemia.

Reports of hepatosplenic T-cell lymphoma in the inflammatory bowel disease (IBD) population have been received when 6-mercaptopurine is used (an unlicensed indication) in combination with anti-TNF agents (see section 4.8 Undesirable Effects).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Vaccinations with live organism vaccines are not recommended in immunocompromised individuals (see Section 4.4 Special Warnings and Precautions for Use).

When Zyloric (allopurinol) and Puri-Nethol are administered concomitantly it is essential that only a quarter of the usual dose of Puri-Nethol is given since Zyloric decreases the rate of catabolism of Puri-Nethol.

Inhibition of the anticoagulant effect of warfarin, when given with Puri-Nethol, has been reported.

As there is in vitro evidence that aminosalicylate derivatives (eg. olsalazine, mesalazine or sulfazalazine) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent Puri-Nethol therapy (see Section 4.4 Special Warnings and Precautions for Use).

4.6 Pregnancy And Lactation

Pregnancy:

6-mercaptopurine is potentially teratogenic. The use of Puri-Nethol should be avoided whenever possible during pregnancy. In any individual case the potential hazard to the foetus must be balanced against the expected benefit to the mother.

As with all cytotoxic chemotherapy, adequate contraceptive precautions should be advised if either partner is receiving Puri-Nethol tablets.

Maternal Exposure:

Studies of 6-mercaptopurine in animals have shown reproductive toxicity (see Section 5.3 Preclinical Safety Data). The potential risk for humans is unclear.

Normal offspring have been born after mercaptopurine therapy administered as a single chemotherapy agent during human pregnancy. Abortions and prematurity have been reported after maternal exposure. Multiple congenital abnormalities have been reported following maternal 6-mercatopurine treatment in combination with other chemotherapy agents.

Paternal Exposure:

Congenital abnormalities and spontaneous abortion have been reported after paternal exposure to 6-mercaptopurine.

Effects on fertility:

The effect of Puri-Nethol therapy on human fertility is largely unknown but there are reports of successful fatherhood/motherhood after receiving treatment during childhood or adolescence. Transient profound oligospermia was observed in a young man who received 6-mercaptopurine 150 mg/day plus prednisone 80 mg/day for acute leukaemia. Two years after cessation of the chemotherapy, he had a normal sperm count and he fathered a normal child.

Lactation:

6-Mercaptopurine has been detected in the breast milk of renal transplant patients receiving immunosuppressive therapy with azathioprine, a pro-drug of 6-mercaptopurine and thus mothers receiving Puri-Nethol should not breast-feed.

4.7 Effects On Ability To Drive And Use Machines

There are no data on the effect of 6-mercaptopurine on driving performance or the ability to operate machinery. A detrimental effect on these activities cannot be predicted from the pharmacology of the drug.

4.8 Undesirable Effects

For mercaptopurine there is a lack of modern clinical documentation which can serve as support for accurately determining the frequency of undesirable effects.

The following convention has been utilised for the classification of undesirable effects:- Very common

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Very Rare: secondary leukaemia and myelodysplasia (see Section 4.4 Special Warnings and Precautions for Use); hepatosplenic T-cell lymphoma in patients with IBD (an unlicensed indication) when used in combination with anti-TNF agents (see Section 4.4 Special Warnings and Precautions for Use).

Blood and lymphatic system disorders
Very common	Bone marrow suppression; leucopenia and thrombocytopenia.
The main side effect of treatment with 6-mercaptopurine is bone marrow suppression leading to leucopenia and thrombocytopenia.
Uncommon	anaemia
Immune system disorders
Hypersensitivity reactions with the following manifestations have been reported:
Rare:	Arthralgia; skin rash; drug fever
Very Rare:	Facial oedema
Metabolism and nutrition disorders
Uncommon	Anorexia
Gastrointestinal disorders
Common	Nausea; vomiting; pancreatitis in the IBD population* (an unlicensed indication)
Rare	Oral ulceration; pancreatitis (in the licensed indications)
Very rare	Intestinal ulceration
Hepato-biliary disorders
Common	Biliary stasis; hepatotoxicity
Rare	Hepatic necrosis

6-mercaptopurine is hepatotoxic in animals and man. The histological findings in man have shown hepatic necrosis and biliary stasis

The incidence of hepatotoxicity varies considerably and can occur with any dose but more frequently when the recommended dose of 2.5 mg/kg bodyweight daily or 75 mg/m² body surface area per day is exceeded.

Monitoring of liver function tests may allow early detection of hepatotoxicity. This is usually reversible if 6-mercaptopurine therapy is stopped soon enough but fatal liver damage has occurred.

