Plavix (sanofi-aventis Bristol-Myers Squibb SNC)

1. Name Of The Medicinal Product

Plavix 75 mg film

Plavix 300 mg film

2. Qualitative And Quantitative Composition

Plavix 75mg tablets:

Each film

Excipients: each tablet contains 3 mg lactose and 3.3 mg hydrogenated castor oil.

Plavix 300mg tablets:

Each film

Excipients: each tablet contains 12 mg lactose and 13.2 mg hydrogenated castor oil.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film

Plavix 75mg tablets: Pink, round, biconvex, engraved with «75» on one side and «1171» on the other side.

Plavix 300mg tablets: Pink, oblong, engraved with «300» on one side and «1332» on the other side.

4. Clinical Particulars

4.1 Therapeutic Indications

Clopidogrel is indicated in adults for the prevention of atherothrombotic events in:

• Patients suffering from myocardial infarction (from a few days until less than 35 days), ischaemic stroke (from 7 days until less than 6 months) or established peripheral arterial disease.

• Patients suffering from acute coronary syndrome:

	- Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), including patients undergoing a stent placement following percutaneous coronary intervention, in combination with acetylsalicylic acid (ASA).
	- ST segment elevation acute myocardial infarction, in combination with ASA in medically treated patients eligible for thrombolytic therapy.

For further information please refer to section 5.1.

4.2 Posology And Method Of Administration

• Adults and elderly

Clopidogrel should be given as a single daily dose of 75 mg with or without food.

The 300 mg tablet of clopidogrel is intended for use as a loading dose in patients suffering from acute coronary syndrome:

	− Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction): clopidogrel treatment should be initiated with a single 300
	- ST segment elevation acute myocardial infarction: clopidogrel should be given as a single daily dose of 75 mg initiated with a 300

• Pharmacogenetics

CYP2C19 poor metaboliser status is associated with diminished response to clopidogrel. The optimal dose regimen for poor metabolisers has yet to be determined (see Section 5.2).

• Paediatric patients

The safety and efficacy of clopidogrel in children and adolescents have not yet been established.

• Renal impairment

Therapeutic experience is limited in patients with renal impairment (see section 4.4).

• Hepatic impairment

Therapeutic experience is limited in patients with moderate hepatic disease who may have bleeding diatheses (see section 4.4).

4.3 Contraindications

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

• Severe liver impairment.

• Active pathological bleeding such as peptic ulcer or intracranial haemorrhage.

4.4 Special Warnings And Precautions For Use

Bleeding and haematological disorders

Due to the risk of bleeding and haematological adverse reactions, blood cell count determination and/or other appropriate testing should be promptly considered whenever clinical symptoms suggestive of bleeding arise during the course of treatment (see section 4.8). As with other antiplatelet agents, clopidogrel should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other pathological conditions and in patients receiving treatment with ASA, heparin, glycoprotein IIb/IIIa inhibitors or non

If a patient is to undergo elective surgery and antiplatelet effect is temporarily not desirable, clopidogrel should be discontinued 7 days prior to surgery. Patients should inform physicians and dentists that they are taking clopidogrel before any surgery is scheduled and before any new medicinal product is taken. Clopidogrel prolongs bleeding time and should be used with caution in patients who have lesions with a propensity to bleed (particularly gastrointestinal and intraocular).

Patients should be told that it might take longer than usual to stop bleeding when they take clopidogrel (alone or in combination with ASA), and that they should report any unusual bleeding (site or duration) to their physician.

Thrombotic Thrombocytopenic Purpura (TTP)

Thrombotic Thrombocytopenic Purpura (TTP) has been reported very rarely following the use of clopidogrel, sometimes after a short exposure. It is characterised by thrombocytopenia and microangiopathic haemolytic anaemia associated with either neurological findings, renal dysfunction or fever. TTP is a potentially fatal condition requiring prompt treatment including plasmapheresis.

Recent ischaemic stroke

In view of the lack of data, clopidogrel cannot be recommended during the first 7 days after acute ischaemic stroke.

Cytochrome P450 2C19 (CYP2C19)

Pharmacogenetics: Based on literature data, patients with genetically reduced CYP2C19 function have lower systemic exposure to the active metabolite of clopidogrel and diminished antiplatelet responses, and generally exhibit higher cardiovascular event rates following myocardial infarction than do patients with normal CYP2C19 function (see section 5.2).

Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of medicinal products that inhibit the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite of clopidogrel. The clinical relevance of this interaction is uncertain. As a precaution concomitant use of medicinal products that inhibit CYP2C19 should be discouraged (see section 4.5 for a list of CYP2C19 inhibitors, see also section 5.2).

Renal impairment

Therapeutic experience with clopidogrel is limited in patients with renal impairment. Therefore clopidogrel should be used with caution in these patients (see section 4.2).

Hepatic impairment

Experience is limited in patients with moderate hepatic disease who may have bleeding diatheses. Clopidogrel should therefore be used with caution in this population (see section 4.2).

Excipients

Plavix contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains hydrogenated castor oil which may cause stomach upset and diarrhoea.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Oral anticoagulants: the concomitant administration of clopidogrel with oral anticoagulants is not recommended since it may increase the intensity of bleedings (see section 4.4).

Glycoprotein IIb/IIIa inhibitors: clopidogrel should be used with caution in patients who receive concomitant glycoprotein IIb/IIIa inhibitors (see section 4.4).

Acetylsalicylic acid (ASA): ASA did not modify the clopidogrel-mediated inhibition of ADP-induced platelet aggregation, but clopidogrel potentiated the effect of ASA on collagen-induced platelet aggregation. However, concomitant administration of 500 mg of ASA twice a day for one day did not significantly increase the prolongation of bleeding time induced by clopidogrel intake. A pharmacodynamic interaction between clopidogrel and acetylsalicylic acid is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution (see section 4.4). However, clopidogrel and ASA have been administered together for up to one year (see section 5.1).

Heparin: in a clinical study conducted in healthy subjects, clopidogrel did not necessitate modification of the heparin dose or alter the effect of heparin on coagulation. Co-administration of heparin had no effect on the inhibition of platelet aggregation induced by clopidogrel. A pharmacodynamic interaction between clopidogrel and heparin is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution (see section 4.4).

Thrombolytics: the safety of the concomitant administration of clopidogrel, fibrin or non

NSAIDs: in a clinical study conducted in healthy volunteers, the concomitant administration of clopidogrel and naproxen increased occult gastrointestinal blood loss. However, due to the lack of interaction studies with other NSAIDs it is presently unclear whether there is an increased risk of gastrointestinal bleeding with all NSAIDs. Consequently, NSAIDs including Cox-2 inhibitors and clopidogrel should be co-administered with caution (see section 4.4).

Other concomitant therapy: Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of medicinal products that inhibit the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite of clopidogrel. The clinical relevance of this interaction is uncertain. As a precaution concomitant use of medicinal products that inhibit CYP2C19 should be discouraged (see sections 4.4 and 5.2).

Medicinal products that inhibit CYP2C19 include omeprazole and esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine and chloramphenicol.

Proton Pump Inhibitors (PPI): In a crossover clinical study, clopidogrel (300-mg loading dose followed by 75 mg/day) alone and with omeprazole (80 mg at the same time as clopidogrel) were administered for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 45% (Day 1) and 40% (Day 5) when clopidogrel and omeprazole were administered together. Mean inhibition of platelet aggregation (IPA) with 5 μM ADP was diminished by 39% (24 hours) and 21% (Day 5) when clopidogrel and omeprazole were administered together. In another study it was shown that administering clopidogrel and omeprazole 12 hours apart did not prevent their interaction that is likely to be driven by the inhibitory effect of omeprazole on CYP2C19. Esomeprazole is expected to give a similar interaction with clopidogrel.

Inconsistent data on the clinical implications of this pharmacokinetic (PK)/pharmacodynamic (PD) interaction in terms of major cardiovascular events have been reported from both observational and clinical studies. As a precaution, concomitant use of omeprazole or esomeprozole should be discouraged (see section 4.4). No conclusive data on the pharmacodynamic interaction of clopidogrel and other PPIs are available.

There is no evidence that other medicinal products that reduce stomach acid such as H2 blockers (except cimetidine which is a CYP2C19 inhibitor) or antacids interfere with antiplatelet activity of clopidogrel.

Other medicinal products: A number of other clinical studies have been conducted with clopidogrel and other concomitant medicinal products to investigate the potential for pharmacodynamic and pharmacokinetic interactions. No clinically significant pharmacodynamic interactions were observed when clopidogrel was co

The pharmacokinetics of digoxin or theophylline were not modified by the co

Data from studies with human liver microsomes indicated that the carboxylic acid metabolite of clopidogrel could inhibit the activity of Cytochrome P450 2C9. This could potentially lead to increased plasma levels of medicinal products such as phenytoin and tolbutamide and the NSAIDs, which are metabolised by Cytochrome P450 2C9. Data from the CAPRIE study indicate that phenytoin and tolbutamide can be safely co-administered with clopidogrel.

Apart from the specific medicinal product interaction information described above, interaction studies with clopidogrel and some medicinal products commonly administered in patients with atherothrombotic disease have not been performed. However, patients entered into clinical trials with clopidogrel received a variety of concomitant medicinal products including diuretics, beta blockers, ACEI, calcium antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic agents (including insulin), antiepileptic agents, and GPIIb/IIIa antagonists without evidence of clinically significant adverse interactions.

4.6 Pregnancy And Lactation

As no clinical data on exposure to clopidogrel during pregnancy are available, it is preferable not to use clopidogrel during pregnancy as a precautionary measure.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).

It is unknown whether clopidogrel is excreted in human breast milk. Animal studies have shown excretion of clopidogrel in breast milk. As a precautionary measure, breast

4.7 Effects On Ability To Drive And Use Machines

Clopidogrel has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable Effects

Clopidogrel has been evaluated for safety in more than 42,000 patients who have participated in clinical studies, including over 9,000 patients treated for 1 year or more. The clinically relevant adverse reactions observed in the CAPRIE, CURE, CLARITY and COMMIT studies are discussed below. Overall, clopidogrel 75 mg/day was comparable to ASA 325 mg/day in CAPRIE regardless of age, gender and race. In addition to clinical studies experience, adverse reactions have been spontaneously reported.

Bleeding is the most common reaction reported both in clinical studies as well as in post

In CAPRIE, in patients treated with either clopidogrel or ASA, the overall incidence of any bleeding was 9.3%. The incidence of severe cases was 1.4% for clopidogrel and 1.6% for ASA.

In CURE, the major bleeding event rate for clopidogrel+ASA was dose-dependent on ASA (<100mg: 2.6%; 100-200mg: 3.5%; >200mg: 4.9%) as was the major bleeding event rate for placebo+ASA (<100mg: 2.0%; 100-200mg: 2.3%; >200mg: 4.0%). The risk of bleeding (life-threatening, major, minor, other) decreased during the course of the trial: 0

In CLARITY, there was an overall increase in bleeding in the clopidogrel + ASA group (17.4%) vs. the placebo + ASA group (12.9%).The incidence of major bleeding was similar between groups (1.3% versus 1.1% for the clopidogrel + ASA and the placebo + ASA groups, respectively). This was consistent across subgroups of patients defined by baseline characteristics, and type of fibrinolytic or heparin therapy.

In COMMIT, the overall rate of noncerebral major bleeding or cerebral bleeding was low and similar in both groups (0.6% versus 0.5% in the clopidogrel + ASA and the placebo + ASA groups, respectively).

Adverse reactions that occurred either during clinical studies or that were spontaneously reported are presented in the table below. Their frequency is defined using the following conventions: common (

System Organ Class	Common	Uncommon	Rare	Very rare
Blood and the lymphatic system disorders		Thrombocytopenia, leucopenia, eosinophilia	Neutropenia, including severe neutropenia	Thrombotic thrombocytopenic purpura (TTP) (see section 4.4), aplastic anaemia, pancytopenia, agranulocytosis, severe thrombocytopenia, granulocytopenia, anaemia
Immune system disorders				Serum sickness, anaphylactoid reactions
Psychiatric disorders				Hallucinations, confusion
Nervous system disorders		Intracranial bleeding (some cases were reported with fatal outcome), headache, paraesthesia, dizziness		Taste disturbances
Eye disorders		Eye bleeding (conjunctival, ocular, retinal)
Ear and labyrinth disorders			Vertigo
Vascular disorders	Haematoma			Serious haemorrhage, haemorrhage of operative wound, vasculitis, hypotension
Respiratory, thoracic and mediastinal disorders	Epistaxis			Respiratory tract bleeding (haemoptysis, pulmonary haemorrhage), bronchospasm, interstitial pneumonitis
Gastrointestinal disorders	Gastrointestinal haemorrhage, diarrhoea, abdominal pain, dyspepsia	Gastric ulcer and duodenal ulcer, gastritis, vomiting, nausea, constipation, flatulence	Retroperitoneal haemorrhage	Gastrointestinal and retroperitoneal haemorrhage with fatal outcome, pancreatitis, colitis (including ulcerative or lymphocytic colitis), stomatitis
Hepato-biliary disorders				Acute liver failure, hepatitis, abnormal liver function test
Skin and subcutaneous tissue disorders	Bruising	Rash, pruritus, skin bleeding (purpura)		Bullous dermatitis (toxic epidermal necrolysis, Stevens Johnson Syndrome, erythema multiforme), angioedema, rash erythematous, urticaria, eczema, lichen planus
Musculoskeletal connective tissue and bone disorders				Musculo
Renal and urinary disorders		Haematuria		Glomerulonephritis blood creatinine increased
General disorders and administration site conditions	Bleeding at puncture site			Fever
Investigations		Bleeding time prolonged, neutrophil count decreased, platelet count decreased

4.9 Overdose

Overdose following clopidogrel administration may lead to prolonged bleeding time and subsequent bleeding complications. Appropriate therapy should be considered if bleedings are observed.

No antidote to the pharmacological activity of clopidogrel has been found. If prompt correction of prolonged bleeding time is required, platelet transfusion may reverse the effects of clopidogrel.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: platelet aggregation inhibitors excl. heparin, ATC Code: B01AC

Clopidogrel is a prodrug, one of whose metabolites is an inhibitor of platelet aggregation. Clopidogrel must be metabolised by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y₁₂ receptor and the subsequent ADP

Because the active metabolite is formed by CYP450 enzymes, some of which are polymorphic or subject to inhibition by other drugs, not all patients will have adequate platelet inhibition.

Repeated doses of 75 mg per day produced substantial inhibition of ADP-induced platelet aggregation from the first day; this increased progressively and reached steady state between Day 3 and Day 7. At steady state, the average inhibition level observed with a dose of 75 mg per day was between 40% and 60%. Platelet aggregation and bleeding time gradually returned to baseline values, generally within 5 days after treatment was discontinued.

The safety and efficacy of clopidogrel have been evaluated in 4 double-blind studies involving over 80,000 patients: the CAPRIE study, a comparison of clopidogrel to ASA, and the CURE, CLARITY and COMMIT studies comparing clopidogrel to placebo, both medicinal products given in combination with ASA and other standard therapy.

Recent myocardial infarction (MI), recent stroke or established peripheral arterial disease

The CAPRIE study included 19,185 patients with atherothrombosis as manifested by recent myocardial infarction (<35 days), recent ischaemic stroke (between 7 days and 6 months) or established peripheral arterial disease (PAD). Patients were randomised to clopidogrel 75 mg/day or ASA 325 mg/day, and were followed for 1 to 3 years. In the myocardial infarction subgroup, most of the patients received ASA for the first few days following the acute myocardial infarction.

Clopidogrel significantly reduced the incidence of new ischaemic events (combined end point of myocardial infarction, ischaemic stroke and vascular death) when compared to ASA. In the intention to treat analysis, 939 events were observed in the clopidogrel group and 1,020 events with ASA (relative risk reduction (RRR) 8.7%, [95% CI: 0.2 to 16.4]; p = 0.045), which corresponds, for every 1,000 patients treated for 2 years, to 10 [CI: 0 to 20] additional patients being prevented from experiencing a new ischaemic event. Analysis of total mortality as a secondary endpoint did not show any significant difference between clopidogrel (5.8%) and ASA (6.0%).

In a subgroup analysis by qualifying condition (myocardial infarction, ischaemic stroke, and PAD) the benefit appeared to be strongest (achieving statistical significance at p = 0.003) in patients enrolled due to PAD (especially those who also had a history of myocardial infarction) (RRR = 23.7%; CI: 8.9 to 36.2) and weaker (not significantly different from ASA) in stroke patients (RRR = 7.3%; CI: -5.7 to 18.7 [p=0.258]). In patients who were enrolled in the trial on the sole basis of a recent myocardial infarction, clopidogrel was numerically inferior, but not statistically different from ASA (RRR = -4.0%; CI: -22.5 to 11.7 [p=0.639]). In addition, a subgroup analysis by age suggested that the benefit of clopidogrel in patients over 75 years was less than that observed in patients

Since the CAPRIE trial was not powered to evaluate efficacy of individual subgroups, it is not clear whether the differences in relative risk reduction across qualifying conditions are real, or a result of chance.