Skin and subcutaneous tissue disorders
Rare	alopecia
Reproductive system and breast disorders
Very Rare	Transient oligospermia

4.9 Overdose

Symptoms and signs:

Gastrointestinal effects, including nausea, vomiting and diarrhoea and anorexia may be early symptoms of overdosage having occurred. The principal toxic effect is on the bone marrow, resulting in myelosuppression. Haematological toxicity is likely to be more profound with chronic overdosage than with a single ingestion of Puri-Nethol. Liver dysfunction and gastroenteritis may also occur.

The risk of overdosage is also increased when Zyloric is being given concomitantly with Puri-Nethol (see Section 4.5 Interactions with other Medicaments and other forms of Interaction).

Management:

As there is no known antidote the blood picture should be closely monitored and general supportive measures, together with appropriate blood transfusion, instituted if necessary. Active measures (such as the use of activated charcoal) may not be effective in the event of 6-mercaptopurine overdose unless the procedure can be undertaken within 60 minutes of ingestion.

Further management should be as clinically indicated or as recommended by the national poisons centre.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC Code: L01BB02

Pharmacotherapeutic group:

6-Mercaptopurine is sulphydryl analogue of the purine base hypoxanthine and acts as a cytotoxic antimetabolite.

Mode of Action:

6-Mercaptopurine is an inactive pro-drug which acts as a purine antagonist but requires cellular uptake and intracellular anabolism to tioguanine nucleotides for cytotoxicity. The 6-mercaptopurine metabolites inhibit de novo purine synthesis and purine nucleotide interconversions. The tioguanine nucleotides are also incorporated into nucleic acids and this contributes to the cytotoxic effects of the drug.

5.2 Pharmacokinetic Properties

The bioavailability of oral 6-mercaptopurine shows considerable inter-individual variability, which probably results from its first-pass metabolism (when administered orally at a dosage of 75 mg/m² to 7 paediatric patients, the bioavailability averaged 16% of the administered dose, with a range of 5 to 37%).

The elimination half-life of 6-mercaptopurine is 90 ± 30 minutes, but the active metabolites have a longer half-life (approximately 5 hours) than the parent drug. The apparent body clearance is 4832 ± 2562 ml/min/m². There is low entry of 6-mercaptopurine into the cerebrospinal fluid.

The main method of elimination for 6-mercaptopurine is by metabolic alteration. The kidneys eliminate approximately 7% of 6-mercaptopurine unaltered within 12 hours of the drug being administered. Xanthine oxidase is the main catabolic enzyme of 6-mercaptopurine and it converts the drug into the inactive metabolite, 6-thiouric acid. This is excreted in the urine.

5.3 Preclinical Safety Data

6-Mercaptopurine, in common with other antimetabolites, is potentially mutagenic in man and chromosome damage has been reported in mice, rats and man.

Teratogenicity

6-Mercaptopurine causes embryolethality and severe teratogenic effects in the mouse, rat, hamster and rabbit at doses that are non-toxic to the mother. In all species, the degree of embryotoxicity and the type of malformations are dependent on the dose and stage of the gestation at the time of administration.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose

Maize Starch

Hydrolysed Starch

Stearic Acid

Magnesium Stearate

Purified Water

6.2 Incompatibilities

None known

6.3 Shelf Life

60 months

6.4 Special Precautions For Storage

Store below 25ºC. Keep the bottle tightly closed.

6.5 Nature And Contents Of Container

Amber glass bottles with child resistant high density polyethylene closures with induction heat seal liners.

Pack size: 25 tablets

6.6 Special Precautions For Disposal And Other Handling

Safe handling and disposal:

It is recommended that 6-mercaptopurine tablets should be handled following the prevailing local recommendations and/or regulations for the handling and disposal of cytotoxic drugs.

Administrative Data

7. Marketing Authorisation Holder

ALKOPHARMA SARL

45-47, rte d'Arlon

L – 1140 Luxembourg

8. Marketing Authorisation Number(S)

PL 36637/0006

9. Date Of First Authorisation/Renewal Of The Authorisation

29 August 2006

10. Date Of Revision Of The Text

September 2010

11. LEGAL STATUS

POM

Haldol Tabs & Oral Solution

1. Name Of The Medicinal Product

HALDOL Tablets 5 mg

HALDOL Tablets 10 mg

HALDOL 2 mg/ml

2. Qualitative And Quantitative Composition

Haloperidol 5 mg

Haloperidol 10 mg

Haloperidol 2mg/ml

3. Pharmaceutical Form

Tablets.

Oral solution

4. Clinical Particulars

4.1 Therapeutic Indications

Adults:

• Schizophrenia: treatment of symptoms and prevention of relapse

• Other psychoses: especially paranoid

• Mania and hypomania

• Mental or behavioural problems such as aggression, hyperactivity and self mutilation in the mentally retarded and in patients with organic brain damage

• As an adjunct to short term management of moderate to severe psychomotor agitation, excitement, violent or dangerously impulsive behaviour

• Intractable hiccup

• Restlessness and agitation in the elderly

• Gilles de la Tourette syndrome and severe tics.