Acute coronary syndrome

The CURE study included 12,562 patients with non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), and presenting within 24 hours of onset of the most recent episode of chest pain or symptoms consistent with ischaemia. Patients were required to have either ECG changes compatible with new ischaemia or elevated cardiac enzymes or troponin I or T to at least twice the upper limit of normal. Patients were randomised to clopidogrel (300 mg loading dose followed by 75 mg/day, N=6,259) or placebo (N=6,303), both given in combination with ASA (75-325 mg once daily) and other standard therapies. Patients were treated for up to one year. In CURE, 823 (6.6%) patients received concomitant GPIIb/IIIa receptor antagonist therapy. Heparins were administered in more than 90% of the patients and the relative rate of bleeding between clopidogrel and placebo was not significantly affected by the concomitant heparin therapy.

The number of patients experiencing the primary endpoint [cardiovascular (CV) death, myocardial infarction (MI), or stroke] was 582 (9.3%) in the clopidogrel-treated group and 719 (11.4%) in the placebo-treated group, a 20% relative risk reduction (95% CI of 10%-28%; p=0.00009) for the clopidogrel-treated group (17% relative risk reduction when patients were treated conservatively, 29% when they underwent percutaneous transluminal coronary angioplasty (PTCA) with or without stent and 10% when they underwent coronary artery bypass graft (CABG)). New cardiovascular events (primary endpoint) were prevented, with relative risk reductions of 22% (CI: 8.6, 33.4), 32% (CI: 12.8, 46.4), 4% (CI: -26.9, 26.7), 6% (CI: -33.5, 34.3) and 14% (CI: -31.6, 44.2), during the 0

The use of clopidogrel in CURE was associated with a decrease in the need of thrombolytic therapy (RRR = 43.3%; CI: 24.3%, 57.5%) and GPIIb/IIIa inhibitors (RRR = 18.2%; CI: 6.5%, 28.3%).

The number of patients experiencing the co-primary endpoint (CV death, MI, stroke or refractory ischaemia) was 1,035 (16.5%) in the clopidogrel-treated group and 1,187 (18.8%) in the placebo-treated group, a 14% relative risk reduction (95% CI of 6%-21%, p=0.0005) for the clopidogrel-treated group. This benefit was mostly driven by the statistically significant reduction in the incidence of MI [287 (4.6%) in the clopidogrel treated group and 363 (5.8%) in the placebo treated group]. There was no observed effect on the rate of rehospitalisation for unstable angina.

The results obtained in populations with different characteristics (e.g. unstable angina or non-Q-wave MI, low to high risk levels, diabetes, need for revascularisation, age, gender, etc.) were consistent with the results of the primary analysis. In particular, in a post-hoc analysis in 2,172 patients (17% of the total CURE population) who underwent stent placement (Stent-CURE), the data showed that clopidogrel compared to placebo, demonstrated a significant RRR of 26.2% favouring clopidogrel for the co-primary endpoint (CV death, MI, stroke) and also a significant RRR of 23.9% for the second co-primary endpoint (CV death, MI, stroke or refractory ischaemia). Moreover, the safety profile of clopidogrel in this subgroup of patients did not raise any particular concern. Thus, the results from this subset are in line with the overall trial results.

The benefits observed with clopidogrel were independent of other acute and long-term cardiovascular therapies (such as heparin/LMWH, GPIIb/IIIa antagonists, lipid lowering medicinal products, beta blockers, and ACE-inhibitors). The efficacy of clopidogrel was observed independently of the dose of ASA (75

In patients with acute ST-segment elevation MI, safety and efficacy of clopidogrel have been evaluated in 2 randomised, placebo-controlled, double-blind studies, CLARITY and COMMIT.

The CLARITY trial included 3,491 patients presenting within 12 hours of the onset of a ST elevation MI and planned for thrombolytic therapy. Patients received clopidogrel (300 mg loading dose, followed by 75 mg/day, n=1,752) or placebo (n=1,739), both in combination with ASA (150 to 325 mg as a loading dose, followed by 75 to 162 mg/day), a fibrinolytic agent and, when appropriate, heparin. The patients were followed for 30 days. The primary endpoint was the occurrence of the composite of an occluded infarct-related artery on the predischarge angiogram, or death or recurrent MI before coronary angiography. For patients who did not undergo angiography, the primary endpoint was death or recurrent myocardial infarction by Day 8 or by hospital discharge. The patient population included 19.7% women and 29.2% patients

Fifteen percent (15.0%) of patients in the clopidogrel group and 21.7% in the placebo group reached the primary endpoint, representing an absolute reduction of 6.7% and a 36 % odds reduction in favor of clopidogrel (95% CI: 24, 47%; p < 0.001), mainly related to a reduction in occluded infarct-related arteries. This benefit was consistent across all prespecified subgroups including patients' age and gender, infarct location, and type of fibrinolytic or heparin used.

The 2x2 factorial design COMMIT trial included 45,852 patients presenting within 24 hours of the onset of the symptoms of suspected MI with supporting ECG abnormalities (i.e. ST elevation, ST depression or left bundle-branch block). Patients received clopidogrel (75 mg/day, n=22,961) or placebo (n=22,891), in combination with ASA (162 mg/day), for 28 days or until hospital discharge. The co-primary endpoints were death from any cause and the first occurrence of re-infarction, stroke or death. The population included 27.8% women, 58.4% patients

Clopidogrel significantly reduced the relative risk of death from any cause by 7% (p = 0.029), and the relative risk of the combination of re-infarction, stroke or death by 9% (p = 0.002), representing an absolute reduction of 0.5% and 0.9%, respectively. This benefit was consistent across age, gender and with or without fibrinolytics, and was observed as early as 24 hours.

5.2 Pharmacokinetic Properties

Absorption

After single and repeated oral doses of 75 mg per day, clopidogrel is rapidly absorbed. Mean peak plasma levels of unchanged clopidogrel (approximately 2.2-2.5 ng/ml after a single 75 mg oral dose) occurred approximately 45 minutes after dosing. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.

Distribution

Clopidogrel and the main circulating (inactive) metabolite bind reversibly in vitro to human plasma proteins (98% and 954% respectively). The binding is non-saturable in vitro over a wide concentration range.

Metabolism

Clopidogrel is extensively metabolised by the liver. In vitro and in vivo, clopidogrel is metabolised according to two main metabolic pathways: one mediated by esterases and leading to hydrolysis into its inactive carboxylic acid derivative (85% of circulating metabolites), and one mediated by multiple cytochromes P450. Clopidogrel is first metabolised to a 2-oxo-clopidogrel intermediate metabolite. Subsequent metabolism of the 2-oxo-clopidogrel intermediate metabolite results in formation of the active metabolite, a thiol derivative of clopidogrel. In vitro, this metabolic pathway is mediated by CYP3A4, CYP2C19, CYP1A2 and CYP2B6. The active thiol metabolite which has been isolated in vitro, binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation.

Elimination

Following an oral dose of ¹⁴C-labelled clopidogrel in man, approximately 50% was excreted in the urine and approximately 46% in the faeces in the 120-hour interval after dosing. After a single oral dose of 75mg, clopidogrel has a half-life of approximately 6 hours. The elimination half-life of the main circulating metabolite was 8 hours after single and repeated administration.

Pharmacogenetics

Several polymorphic CYP450 enzymes activate clopidogrel. CYP2C19 is involved in the formation of both the active metabolite and the 2-oxo-clopidogrel intermediate metabolite. Clopidogrel active metabolite pharmacokinetics and antiplatelet effects, as measured by ex vivo platelet aggregation assays, differ according to CYP2C19 genotype. The CYP2C19*1 allele corresponds to fully functional metabolism while the CYP2C19*2 and CYP2C19*3 alleles correspond to reduced metabolism. The CYP2C19*2 and CYP2C19*3 alleles account for 85% of reduced function alleles in whites and 99% in Asians. Other alleles associated with reduced metabolism include CYP2C19*4, *5, *6, *7, and *8, but these are less frequent in the general population. Published frequencies for the common CYP2C19 phenotypes and genotypes are listed in the table below.