Children:

• Childhood behavioural disorders, especially when associated with hyperactivity and aggression

• Gilles de la Tourette syndrome

• Childhood schizophrenia.

4.2 Posology And Method Of Administration

For oral administration.

Since the oral solution is not intended for administration in multiples of 5 ml, the quantities given are expressed per ml.

Dosage for all indications should be individually determined and is best initiated and titrated under close clinical supervision. To determine the initial dose, consideration should be given to the patient's age, severity of symptoms and previous response to other neuroleptic drugs.

Patients who are elderly or debilitated or those with previously reported adverse reactions to neuroleptic drugs may require less Haldol. The normal starting dose should be halved, followed by a gradual titration to achieve optimal response.

Adults

Schizophrenia, psychoses, mania and hypomania, mental or behavioural problems, psychomotor agitation, excitement, violent or dangerously impulsive behaviour, organic brain damage

Initial dose:

Moderate symptomatology 1.5-3.0 mg bd or tds

Severe symptomatology/resistant patients 3.0-5.0 mg bd or tds

The same starting doses may be employed in adolescents and resistant schizophrenics who may require up to 30 mg/day.

Maintenance dosage:

Once satisfactory control of symptoms has been achieved, dosage should be gradually reduced to the lowest effective maintenance dose, often as low as 5 or 10 mg/day. Too rapid a dosage reduction should be avoided.

Restlessness or agitation in the elderly

Initial dose 1.5-3.0 mg bd or tds titrated as required, to attain an effective maintenance dose (1.5 –30 mg daily).

Gilles de la Tourette syndrome, severe tics, intractable hiccup

Starting dose 1.5 mg tds adjusted according to response. A daily maintenance dose of 10 mg may be required in Gilles de la Tourette syndrome.

Children

Childhood behavioural disorders and schizophrenia

Total daily maintenance dose of 0.025-0.05 mg/kg/day. Half the dose should be given in the morning and the other half in the evening, up to a maximum of 10 mg daily.

Gilles de la Tourette syndrome

Oral maintenance doses of up to 10 mg/day in most patients.

4.3 Contraindications

Comatose states, CNS depression, Parkinson's disease, known hypersensitivity to haloperidol, lesions of basal ganglia.

4.4 Special Warnings And Precautions For Use

Please also refer to section 4.5. Interactions with other Medicinal Products and other forms of Interaction.

Caution is advised in patients with liver disease, renal failure, phaeochromocytoma, epilepsy and conditions predisposing to epilepsy (eg alcohol withdrawal and brain damage) or convulsions. Haloperidol should only be used with great caution in patients with disturbed thyroid function. Antipsychotic therapy in those patients must always be accompanied by adequate management of the underlying thyroid dysfunction.

Cases of sudden death have been reported in psychiatric patients receiving antipsychotic drugs, including haloperidol.

The risk-benefit of haloperidol treatment should be fully assessed before treatment is commenced and patients with risk factors for ventricular arrhythmias such as cardiac disease, subarachnoid haemorrhage, metabolic abnormalities such as hypokalaemia, hypocalcaemia or hypomagnesaemia, starvation, alcohol abuse or those receiving concomitant therapy with other drugs known to prolong the QT interval, should be monitored carefully (ECGs and potassium levels), particularly during the initial phase of treatment, to obtain steady plasma levels.

Acute withdrawal symptoms including nausea, vomiting and insomnia have very rarely been described after abrupt cessation of high doses of antipsychotic drugs. Relapse may also occur and gradual withdrawal is advisable.

In schizophrenia, the response to antipsychotic drug treatment may be delayed. If drugs are withdrawn, recurrence of symptoms may not become apparent for several weeks or months.

As with all antipsychotic agents, haloperidol should not be used alone where depression is predominant. It may be combined with antidepressants to treat those conditions in which depression and psychosis co-exist. Haloperidol may impair the metabolism of tricyclic antidepressants (clinical significance unknown).

If concomitant anti-Parkinson medication is required, it may have to be continued after haloperidol is discontinued to take account of any differences in excretion rates. The physician should keep in mind the possible anticholinergic effects associated with anti-Parkinson agents.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

In common with all neuroleptics, haloperidol can increase the central nervous system depression produced by other CNS-depressant drugs, including alcohol, hypnotics, sedatives or strong analgesics.

An enhanced CNS effect, when combined with methyldopa, has been reported.

Haloperidol may antagonise the action of adrenaline and other sympathomimetic agents and reverses the blood pressure lowering effects of adrenergic-blocking agents such as guanethidine.