CYP2C19 Phenotype and Genotype Frequency

	Frequency (%)
	White (n=1356)	Black (n=966)	Chinese (n=573)
Extensive metabolism: CYP2C19*1/*1	74	66	38
Intermediate metabolism: CYP2C19*1/*2 or *1/*3	26	29	50
Poor metabolism: CYP2C19*2/*2, *2/*3 or *3/*3	2	4	14

To date, the impact of CYP2C19 genotype on the pharmacokinetics of the active metabolite of clopidogrel has been evaluated in 227 subjects from 7 reported studies. Reduced CYP2C19 metabolism in intermediate and poor metabolisers decreased the C_max and AUC of the active metabolite by 30

The association between CYP2C19 genotype and clopidogrel treatment outcome was evaluated in 2 post hoc clinical trial analyses (substudies of CLARITY [n=465] and TRITON

Pharmacogenetic testing can identify genotypes associated with variability in CYP2C19 activity.

There may be genetic variants of other CYP450 enzymes with effects on the ability to form the active metabolite of clopidogrel.

Special populations

The pharmacokinetics of the active metabolite of clopidogrel is not known in these special populations.

Renal impairment

After repeated doses of 75 mg clopidogrel per day in subjects with severe renal disease (creatinine clearance from 5 to 15 ml/min), inhibition of ADP-induced platelet aggregation was lower (25%) than that observed in healthy subjects, however, the prolongation of bleeding time was similar to that seen in healthy subjects receiving 75 mg of clopidogrel per day. In addition, clinical tolerance was good in all patients.

Hepatic impairment

After repeated doses of 75 mg clopidogrel per day for 10 days in patients with severe hepatic impairment, inhibition of ADP

Race

The prevalence of CYP2C19 alleles that result in intermediate and poor CYP2C19 metabolism differs according to race/ethnicity (see Pharmacogenetics). From literature, limited data in Asian populations are available to assess the clinical implication of genotyping of this CYP on clinical outcome events.

5.3 Preclinical Safety Data

During non clinical studies in rat and baboon, the most frequently observed effects were liver changes. These occurred at doses representing at least 25 times the exposure seen in humans receiving the clinical dose of 75 mg/day and were a consequence of an effect on hepatic metabolising enzymes. No effect on hepatic metabolising enzymes was observed in humans receiving clopidogrel at the therapeutic dose.

At very high doses, a poor gastric tolerability (gastritis, gastric erosions and/or vomiting) of clopidogrel was also reported in rat and baboon.

There was no evidence of carcinogenic effect when clopidogrel was administered for 78 weeks to mice and 104 weeks to rats when given at doses up to 77 mg/kg per day (representing at least 25 times the exposure seen in humans receiving the clinical dose of 75 mg/day).

Clopidogrel has been tested in a range of in vitro and in vivo genotoxicity studies, and showed no genotoxic activity.

Clopidogrel was found to have no effect on the fertility of male and female rats and was not teratogenic in either rats or rabbits. When given to lactating rats, clopidogrel caused a slight delay in the development of the offspring. Specific pharmacokinetic studies performed with radiolabelled clopidogrel have shown that the parent compound or its metabolites are excreted in the milk. Consequently, a direct effect (slight toxicity), or an indirect effect (low palatability) cannot be excluded.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Core:

Mannitol (E421)

Macrogol 6000

Microcrystalline cellulose

Hydrogenated castor oil

Low substituted hydroxypropylcellulose

Coating:

Hypromellose (E464)

Lactose

Triacetin (E1518)

Titanium dioxide (E171)

Red iron oxide (E172)

Polishing agent:

Carnauba wax

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

Plavix 75mg: 3 years

Plavix 300mg: 3 years

6.4 Special Precautions For Storage

Plavix 75mg tablets: Store below 30^oC.

Plavix 300mg tablets: This medicinal product does not require any special storage conditions.

6.5 Nature And Contents Of Container

Plavix 75mg tablets: PVC/PVDC/Aluminium blisters in cardboard cartons containing 30 film

Plavix 300mg tablets: Aluminium perforated unit

6.6 Special Precautions For Disposal And Other Handling

Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

Sanofi Pharma Bristol-Myers Squibb SNC

174 Avenue de France

F-75013 Paris – France

8. Marketing Authorisation Number(S)

Plavix 75mg tablets: EU/1/98/069/005a - Cartons of 30 film

Plavix 300mg tablets: EU/1/98/069/009 - Cartons of 30x1 film

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 15 July 1998

Date of latest renewal: 15 July 2008

10. Date Of Revision Of The Text

75mg tablet: 29 April 2010

300mg tablet: 29 April 2010

Legal Category

POM

Minims Lidocaine & Fluorescein

Minims*

Lidocaine and Fluorescein

4% w/v Lidocaine hydrochloride and 0.25% w/v Fluorescein Sodium

About your eye drops

The name of this medicine is Minims Lidocaine & Fluorescein. Each Minims unit contains a solution of 4% w/v Lidocaine hydrochloride with 0.25% w/v fluorescein sodium.

One of the active ingredients in this medicine is lidocaine hydrochloride. This is the new name for lignocaine hydrochloride. The ingredient itself has not changed.

It also contains purified water, povidone and hydrochloric acid. Each Minims unit is a sterile, single-use container which holds approximately 0.5ml of solution. Each carton holds 20 Minims units. Lidocaine is a local anaesthetic which temporarily numbs the surface of the eye. Fluorescein temporarily colours your eyes orange or green and helps your doctor or eye specialist to examine them.

Who makes your eye drops?

Minims Lidocaine and Fluorescein are manufactured by

Laboratoire Chauvin S.A.

ZI Ripotier

07200/Aubenas

France

The Marketing Authorisations for Minims Lidocaine and Fluorescein (PL 0033/0073 & PA 118/24/1) are held by

Chauvin Pharmaceuticals Ltd.

106 London Road

Kingston-Upon-Thames

KT2 6TN

England

What are your eye drops for?

Your eye drops are used to numb and stain the surface of the eye, for a short time only, to allow the doctor or eye specialist to examine your eye.

Most often, your eye drops are used to allow the pressure inside your eyes to be measured.

Before using your eye drops

You should not use this product if you are allergic to fluorescein or Lidocaine and other similar types of local anaesthetic.

This product should be used with care in eyes that are inflamed (red and painful).

Your eye drops are not intended for long term use. Frequent use of local anaesthetic in the eye over long periods of time may affect your eyesight.

Using your eye drops

The doctor or eye specialist will put the drops in for you. You may be asked to press on the inner corners of your eyes for a minute to stop the solution draining into your nose and throat through the tear ducts.

It is important to protect your eye from dust during the time your eye is numb. Your doctor or eye specialist will make sure that your eye is properly protected.

The Minims unit should be thrown away after a single use, even if some solution remains.

It is unlikely that you will suffer an overdose from Minims Lidocaine & Fluorescein, but if you do suddenly feel unwell after receiving the drops, tell your doctor or eye specialist.

Following administration of Minims Lidocaine & Fluorescein you may experience very rare side effects which includes redness and irriatation of the eye, swelling around the eye, rarely difficulty in breathing and symptoms of shock and itchy skin rash with raised red blotches.

After using your eye drops

Tell your doctor or eye specialist if you suffer from any unwanted effects after using Minims Lidocaine & Fluorescein, that are not mentioned in this leaflet.

Storing your eye drops

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

Your eye drops should be stored below 25°C and in original container to protect from light. Do not allow to freeze.

This leaflet applies only to Minims Lidocaine & Fluorescein, but does not contain all the

If you have any questions or are not sure about anything, ask a doctor, eye specialist or pharmacist.

Date of (Partial) Revision of Text:

August 2005.

* Trade Mark

Chauvin Pharmaceuticals Ltd.

106 London Road

Kingston-Upon-Thames

KT2 6TN

England

Tel:020 8781 2900

Fax:020 8781 2901

Art. 76441 0504128/4

acetaminophen and tramadol

Generic Name: acetaminophen and tramadol (a SEET a MIN o fen and TRAM a dol)

Brand Names: Ultracet

What is acetaminophen and tramadol?

Tramadol is a narcotic-like pain reliever. Acetaminophen is a less potent pain reliever that increases the effects of tramadol.

The combination of acetaminophen and tramadol is used to treat moderate to severe pain.

Acetaminophen and tramadol may also be used for purposes not listed in this medication guide.