The dosage of anticonvulsants may need to be increased to take account of the lowered seizure threshold.

Co-administration of enzyme-inducing drugs such as carbamazepine, phenobarbitone and rifampicin with haloperidol may result in a significant reduction of haloperidol plasma levels. The haloperidol dose may therefore need to be increased, according to the patient's response. After stopping such drugs, it may be necessary to re-adjust the dosage of haloperidol.

Haloperidol may impair the metabolism of tricyclic antidepressants (clinical significance unknown) and the anti-Parkinson effects of levodopa.

In pharmacokinetic studies, increased haloperidol levels have been reported when haloperidol was given concomitantly with the following drugs: quinidine, buspirone and fluoxetine. Haloperidol plasma levels should therefore be monitored and reduced if necessary.

Antagonism of the effect of phenindione has been reported.

In rare cases, an encephalopathy-like syndrome has been reported in combination with lithium and haloperidol. It remains controversial whether these cases represent a distinct clinical entity or whether they are in fact cases of NMS and/or lithium toxicity. Signs of encephalopathy-like syndrome include confusion, disorientation, headache, disturbances of balance and drowsiness. One report showing symptomless EEG abnormalities on the combination has suggested that EEG monitoring might be advisable. When lithium and haloperidol therapy are used concomitantly, haloperidol should be given in the lowest effective dose and lithium levels should be monitored and kept below 1 mmol/l. If symptoms of encephalopathy-like syndrome occur, therapy should be stopped immediately.

4.6 Pregnancy And Lactation

The safety of haloperidol in pregnancy has not been established. There is some evidence of harmful effects in some but not all animal studies. There have been a number of reports of birth defects following foetal exposure to haloperidol for which a causal role for haloperidol cannot be excluded. Haldol should be used during pregnancy only if the anticipated benefit outweighs the risk and the administered dose and duration of treatment should be as low and as short as possible.

Haloperidol is excreted in breast milk. There have been isolated cases of extrapyramidal symptoms in breast-fed children. If the use of Haldol is essential, the benefits of breast feeding should be balanced against its potential risks.

4.7 Effects On Ability To Drive And Use Machines

Some degree of sedation or impairment of alertness may occur, particularly with higher doses and at the start of treatment, and may be potentiated by alcohol or other CNS depressants. Patients should be advised not to undertake activities requiring alertness such as driving or operating machinery during treatment, until their susceptibility is known.

4.8 Undesirable Effects

Central nervous system

In common with all neuroleptics, extrapyramidal symptoms may occur, eg tremor, rigidity, hypersalivation, bradykinesia, akathisia, acute dystonia, oculogyric crisis and laryngeal dystonia. Anti-Parkinson agents should not be prescribed routinely.

As with all antipsychotic agents, tardive dyskinesia may appear in some patients on long term therapy or after drug discontinuation. The syndrome is mainly characterised by rhythmical involuntary movements of the tongue, face, mouth or jaw. The manifestations may be permanent in some patients. The syndrome may be masked when treatment is reinstituted, when the dosage is increased or when a switch is made to a different antipsychotic drug. Treatment should be discontinued as soon as possible.

However, since its occurrence may be related to duration of treatment, as well as daily dose, Haldol should be given in the minimum effective dose for the minimum possible time, unless it is established that long term administration for the treatment of schizophrenia is required.

It has been reported that fine vermicular movements of the tongue may be an early warning sign of tardive dyskinesia and that the full syndrome may not develop if the medication is stopped at that time.

The following effects have been reported rarely; confusional states or epileptic fits, depression, sedation, agitation, drowsiness, insomnia, headache, vertigo and apparent exacerbation of psychotic symptoms.

In common with other antipsychotic drugs, haloperidol has been associated with neuroleptic malignant syndrome (NMS), an idiosyncratic response characterised by hyperthermia, generalised muscle rigidity, autonomic instability, altered consciousness, coma and elevated CPK. Signs of autonomic dysfunction such as tachycardia, labile arterial pressure and sweating may precede onset of hyperthermia, acting as early warning signs. Antipsychotic treatment should be withdrawn immediately and appropriate supportive therapy and careful monitoring instituted.

Haloperidol, even in low dosage in susceptible (especially non-psychotic) individuals, may cause unpleasant subjective feelings of being mentally dulled or slowed down, dizziness, headache or paradoxical effects of excitement, agitation or insomnia.

Gastro-intestinal system

Gastro-intestinal symptoms, nausea, loss of appetite, constipation and dyspepsia have been reported.

Endocrinological system

Hormonal effects of antipsychotic neuroleptic drugs include hyperprolactinaemia, which may cause galactorrhoea, gynaecomastia and oligo- or amenorrhoea. Hypoglycaemia and the syndrome of inappropriate antidiuretic hormone secretion have been reported rarely. Impairment of sexual function including erection and ejaculation has also been occasionally reported.

Cardiovascular system

Tachycardia and dose related hypotension are uncommon, but can occur, particularly in the elderly, who are more susceptible to the sedative and hypotensive effects. Less commonly, hypertension has also been reported.

Cardiac effects such as QT-interval prolongation, Torsade de Pointes and/or ventricular arrhythmias have been reported rarely. They may occur more frequently with high doses, intravenous administration and in predisposed patients (see 4.4. Special Warnings and Special Precautions for Use).

Autonomic nervous system

Dry mouth as well as excessive salivation, blurred vision, urinary retention and hyperhidrosis have been reported.

Dermatological system

The following effects have been reported rarely: oedema, various skin rashes and reactions including urticaria, exfoliative dermatitis and erythema multiforme. Photosensitive skin reactions have been reported very rarely.

Other adverse reactions

The following effects have been reported rarely: jaundice, cholestatic hepatitis or transient abnormalities of liver function in the absence of jaundice; priapism and weight changes. Temperature disorders may also occur, characteristically hyperthermia associated with NMS, although hypothermia has also been reported.

The following have been reported very rarely: blood dyscrasia, including agranulocytosis, thrombocytopenia and transient leucopenia; hypersensitivity reactions including anaphylaxis.

4.9 Overdose

Symptoms

In general, the manifestations of haloperidol overdosage are an extension of its pharmacological actions, the most prominent of which would be severe extrapyramidal symptoms, hypotension and psychic indifference with a transition to sleep. The risk of ventricular arrhythmias possibly associated with QT-prolongation should be considered. The patient may appear comatose with respiratory depression and hypotension which could be severe enough to produce a shock-like state. Paradoxically hypertension rather than hypotension may occur. Convulsions may also occur.

Treatment

There is no specific antidote to haloperidol. A patent airway should be established and maintained with mechanically assisted ventilation if necessary. In view of isolated reports of arrhythmia ECG monitoring is strongly advised. Hypotension and circulatory collapse should be treated by plasma volume expansion and other appropriate measures. Adrenaline should not be used. The patient should be monitored carefully for 24 hours or longer, body temperature and adequate fluid intake should be maintained.

In cases of severe extrapyramidal symptoms, appropriate anti-Parkinson medication should be administered.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Haloperidol acts as a central dopamine receptor antagonist. It also has some anticholinergic activity and binds to opiate receptors. It also acts at peripheral dopamine receptors.

5.2 Pharmacokinetic Properties

Pharmacotherapeutic group: Butyrophenone Derivatives: ATC code: NP5A DO1

Haloperidol is absorbed rapidly with a bioavailability of 44-74% (mean 60%) after tablets and a bioavailability of 38-86% (mean 58%) after oral solution. Variable bioavailability is likely to be due to interindividual differences in gastro-intestinal absorption and extent of first-pass hepatic metabolism.

Haloperidol is rapidly distributed to extravascular tissues especially liver and adipose tissue. Haloperidol crosses the blood-brain barrier and is excreted in human breast milk. It is approximately 92% bound to plasma proteins.

Metabolism is by oxidative dealkylation. The elimination half-life is approximately 20 hours, with considerable diurnal variation.

5.3 Preclinical Safety Data

No relevant information other than that contained elsewhere in the Summary of Product Characteristics.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Haldol 5 mg

Lactose monohydrate

Maize starch

Talc

Cottonseed oil - hydrogenated

Indigotindisulphonate sodium (E132)

Purified water (not in final product)

Haldol 10 mg

Calcium hydrogen phosphate dihydrate

Maize starch

Calcium stearate

Quinoline yellow (E104)

Purified water (not in final product)

Haldol 2mg/ml

Lactic acid

Methyl parahydroxybenzoate

Purified water

6.2 Incompatibilities

None known.

6.3 Shelf Life

60 months.

6.4 Special Precautions For Storage

5 mg, 10 mg tablets:	Do not store above 25°C.
2 mg/ml oral solution:	Do not store above 25°C
	Do not refrigerate or freeze

Keep out of reach and sight of children.

6.5 Nature And Contents Of Container

5,10mg tablets: Blister packs of aluminium foil and polyvinylchloride genotherm glass clear. The strips are packed in cardboard cartons containing 100 tablets per pack.

2mg/ml oral solution: Bottle: Amber glass (Type III, Ph.Eur); 100 ml

Closure:

Aluminium screw cap, tamper resistant, coated on the inner side with polyvinylchloride.

OR

Child resistant, polypropylene screw cap with low density polyethylene insert.

Dosing Device:

2.5 ml glass pipette with 0.5 ml graduations fitted on a butyl rubber bulb with a polypropylene screw cap.