What is the most important information I should know about acetaminophen and tramadol?

Tell your doctor if you have ever had alcoholic liver disease (cirrhosis) or if you drink more than 3 alcoholic beverages per day. You may not be able to take medicine that contains acetaminophen. Do not take more of this medication than is recommended. An acetaminophen and tramadol overdose can damage your liver or cause death. The maximum amount of acetaminophen and tramadol is 2 tablets per dose, or 8 tablets per day. You should not take this medication if you are allergic to acetaminophen and tramadol, if you are intoxicated (drunk), or if you have recently used narcotic pain medicine, a sedative or tranquilizer, medicine for depression or mental illness, or any type of street drug. Do not drink alcohol while you are taking acetaminophen and tramadol. Alcohol may cause a dangerous decrease in your breathing when used together with acetaminophen and tramadol. Alcohol may also increase your risk of liver damage while taking acetaminophen. Acetaminophen and tramadol may be habit-forming and should be used only by the person it was prescribed for. Never share this medication with another person, especially someone with a history of drug abuse or addiction. Keep the medication in a place where others cannot get to it.

What should I discuss with my healthcare provider before taking acetaminophen and tramadol?

You should not take this medication if you are allergic to it, if you are intoxicated (drunk), or if you have recently used any of the following drugs:

• 
  

  alcohol;

  
  


• 
  

  tramadol (Ultram) or narcotic pain medicine;

  
  


• 
  

  sedatives or tranquilizers (such as Valium);

  
  


• 
  

  medicine for depression or anxiety;

  
  


• 
  

  medicine for mental illness (such as bipolar disorder, schizophrenia); or

  
  


• 
  

  street drugs.

  
  

Tell your doctor if you have ever had alcoholic liver disease (cirrhosis) or if you drink more than 3 alcoholic beverages per day. You may not be able to take medicine that contains acetaminophen.

Seizures have occurred in some people taking acetaminophen and tramadol. Your risk of a seizure may be higher if you have any of these conditions:

• 
  

  a history of drug or alcohol addiction;

  
  


• 
  

  a history of epilepsy or other seizure disorder;

  
  


• 
  

  a history of head injury;

  
  


• 
  

  a metabolic disorder;

  
  


• 
  

  an infection of your brain or spinal cord, such as meningitis or encephalitis;

  
  


• 
  

  if you are also taking an antidepressant, mood stabilizer, or another narcotic pain medicine; or

  
  


• 
  

  if you have taken an MAO inhibitor such as isocarboxazid (Marplan), linezolid (Zyvox), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate) within the past 14 days.

  
  

Talk with your doctor about your individual risk of having a seizure.

To make sure you can safely take acetaminophen and tramadol, tell your doctor if you have any of these other conditions:

• 
  

  kidney disease;

  
  


• 
  

  liver disease;

  
  


• 
  

  asthma or other breathing disorder;

  
  


• 
  

  a stomach disorder; or

  
  


• 
  

  a history of depression, mental illness, or suicide attempt.

  
  

Acetaminophen and tramadol may be habit-forming and should be used only by the person it was prescribed for. Never share this medication with another person, especially someone with a history of drug abuse or addiction. Keep the medication in a place where others cannot get to it. FDA pregnancy category C. It is not known whether the combination of acetaminophen and tramadol is harmful to an unborn baby. Tramadol alone may have caused serious or fatal side effects in newborns of mothers who used the medication during pregnancy or labor. Tell your doctor if you are pregnant or plan to become pregnant during treatment with acetaminophen and tramadol. Acetaminophen and tramadol 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 acetaminophen and tramadol?

Take exactly as prescribed by your doctor. Do not take more of this medication than is recommended. An overdose of acetaminophen and tramadol can damage your liver or cause death. Follow the directions on your prescription label.

The maximum amount of acetaminophen and tramadol is 2 tablets per dose, or 8 tablets per day. Acetaminophen and tramadol should not be used for longer than 5 days in a row.

Acetaminophen and tramadol can be taken with or without food, but take it the same way each time.

Do not stop using this medicine suddenly, or you could have unpleasant withdrawal symptoms. Ask your doctor how to avoid withdrawal symptoms when you stop using acetaminophen and tramadol. Store at room temperature away from moisture and heat. Keep track of the amount of medicine used from each new bottle. Acetaminophen and tramadol is a drug of abuse and you should be aware if anyone is using your medicine improperly or without a prescription.

See also: Acetaminophen and tramadol dosage (in more detail)

What happens if I miss a dose?

Since pain medicine is taken as needed, you may not be on a dosing schedule. If you are taking the medication regularly, take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. An acetaminophen and tramadol overdose can be fatal.

The first signs of an acetaminophen overdose include loss of appetite, nausea, vomiting, stomach pain, sweating, and confusion or weakness. Later symptoms may include pain in your upper stomach, dark urine, and yellowing of your skin or the whites of your eyes.

Overdose symptoms may also include drowsiness, shallow breathing, slow heartbeat, extreme weakness, sweating, cold or clammy skin, feeling light-headed, fainting, seizure, or coma.

What should I avoid while taking acetaminophen and tramadol?

Do not drink alcohol while you are taking acetaminophen and tramadol. Alcohol may cause a dangerous decrease in your breathing when used together with acetaminophen and tramadol. Alcohol may also increase your risk of liver damage while taking acetaminophen. Acetaminophen and tramadol may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert. Ask a doctor or pharmacist before using any other cold, allergy, pain, or sleep medication. Acetaminophen (sometimes abbreviated as APAP) is contained in many combination medicines. Taking certain products together can cause you to get too much acetaminophen which can lead to a fatal overdose. Check the label to see if a medicine contains acetaminophen or APAP.

Acetaminophen and tramadol 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 using acetaminophen and tramadol and call your doctor at once if you have any of these serious side effects:

• 
  

  seizure (convulsions);

  
  


• 
  

  agitation, hallucinations, fever, fast heart rate, overactive reflexes, nausea, vomiting, diarrhea, loss of coordination, fainting;

  
  


• 
  

  a red, blistering, peeling skin rash; or

  
  


• 
  

  shallow breathing, weak pulse.

  
  

Less serious side effects may include:

• 
  

  dizziness, drowsiness, weakness, tired feeling;

  
  


• 
  

  stomach pain, constipation, loss of appetite;

  
  


• 
  

  dry mouth, blurred vision;

  
  


• 
  

  feeling nervous or anxious;

  
  


• 
  

  sweating, itching; or

  
  


• 
  

  sleep problems (insomnia).

  
  

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.

Acetaminophen and tramadol Dosing Information

Usual Adult Dose for Pain:

Short term management of acute pain (5 days or less): 2 tablets every 4 to 6 hours as needed for pain.
Maximum dose: 8 tablets per day.

Usual Geriatric Dose for Pain:

Short term management of acute pain (5 days or less): 2 tablets every 4 to 6 hours as needed for pain.
Maximum dose: 8 tablets per day.

What other drugs will affect acetaminophen and tramadol?

Cold or allergy medicine, sedatives, sleeping pills, muscle relaxers, and medicine for seizures, depression or anxiety can add to sleepiness caused by tramadol. Tell your doctor if you regularly use any of these medicines, or any narcotic pain medicine.

The following drugs can interact with acetaminophen and tramadol. Tell your doctor if you are using any of these:

• 
  

  carbamazepine (Carbatrol, Equetro, Tegretol);

  
  


• 
  

  warfarin (Coumadin, Jantoven);

  
  


• 
  

  digoxin (Lanoxin, Lanoxicaps);

  
  


• 
  

  ketoconazole (Nizoral);

  
  


• 
  

  erythromycin (E-Mycin, E.E.S., Ery-Tab);

  
  


• 
  

  rifampin (Rifadin, Rimactane, Rifater);

  
  


• 
  

  quinidine (Quin-G);

  
  


• 
  

  St. John's wort;

  
  


• 
  

  sumatriptan (Imitrex, Treximet) and other migraine headache medicines;

  
  


• 
  

  an antidepressant such as amitriptyline (Elavil), citalopram (Celexa), desipramine (Norpramin), fluoxetine (Prozac, Sarafem), imipramine (Tofranil), nortriptyline (Pamelor), paroxetine (Paxil), or sertraline (Zoloft); or

  
  


• 
  

  drugs to treat high blood pressure or a prostate disorder, such as alfuzosin (Uroxatral), doxazosin (Cardura), prazosin (Minipress), terazosin (Hytrin), tamsulosin (Flomax).

  
  

This list is not complete and other drugs may interact with acetaminophen and tramadol. Tell your doctor about all medications you use. This includes prescription, over the counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More acetaminophen and tramadol resources

• Acetaminophen and tramadol Dosage
• Acetaminophen and tramadol Use in Pregnancy & Breastfeeding
• Drug Images
• Acetaminophen and tramadol Drug Interactions
• Acetaminophen and tramadol Support Group
• 25 Reviews for Acetaminophen and tramadol - Add your own review/rating

Compare acetaminophen and tramadol with other medications

• Pain
• Rheumatoid Arthritis

Where can I get more information?

• Your pharmacist can provide more information about acetaminophen and tramadol.

Feostat Chewable Tablets

Pronunciation: FER-us FYOO-ma-rate
Generic Name: Ferrous Fumarate
Brand Name: Feostat

Accidental overdose of iron-containing products is a leading cause of fatal poisoning in children younger than 6 years of age. Keep this product out of the reach of children. In case of accidental overdose, call a doctor or poison control center immediately.

Feostat Chewable Tablets are used for:

Preventing or treating low levels of iron in the blood. It also may be used to treat other conditions as determined by your doctor.

Feostat Chewable Tablets are an essential body mineral. It works by replacing iron in the body when the body does not produce enough on its own.

Do NOT use Feostat Chewable Tablets if:

• you are allergic to any ingredient in Feostat Chewable Tablets


• you have high levels of iron in your blood

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

Before using Feostat Chewable Tablets:

Some medical conditions may interact with Feostat Chewable Tablets. 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 medicine, herbal preparation, or dietary supplement


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


• if you have inflammation of the intestines, Crohn disease, digestive problems, ulcers, anemia, or a blood disease (eg, porphyria, thalassemia)


• if you have had multiple blood transfusions

Some MEDICINES MAY INTERACT with Feostat Chewable Tablets. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Doxycycline, mycophenolate, penicillamine, or thyroid hormones (eg, levothyroxine) because the effectiveness of these medicines may be decreased

This may not be a complete list of all interactions that may occur. Ask your health care provider if Feostat Chewable Tablets 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 Feostat Chewable Tablets:

Use Feostat Chewable Tablets as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Feostat Chewable Tablets are absorbed better on an empty stomach but may be taken with food if it upsets your stomach.


• Chew thoroughly before swallowing.


• If you are also taking a bisphosphonate (eg, alendronate), cephalosporin (eg, cephalexin), methyldopa, penicillamine, quinolone (eg, ciprofloxacin), or tetracycline (eg, minocycline) along with Feostat Chewable Tablets, you may need to space the doses several hours apart. Ask your doctor or pharmacist how much time is needed between doses of Feostat Chewable Tablets and your other medicines.


• Do not take Feostat Chewable Tablets within 1 hour before or 2 hours after antacids, eggs, whole grain breads or cereal, milk, milk products, coffee, or tea.


• Take Feostat Chewable Tablets with a full glass of water (8 oz/240 mL). Do not lie down for 30 minutes after taking Feostat Chewable Tablets.


• If you miss a dose of Feostat Chewable Tablets, take it as soon as possible. If it is almost time for your next dose, 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 Feostat Chewable Tablets.

Important safety information:

• Do not take large doses of vitamins (megadoses or megavitamin therapy) unless otherwise directed by your doctor.


• Do not exceed the recommended dose or take Feostat Chewable Tablets for longer than 6 months without checking with your doctor.


• Feostat Chewable Tablets contains iron. Accidental overdose of iron-containing products is a leading cause of fatal poisoning in children younger than 6 years of age. In case of accidental overdose, call a doctor or poison control center immediately.


• LAB TESTS, including blood tests and iron levels, may be performed to monitor your progress or to check for side effects. Be sure to keep all doctor and lab appointments.


• Use Feostat Chewable Tablets with extreme caution in CHILDREN; safety and effectiveness have not been confirmed.


• Feostat Chewable Tablets contains iron. Accidental overdose of iron-containing products is a leading cause of fatal poisoning in children under 6 years of age. In case of accidental overdose, call a doctor or poison control center immediately.


• PREGNANCY and BREAST-FEEDING: If you plan on becoming pregnant, discuss with your doctor the benefits and risks of using Feostat Chewable Tablets during pregnancy. If you are or will be breast-feeding while you are using Feostat Chewable Tablets, check with your doctor or pharmacist to discuss the risks to your baby.

Possible side effects of Feostat Chewable Tablets:

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:

Constipation; darkened or green stools; diarrhea; nausea; stomach upset.

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

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); black, tarry stools; blood or streaks of blood in the stool; fever; vomiting with continuing sharp stomach pain.

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: Feostat 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 difficulty breathing; loss of consciousness; seizures; severe nausea; stomach pain; tarry stools; unusual tiredness; vomiting; weak, fast heartbeat.

Proper storage of Feostat Chewable Tablets:

Store Feostat Chewable Tablets at room temperature, between 68 and 77 degrees F (20 and 25 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Feostat Chewable Tablets out of the reach of children and away from pets.

General information:

• If you have any questions about Feostat Chewable Tablets, please talk with your doctor, pharmacist, or other health care provider.


• Feostat Chewable Tablets are 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 a summary only. It does not contain all information about Feostat Chewable Tablets. 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.

More Feostat resources

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

Compare Feostat with other medications

• Anemia Associated with Chronic Renal Failure
• Iron Deficiency Anemia
• Vitamin/Mineral Supplementation and Deficiency
• Vitamin/Mineral Supplementation during Pregnancy/Lactation

CLARELUX cutaneous foam

1. Name Of The Medicinal Product

CLARELUX 500 microgram/g cutaneous foam in pressurised container.

2. Qualitative And Quantitative Composition

Each gram contains 500 microgram clobetasol propionate.

For a full list of excipients, see section 6.1.

Excipients: also includes cetyl alcohol 11.5 mg/g, stearyl alcohol 5.2 mg/g and propylene glycol 20.9 mg/g.

3. Pharmaceutical Form

Cutaneous foam in pressurised container.

White foam that breaks down upon contact with skin.

4. Clinical Particulars

4.1 Therapeutic Indications

Short-course treatment of steroid responsive dermatoses of the scalp such as psoriasis, which do not respond satisfactorily to less active steroids.

4.2 Posology And Method Of Administration

CLARELUX is a highly potent topical corticosteroid; therefore, treatment should be limited to 2 consecutive weeks and amounts greater than 50 g/week should not be used.

Note: for proper dispensing of foam, hold the container upside down and depress the actuator.

Route of administration: for cutaneous use.

Avoid contact with eyes, nose and mouth. Do not use near a naked flame.

Use in adults

CLARELUX should be applied to the affected area twice daily. There are no data from clinical studies evaluating the efficacy of once daily application.

The foam application has been designed so that the preparation spreads easily without being too fluid and allows easy application direct to the affected area.

Invert the container and dispense a small amount (of the size of a walnut or one teaspoon) of CLARELUX directly on the lesions, or dispense a small amount into the cap of the container, onto a saucer or other cool surface, taking care to avoid contact with eyes, nose, and mouth. Dispensing directly onto hands is not recommended, as the foam will begin to melt immediately upon contact with warm skin. Gently massage into affected area until the foam disappears and is absorbed. Repeat until entire affected area is treated. Move the hair away from the affected area so that the foam can be applied to each affected area.

Use in Children and Adolescents

As there are no data regarding the use of CLARELUX in children and adolescents, use in these patients is not recommended.

4.3 Contraindications

CLARELUX is contraindicated in patients with hypersensitivity to clobetasol propionate, to other corticosteroids, or to any of the excipients.

CLARELUX is contraindicated in patients with burns, rosacea, acne vulgaris, perioral dermatitis, perianal and genital pruritus.

The use of CLARELUX is contraindicated in the treatment of primary infected skin lesions caused by infection with viruses, fungi or bacteria.

CLARELUX should not be used on the face.

4.4 Special Warnings And Precautions For Use

Long-term continuous topical therapy should be avoided as adrenal suppression can occur readily even without use with an occlusive dressing. Upon clearing of lesions or after a maximum treatment period of two weeks, change to intermittent therapy or consider replacing with a weaker steroid. With chronic intermittent use, Hypothalamic-Pituitary-Adrenal (HPA) axis function should be assessed periodically.

Secondary infection may develop, requiring the withdrawal of topical corticosteroid therapy and administration of appropriate antimicrobial products.