OR

2.5 ml glass pipette with 0.5 ml graduations fitted on a black siliconised rubber bulb. The pipette has a white polypropylene child-resistant screw cap and polypropylene sheath.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Janssen-Cilag Limited

Saunderton

High Wycombe

Buckinghamshire

HP14 4HJ

UK

8. Marketing Authorisation Number(S)

Haldol 5 mg:	0242/0031R
Haldol 10 mg:	0242/0039R
Haldol 2 mg/ml:	0242/0035R

9. Date Of First Authorisation/Renewal Of The Authorisation

Haldol 5 mg:	20 June 1986/12 January 1998
Haldol 10 mg:	17 June 1986/4 February 2002
Haldol 2 mg/ml:	7 June 1989/30 March 2000

10. Date Of Revision Of The Text

Haldol 5 mg:	28 July 2003
Haldol 10 mg:	29 July 2003
Haldol 2 mg/ml:	15 June 2001

Legal status POM

Meclomen

Generic Name: meclofenamate (me kloe fen AM ate)

Brand Names: Meclomen

What is Meclomen (meclofenamate)?

Meclofenamate is in a group of drugs called nonsteroidal anti-inflammatory drugs (NSAIDs). Meclofenamate works by reducing hormones that cause inflammation and pain in the body.

Meclofenamate is used to treat pain or inflammation caused by arthritis. It is also used to treat menstrual pain.

Meclofenamate may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about Meclomen (meclofenamate)?

This medicine can increase your risk of life-threatening heart or circulation problems, including heart attack or stroke. Do not use this medicine just before or after having heart bypass surgery (also called coronary artery bypass graft, or CABG).

Seek emergency medical help if you have symptoms of heart or circulation problems, such as chest pain, weakness, shortness of breath, slurred speech, or problems with vision or balance.

This medicine can also increase your risk of serious effects on the stomach or intestines, including bleeding or perforation (forming of a hole). These conditions can be fatal and gastrointestinal effects can occur without warning at any time while you are taking meclofenamate. Older adults may have an even greater risk of these serious gastrointestinal side effects.

Call your doctor at once if you have symptoms of bleeding in your stomach or intestines. This includes black, bloody, or tarry stools, or coughing up blood or vomit that looks like coffee grounds.

What should I discuss with my healthcare provider before taking Meclomen (meclofenamate)?

Taking an NSAID can increase your risk of life-threatening heart or circulation problems, including heart attack or stroke. This risk will increase the longer you use an NSAID. Do not use this medicine just before or after having heart bypass surgery (also called coronary artery bypass graft, or CABG).

NSAIDs can also increase your risk of serious effects on the stomach or intestines, including bleeding or perforation (forming of a hole). These conditions can be fatal and gastrointestinal effects can occur without warning at any time while you are taking an NSAID. Older adults may have an even greater risk of these serious gastrointestinal side effects.

Do not use this medication if you are allergic to meclofenamate, or to aspirin or other NSAIDs.

Before taking meclofenamate, tell your doctor if you are allergic to any drugs, or if you have:

• 
  

  a history of heart attack, stroke, or blood clot;

  
  


• 
  

  heart disease, congestive heart failure, high blood pressure;

  
  


• 
  

  a history of stomach ulcers or bleeding, bowel problems, diverticulosis;

  
  


• liver or kidney disease;


• 
  

  asthma;

  
  


• 
  

  polyps in your nose; or

  
  


• 
  

  if you smoke.

  
  

If you have any of these conditions, you may need a dose adjustment or special tests to safely take meclofenamate.

FDA pregnancy category C. This medication may be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. Taking meclofenamate during the last 3 months of pregnancy may harm the unborn baby. Do not take meclofenamate during pregnancy unless your doctor has told you to. Meclofenamate passes 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. Do not give this medicine to a child younger than 14 years old without the advice of a doctor.

How should I take Meclomen (meclofenamate)?

Take this medication exactly as it was prescribed for you. Do not take the medication in larger amounts, or take it for longer than recommended by your doctor. Follow the directions on your prescription label. The maximum amount of meclofenamate for adults is 400 milligrams (mg) per day. Know the amount of meclofenamate in the specific product you are taking.

If you take meclofenamate for a long period of time, your doctor may want to check you on a regular basis to make sure this medication is not causing harmful effects. Do not miss any scheduled visits to your doctor.

Store meclofenamate at room temperature, away from moisture, heat, and light.

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 your 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.

Overdose symptoms may include nausea, vomiting, dizziness, drowsiness, ringing in your ears, numbness or tingling, black or bloody stools, coughing up blood, fever, urinating less than usual or not at all, shallow breathing, fainting, and seizure (convulsions).

What should I avoid while taking Meclomen (meclofenamate)?