Special caution should be exercised if liver impairment is proven.

Topical corticosteroids may be hazardous because rebound relapses can follow development of tolerance. Patients may also be exposed to the risk of developing generalised pustular psoriasis and local or systemic toxicity due to impaired barrier function of the skin. Careful patient supervision is important.

Unless supervised by a physician, CLARELUX should not be used with occlusive dressings.

There have been a few reports in the literature of the development of cataracts in patients who have been using corticosteroids for prolonged periods of time. Although it is not possible to rule out systemic corticosteroids as a known factor, prescribers should be aware of the possible role of corticosteroids in cataract development.

This medicinal product contains propylene glycol, which may cause skin irritation. This medicinal product also contains cetyl alcohol and stearyl alcohol, which may cause local skin reactions (e.g. contact dermatitis).

As there are no data regarding the use of CLARELUX in children and adolescents, use in these patients is not recommended.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No interaction studies have been performed using CLARELUX.

4.6 Pregnancy And Lactation

Administration of corticosteroids to pregnant animals can cause abnormalities of foetal development (see 5.3 Preclinical Safety Data). There are no adequate and well-controlled studies of clobetasol propionate in pregnant women. Epidemiological studies in pregnant women following use of oral corticosteroids have indicated little or no risk with regard to an association with cleft palate.

CLARELUX should not be used during pregnancy unless clearly necessary.

The safe use of clobetasol propionate during lactation has not been established. Glucocorticosteroids are excreted in breast milk, therefore CLARELUX should not be used in breast-feeding women unless clearly necessary.

4.7 Effects On Ability To Drive And Use Machines

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

4.8 Undesirable Effects

The most commonly observed adverse reactions associated with the use of clobetasol propionate cutaneous foam formulations in clinical trials were application site reactions including burning (5%) and other non

Adverse reactions observed with clobetasol propionate cutaneous foam formulations in clinical trials are classified in body systems and listed below as very common (>10%), common (1-10%), uncommon (0.1 - 1%), rare (0.01 - 0.1%) and very rare (<0.01%), including isolated reports.

Nervous system disorders - Very rare: paraesthesia.

Eye disorders - Very rare: eye irritation.

Vascular disorders - Very rare: vein distended.

Skin and subcutaneous tissue disorders - Very rare: dermatitis not otherwise specified (NOS), dermatitis contact, psoriasis aggravated, skin irritation, skin tenderness, skin tightness.

General disorders and administration site conditions - Common: application site burning, application site reaction NOS; very rare: application site erythema, application site pruritus, pain NOS.

Investigations - Very rare: blood urine present, mean cell volume increased, protein urine present, urine nitrogen.

As with other topical corticosteroids, prolonged use of large amounts, or treatment of extensive areas can result in adrenocortical suppression. This is likely to be transient if the weekly dosage does not exceed 50g in adults.

Prolonged and intensive treatment with a highly active corticosteroid preparation may cause local atrophic changes in the skin such as thinning, striae, and dilatation of the superficial blood vessels, particularly when occlusive dressings are used or when skin folds are involved.

In rare instances, treatment of psoriasis with corticosteroids (or its withdrawal) is thought to have provoked the pustular form of the disease (see 4.4 Special warning and precautions for use).

There are reports of pigmentation changes and hypertrichosis with topical steroids.

If signs of hypersensitivity appear, applications should be stopped immediately. Exacerbation of symptoms may occur.

Additional local adverse events associated with glucorticosteroids include perioral dermatitis, rosacea-like dermatitis, delayed wound healing, rebound phenomenon which can lead to dependence on corticosteroids, and effects on the eyes. Raise of intraocular pressure and increased risk for cataract are known side effects for glucocorticosteroids. Contact allergy to CLARELUX or one of the excipients may also occur. If the product is not used properly, bacterial, viral, parasitic, and fungal infections may be masked and/or aggravated. Folliculitis has also been reported.

4.9 Overdose

No overdoses have been reported. Topically applied CLARELUX can be absorbed in sufficient amounts to produce systemic effects. If features of hypercorticoidism appear topical steroids should be discontinued gradually and, because of the risk of acute adrenal suppression, this should be done under medical supervision.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Corticosteroids, very potent (group IV)

ATC code: D07A D01

Like other topical corticosteroids, clobetasol propionate has anti-inflammatory, antipruritic, and vasoconstrictive properties. The precise mechanism of the anti-inflammatory activity of topical steroids in the treatment of steroid-responsive dermatoses, in general, is uncertain. However, corticosteroids are thought to act by the induction of phospholipase A₂ inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A₂.

A vasoconstrictor study has shown that CLARELUX has a comparable potency, based upon skin blanching response, as other clobetasol propionate formulations.

5.2 Pharmacokinetic Properties

Topical corticosteroids can be absorbed from intact healthy skin. The extent of percutaneous absorption of topical corticosteroids is determined by many factors, including the vehicle and the integrity of the epidermal barrier. Occlusion, inflammation and/or other disease processes in the skin may also increase percutaneous absorption.

Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. They are metabolised, primarily in the liver, and are then excreted by the kidneys. In addition, some corticosteroids and their metabolites are also excreted in the bile.

In a controlled pharmacokinetic study, 3 of 13 subjects experienced reversible suppression of the adrenals at any time during the 14 days of CLARELUX therapy to at least 20% of the body surface area.

5.3 Preclinical Safety Data

Parenteral administration of corticosteroids, including clobetasol propionate, to pregnant animals can cause abnormalities of foetal development including cleft palate and intrauterine growth retardation. Animal studies have indicated that intrauterine exposure to corticosteroids may contribute to the development of cardiovascular and metabolic diseases in adult life, but there is a lack of evidence for the occurrence of such effects in humans (see 4.6 Pregnancy and Lactation).

6. Pharmaceutical Particulars

6.1 List Of Excipients

Ethanol anhydrous

Purified water

Propylene glycol

Cetyl alcohol

Stearyl alcohol

Polysorbate 60

Citric acid anhydrous

Potassium citrate

Propellant: propane/n-butane/isobutane

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

Do not store above 25ºC. Do not refrigerate. Store upright.

The canister contains a pressurised, flammable liquid. Do not use near a naked flame. Do not expose to temperatures higher than 50ºC or to direct sunlight. Do not pierce or burn the canister, even when empty.

6.5 Nature And Contents Of Container

Pressurised aluminium container closed with an inverted valve, containing 50g or 100g of foam. The inside of the can is lined with a double coated, clear epoxy-phenolic lacquer. Each filled canister is fitted into a spout actuator with dust cap.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Pierre Fabre Dermatologie

45 place Abel Gance

92100 Boulogne

France

8. Marketing Authorisation Number(S)

PL 20693/0004

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 23^rd March 2005

Date of last renewal : 12/06/2008

10. Date Of Revision Of The Text

12 June 2008

Periactin

1. Name Of The Medicinal Product

PERIACTIN^® 4 mg Tablets

2. Qualitative And Quantitative Composition

Each 'Periactin' tablet contains cyproheptadine hydrochloride equivalent to 4 mg anhydrous cyproheptadine hydrochloride.

3. Pharmaceutical Form

White round bevelled edged tablet with a scoreline on one side and marked 'MSD 62' on the other.

4. Clinical Particulars

4.1 Therapeutic Indications

'Periactin' is a serotonin and histamine antagonist with anticholinergic and sedative properties.

In allergy and pruritus: 'Periactin' has a wide range of anti

'Periactin' is indicated as adjunctive therapy to adrenaline and other standard measures for the relief of anaphylactic reactions after the acute manifestations have been controlled.

In migraine and vascular headache: 'Periactin' has been reported to have beneficial effects in a significant number of patients having vascular types of headache. Many patients who have responded inadequately to all other agents have reported amelioration of symptoms with 'Periactin'. The characteristic headache and feeling of malaise may disappear within an hour or two of the first dose.

4.2 Posology And Method Of Administration

Route of administration: oral.

There is no recommended dosage for children under 2 years old. 'Periactin' is not recommended for elderly, debilitated patients.

For the treatment of allergy and pruritus:

Dosage must be determined on an individual basis. The effect of a single dose usually lasts for four to six hours. For continuous effective relief, the daily requirement should be given in divided doses, usually three times a day, or as often as necessary, to provide continuous relief.

Adults: The therapeutic range is 4-20 mg (1 to 5 tablets) a day, most patients requiring 12-16 mg a day. It is recommended that dosage be initiated with 4 mg three times a day and then adjusted according to the weight and response of the patient up to a maximum of 32 mg a day.