Do not use any other over-the-counter cold, allergy, or pain medication without first asking your doctor or pharmacist. Many medicines available over the counter contain medicines similar to meclofenamate (such as aspirin, ibuprofen, ketoprofen, or naproxen). If you take certain products together you may accidentally take too much of this type of medication. Read the label of any other medicine you are using to see if it contains aspirin, ibuprofen, ketoprofen, or naproxen. Do not drink alcohol while taking meclofenamate. Alcohol can increase the risk of stomach bleeding.

If you take cholestyramine (Prevalite, Questran), avoid taking it within 2 hours before or after you take meclofenamate.

Meclomen (meclofenamate) 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. Stop taking meclofenamate and call your doctor at once if you have any of these serious side effects:

• 
  

  chest pain, weakness, shortness of breath, slurred speech, problems with vision or balance;

  
  


• 
  

  black, bloody, or tarry stools, coughing up blood or vomit that looks like coffee grounds;

  
  


• 
  

  urinating less than usual or not at all;

  
  


• 
  

  nausea, stomach pain, low fever, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);

  
  


• 
  

  fever, sore throat, and headache with a severe blistering, peeling, and red skin rash; or

  
  


• 
  

  bruising, severe tingling, numbness, pain, muscle weakness.

  
  

Less serious side effects may include:

• 
  

  upset stomach, mild heartburn or stomach pain, diarrhea, constipation; bloating, gas;

  
  


• 
  

  dizziness, headache, nervousness;

  
  


• 
  

  skin itching or rash;

  
  


• 
  

  dry mouth;

  
  


• 
  

  increased sweating, runny nose;

  
  


• 
  

  blurred vision; or

  
  


• 
  

  ringing in your ears.

  
  

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Meclomen (meclofenamate)?

Before taking meclofenamate, tell your doctor if you are taking any of the following drugs:

• 
  

  cyclosporine (Gengraf, Neoral, Sandimmune);

  
  


• 
  

  a diuretic (water pill) such as furosemide (Lasix);

  
  


• 
  

  lithium (Eskalith, Lithobid);

  
  


• 
  

  a blood thinner such as warfarin (Coumadin);

  
  


• 
  

  steroids (prednisone and others); or

  
  


• 
  

  heart or blood pressure medication such as candesartan (Atacand), eprosartan (Teveten), irbesartan (Avapro), losartan (Cozaar, Hyzaar), olmesartan (Benicar), telmisartan (Micardis), or valsartan (Diovan);

  
  


• 
  

  a beta-blocker such as atenolol (Tenormin), carvedilol (Coreg), esmolol (Brevibloc), labetalol (Normodyne, Trandate), metoprolol (Lopressor, Toprol), nadolol (Corgard), propranolol (Inderal, InnoPran), sotalol (Betapace), and others;

  
  


• 
  

  an ACE inhibitor such as benazepril (Lotensin), captopril (Capoten), fosinopril (Monopril), enalapril (Vasotec), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), ramipril (Altace), or trandolapril (Mavik); or

  
  


• 
  

  aspirin or other NSAIDs (non-steroidal anti-inflammatory drugs) 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 drugs that can interact with meclofenamate. 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 Meclomen resources

• Meclomen Use in Pregnancy & Breastfeeding
• Drug Images
• Meclomen Drug Interactions
• Meclomen Support Group
• 0 Reviews for Meclomen - Add your own review/rating

• Meclofenamate MedFacts Consumer Leaflet (Wolters Kluwer)


• Meclofenamate Prescribing Information (FDA)


• Meclofenamate Sodium Monograph (AHFS DI)

Compare Meclomen with other medications

• Premenstrual Dysphoric Disorder
• Rheumatoid Arthritis

Where can I get more information?

• Your pharmacist can provide more information about meclofenamate.

Tranxene T-Tab

Pronunciation: klor-AZ-e-pate
Generic Name: Clorazepate
Brand Name: Tranxene T-Tab

Tranxene T-Tab is used for:

Treating anxiety disorders, certain types of seizures, and symptoms of alcohol withdrawal. It may also be used for other conditions as determined by your doctor.

Tranxene T-Tab is a benzodiazepine. It works by slowing down the movement of chemicals in the brain. This results in a reduction in nervous tension (anxiety) and may cause some drowsiness.

Do NOT use Tranxene T-Tab if:

• you are allergic to any ingredient in Tranxene T-Tab


• you are taking sodium oxybate (GHB)


• you have narrow-angle glaucoma or severe liver disease

Contact your doctor or health care provider right away if any of these apply to you.

Video: Treatment for Depression

Treatments for depression are getting better everyday and there are things you can start doing right away.