Children aged 7: Usually 4 mg two or three times a day, according to the patient's weight and response. If an additional dose is required, it should be given at bedtime. Maximum 16 mg a day.

Children aged 2: Initially 2 mg two or three times a day, adjusted according to the patient's weight and response. If an additional dose is required, it should be given at bedtime. Maximum 12 mg a day.

For treatment of vascular headache and migraine

For both prophylactic and therapeutic use, an initial dose of 4 mg, repeated if necessary after half an hour. Patients who respond usually obtain relief with 8 mg, and this dose should not be exceeded within a 4

Maintenance: 4 mg every four to six hours.

Use in the elderly: 'Periactin' should not be used in elderly, debilitated patients. Elderly patients are more likely to experience dizziness, sedation, and hypotension.

4.3 Contraindications

'Periactin' is contraindicated in:

• patients undergoing therapy for an acute asthmatic attack;

• newborn or premature infants; use in infants has been associated with apnoea, cyanosis and respiratory difficulty

• breast-feeding mothers;

• patients with known sensitivity to cyproheptadine hydrochloride or drugs with similar chemical structure;

• concurrent use with monoamine oxidase inhibitors;

• glaucoma;

• patients with pyloroduodenal obstruction, stenosing peptic ulcer, symptomatic prostatic hypertrophy, predisposition to urinary retention or bladder neck obstruction;

• elderly, debilitated patients.

4.4 Special Warnings And Precautions For Use

Antihistamines should not be used to treat lower respiratory tract symptoms, including those of acute asthma.

The safety and efficacy of 'Periactin' is not established in children under 2 years old.

Overdosage of antihistamines, particularly in infants and children, may produce hallucinations, central nervous system depression, convulsions, respiratory and cardiac arrest, and death.

Antihistamines may diminish mental alertness; conversely, particularly in the young child, they may occasionally produce excitation.

Patients should be warned against engaging in activities requiring motor co

Rarely, prolonged therapy with antihistamines may cause blood dyscrasias.

Because 'Periactin' has an atropine

Excipients

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

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

MAO inhibitors prolong and intensify the anticholinergic effects of antihistamines.

Antihistamines may have additive effects with alcohol and other CNS depressants, e.g. hypnotics, sedatives, tranquillisers and anti

Drugs with anti-serotonin activity, such as cyproheptadine, may interfere with serotonin-enhancing anti-depressants including selective serotonin re-uptake inhibitors (SSRI's). This may result in possible recurrence of depression and related symptoms.

Cyproheptadine may cause a false positive test result for tricyclic antidepressant drugs (TCA) when evaluating a drug screen (e.g. urine, serum). Because cyproheptadine and TCAs may produce similar overdose symptoms, physicians should carefully monitor patients for TCA toxicity in the event of combined overdose.

4.6 Pregnancy And Lactation

The use of any drug in pregnancy or in women of child

4.7 Effects On Ability To Drive And Use Machines

This product may cause drowsiness and somnolence. Patients receiving it should not drive or operate machinery unless it has been shown that their physical and mental capacity remains unaffected.

4.8 Undesirable Effects

The side effects that appear frequently are drowsiness and somnolence. Many patients who initially complain of drowsiness may no longer do so after the first three to four days of continuous administration.

Side effects reported with antihistamines are:

Central nervous system: Sedation, sleepiness (often transient), dizziness, disturbed co

Integumentary: Allergic manifestations of rash and oedema, excessive perspiration, urticaria, photosensitivity.

Special senses: Acute labyrinthitis, blurred vision, diplopia, vertigo, tinnitus.

Cardiovascular: Hypotension, palpitation, tachycardia, extrasystoles, anaphylactic shock.

Haematological: Haemolytic anaemia, leucopenia, agranulocytosis, thrombocytopenia.

Digestive system: Cholestasis, hepatic failure, hepatitis, hepatic function abnormality, dryness of mouth, epigastric distress, anorexia, nausea, vomiting, diarrhoea, constipation, jaundice.

Genito: Frequency and difficulty of micturition, urinary retention, early menses.

Respiratory: Dryness of the nose and throat, thickening of bronchial secretions, tightness of chest and wheezing, nasal stuffiness, epistaxis.

Miscellaneous: Fatigue, rigors, headache, increased appetite/weight gain.

4.9 Overdose

Antihistamine overdosage reactions may vary from CNS depression or stimulation to convulsions, respiratory and cardiac arrest and death, especially in infants and children. Atropine

If vomiting has not occurred spontaneously, it should be induced in the conscious patient with syrup of ipecac. If the patient cannot vomit, gastric lavage with isotonic or half isotonic saline is indicated, followed by activated charcoal. Precautions against aspiration must be taken, especially in infants and children.

Life

Saline cathartics usefully draw water into the bowel by osmosis to dilute bowel content rapidly.

Central stimulants must not be used, but vasopressors may be used to counteract hypotension.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Cyproheptadine hydrochloride is a serotonin and histamine antagonist with anticholinergic and sedative effects. Antiserotonin and antihistamine drugs appear to compete with serotonin and histamine, respectively, for receptor sites.

Cyproheptadine hydrochloride antagonises the following effects of serotonin, in laboratory animals:

Bronchoconstrictor (guinea-pig)

Vasopressor (dog)

Spasmogenic (isolated rat uterus)

Oedema (rat)

Lethal (haemophilus pertussis-treated mouse)

In these effects it equals or surpasses the activity of many of the activities of specific serotonin antagonists, such as 1-Benzyl-2-methyl-5-methoxy-tryptame (BAS) and 1 Benzyl-2methyl-5-hydroxy-tryptamine (BMS), in contrast, specific antihistamines, even the most potent, show little or no serotonin antagonism.

Cyproheptadine hydrochloride antagonises or blocks the following effects of histamine in laboratory animals:

Bronchoconstrictor (guinea-pig)

Vasopressor (dog)

Spasmogenic (isolated rat uterus)

Anaphylactic shock, active and passive (guinea-pig and mouse)

Increased gastric secretion (Heidenhain pouch dog.)

It is unusual that cyproheptadine hydrochloride protects both the guinea-pig and mice against anaphylactic shock. In guinea-pigs, the pulmonary aspects of anaphylactic shock are attributable to the release of endogenous histamine and can be controlled by substances with specific antihistamine activity. In mice however, where histamine release seems to be less important and serotonin release may be involved, specific antihistamines are of little value in protecting against anaphylaxis. Thus the protective effect of cyproheptadine hydrochloride in mice may be an anti-serotonin effect.

The inhibitory effect of cyproheptadine in histamine-induced gastric secretion is also unusual as specific antihistamines do not influence this effect.

Cyproheptadine has appetite stimulation properties in laboratory animals.

5.2 Pharmacokinetic Properties

After a single 4 mg oral dose of ¹⁴C-labelled cyproheptadine hydrochloride in normal subjects given as tablets or syrup, 2 to 20% of the radioactivity was excreted in the stools. Only about 34% of the stool radioactivity was unchanged drug, corresponding to less than 5.7% of the dose. At least 40% of the administered radioactivity was excreted in the urine.

No significant difference in the mean urinary excretion exists between the tablet and syrup formulations. No detectable amounts of unchanged drug were present in the urine of patients on chronic 12-20 mg daily doses of 'Periactin' syrup. The principle metabolite found in human urine has been identified as a quaternary ammonium glucuronide conjugate of cyproheptadine. Elimination is diminished in renal insufficiency.

5.3 Preclinical Safety Data

No relevant information.

6. Pharmaceutical Particulars

6.1 List Of Excipients

'Periactin' tablets contain the following inactive ingredients: calcium hydrogen phosphate E341, lactose, magnesium stearate E572, potato starch and pregelatinised maize starch.

6.2 Incompatibilities

None known.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

Do not store above 25°C. Store in the original package.

6.5 Nature And Contents Of Container

30 tablets in opaque PVC blisters with hard-temper aluminium lidding.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Merck Sharp & Dohme Limited

Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, UK.

8. Marketing Authorisation Number(S)

Tablets PL 0025/5017R

9. Date Of First Authorisation/Renewal Of The Authorisation

Licence granted : 3 October 1990

Last renewed: 14 August 2001

10. Date Of Revision Of The Text

14 November 2008

LEGAL CATEGORY

P.

® denotes registered trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.

© Merck Sharp & Dohme Limited 2007. All rights reserved.

SPC.PCTT.07.UK.2804