Before using Tranxene T-Tab:

Some medical conditions may interact with Tranxene T-Tab. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicines, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have glaucoma, liver or kidney problems, seizures, muscle problems, a blood disorder, or lung problems


• if you have a history of mental or mood problems (eg, depression), suicidal thoughts or actions, or psychosis


• if you have a history of alcohol or substance abuse or dependence

Some MEDICINES MAY INTERACT with Tranxene T-Tab. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Hydantoins (eg, phenytoin) or rifampin because they may decrease Tranxene T-Tab's effectiveness


• Cimetidine, clozapine, disulfiram, HIV protease inhibitors (eg, ritonavir), hormonal birth control (eg, birth control pills), methadone, nefazodone, omeprazole, sodium oxybate (GHB), or valproic acid because side effects, such as confusion and increased drowsiness, may occur

This may not be a complete list of all interactions that may occur. Ask your health care provider if Tranxene T-Tab may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Tranxene T-Tab:

Use Tranxene T-Tab as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Take Tranxene T-Tab by mouth with or without food.


• If you also take clozapine, do not take it within 2 hours before or after taking Tranxene T-Tab. These doses must be separated. Check with your doctor if you have questions.


• Do not suddenly stop taking Tranxene T-Tab. You may have an increased risk of serious side effects.


• If you miss a dose of Tranxene T-Tab and are using it regularly, take it as soon as possible. If you do not remember until later, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Tranxene T-Tab.

Important safety information:

• Tranxene T-Tab may cause blurred vision, dizziness, drowsiness, or lightheadedness. These effects may be worse if you take it with alcohol or certain medicines. Use Tranxene T-Tab with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Do not drink alcohol or use medicines that may cause drowsiness (eg, sleep aids, muscle relaxers) while you are using Tranxene T-Tab; it may add to their effects. Ask your pharmacist if you have questions about which medicines may cause drowsiness.


• The risk of Tranxene T-Tab becoming habit-forming may be greater if you take Tranxene T-Tab in high doses or for a long time. Do NOT take more than the recommended dose or take for longer than prescribed without checking with your doctor.


• Patients who take Tranxene T-Tab may be at increased risk for suicidal thoughts or actions. The risk may be greater in patients who have had suicidal thoughts or actions in the past. Watch patients who take Tranxene T-Tab closely. Contact the doctor at once if new, worsened, or sudden symptoms such as depressed mood; anxious, restless, or irritable behavior; panic attacks; or any unusual change in mood or behavior occur. Contact the doctor right away if any signs of suicidal thoughts or actions occur.


• Lab tests, including complete blood cell counts, liver and kidney tests, may be performed while you use Tranxene T-Tab. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Use Tranxene T-Tab with caution in the ELDERLY; they may be more sensitive to its effects.


• Tranxene T-Tab should be used with extreme caution in CHILDREN younger than 9 years old; safety and effectiveness in these children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: Tranxene T-Tab has been shown to cause harm to the fetus. If you think you may be pregnant, contact your doctor. You will need to discuss the benefits and risks of using Tranxene T-Tab while you are pregnant. Tranxene T-Tab is found in breast milk. Do not breast-feed while taking Tranxene T-Tab.

When used for long periods of time or at high doses, Tranxene T-Tab may not work as well and may require higher doses to obtain the same effect as when originally taken. This is known as TOLERANCE. Talk with your doctor if Tranxene T-Tab stops working well. Do not take more than prescribed.

Some people who use Tranxene T-Tab for a long time may develop a need to continue taking it. People who take high doses are also at risk. This is known as DEPENDENCE or addiction.

If you suddenly stop taking Tranxene T-Tab, you may experience WITHDRAWAL symptoms.

Possible side effects of Tranxene T-Tab:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Blurred vision; clumsiness; confusion; dizziness; drowsiness; dry mouth; headache; lightheadedness; nervousness; stomach upset; unsteadiness; unusual weakness.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); decreased urination or change in the amount of urine produced; double vision; new or worsening mental or mood changes (eg, depression, agitation, anxiety, panic attacks, aggressiveness, impulsiveness, irritability, hostility, exaggerated feeling of well-being, restlessness, inability to sit still); new or worsening seizures; slurred speech; suicidal thoughts or actions; tremor; trouble sleeping.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Tranxene T-Tab side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include clumsiness; confusion; deep sleep; drowsiness; impaired coordination; loss of consciousness; slow reflexes.

Proper storage of Tranxene T-Tab:

Store Tranxene T-Tab between 68 and 77 degrees F (20 and 25 degrees C). Store in a tightly closed container. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Tranxene T-Tab out of the reach of children and away from pets.

General information:

• If you have any questions about Tranxene T-Tab, please talk with your doctor, pharmacist, or other health care provider.


• Tranxene T-Tab is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is summary only. It does not contain all information about Tranxene T-Tab. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

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