Indapamide

Dosage Form: tablet

Indapamide Description

DESCRIPTION

Indapamide is an oral antihypertensive/diuretic. Its molecule contains both a polar sulfamoyl chlorobenzamide moiety and a lipid-soluble methylindoline moiety. It differs chemically from the thiazides in that it does not possess the thiazide ring system and contains only one sulfonamide group. The chemical name of Indapamide is 4-Chloro-N-(2-methyl-1-indolinyl)-3-Sulfamoylbenzamide, and its molecular weight is 365.84. The compound is a weak acid, pKa=8.8, and is soluble in aqueous solutions of strong bases. It is a white to yellow-white crystalline (tetragonal) powder.

Each tablet, for oral administration, contains 1.25 mg or 2.5 mg of Indapamide, USP and the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, pregelatinized starch, sodium lauryl sulfate, and titanium dioxide. Additionally, the 1.25 mg product contains glyceryl triacetate and D and C Red No. 30 Aluminum Lake and the 2.5 mg product contains triacetin.

INACTIVE INGREDIENT

The following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, pregelatinized starch, sodium lauryl sulfate, and titanium dioxide. Additionally, the 1.25 mg product contains glyceryl triacetate and D and C Red No. 30 Aluminum Lake and the 2.5 mg product contains triacetin.

Indapamide - Clinical Pharmacology

CLINICAL PHARMACOLOGY

Indapamide is the first of a new class of antihypertensive/diuretics, the indolines. The oral administration of 2.5 mg (two 1.25 mg tablets) of Indapamide to male subjects produced peak concentrations of approximately 115 ng/mL of the drug in the blood within 2 hours. The oral administration of 5 mg (two 2.5 mg tablets) of Indapamide to healthy male subjects produced peak concentrations of approximately 260 ng/mL of the drug in the blood within 2 hours. A minimum of 70 percent of a single oral dose is eliminated by the kidneys and an additional 23 percent by the gastrointestinal tract, probably including the biliary route. The half-life of Indapamide in whole blood is approximately 14 hours.

Indapamide is preferentially and reversibly taken up by the erythrocytes in the peripheral blood. The whole blood/plasma ratio is approximately 6:1 at the time of peak concentration and decreases to 3.5:1 at 8 hours. From 71% to 79 percent of the Indapamide in plasma is reversibly bound to plasma proteins.

Indapamide is an extensively metabolized drug, with only about 7 percent of the total dose administered, recovered in the urine as unchanged drug during the first 48 hours after administration. The urinary elimination of 14C-labeled Indapamide and metabolites is biphasic with a terminal half-life of excretion of total radioactivity of 26 hours.

In a parallel design double-blind, placebo controlled trial in hypertension, daily doses of Indapamide between 1.25 mg and 10 mg produced dose related antihypertensive effects. Doses of 5 mg and 10 mg were not distinguishable from each other although each was differentiated from placebo and 1.25 mg Indapamide. At daily doses of 1.25 mg, 5 mg and 10 mg, a mean decrease of serum potassium of 0.28, 0.61 and 0.76 mEq/L, respectively, was observed and uric acid increased by about 0.69 mg/100 mL.

In other parallel design, dose-ranging clinical trials in hypertension and edema, daily doses of Indapamide between 0.5 mg and 5 mg produced dose related effects. Generally, doses of 2.5 mg and 5 mg were not distinguishable from each other although each was differentiated from placebo and from 0.5 mg or 1 mg Indapamide. At daily doses of 2.5 mg and 5 mg a mean decrease of serum potassium of 0.5 and 0.6 mEq/Liter, respectively, was observed and uric acid increased by about 1 mg/100 mL.

At these doses, the effects of Indapamide on blood pressure and edema are approximately equal to those obtained with conventional doses of other antihypertensive/diuretics.

In hypertensive patients, daily doses of 1.25 mg, 2.5 mg and 5 mg of Indapamide have no appreciable cardiac inotropic or chronotropic effect. The drug decreases peripheral resistance, with little or no effect on cardiac output, rate or rhythm. Chronic administration of Indapamide to hypertensive patients has little or no effect on glomerular filtration rate or renal plasma flow.

Indapamide had an antihypertensive effect in patients with varying degrees of renal impairment, although in general, diuretic effects declined as renal function decreased.

In a small number of controlled studies, Indapamide taken with other antihypertensive drugs such as hydralazine, propranolol, guanethidine and methyldopa, appeared to have the additive effect typical of thiazide-type diuretics.

INDICATIONS & USAGE

INDICATIONS AND USAGE

Indapamide tablets are indicated for the treatment of hypertension, alone or in combination with other antihypertensive drugs.

Indapamide tablets are also indicated for the treatment of salt and fluid retention associated with congestive heart failure.

Usage in Pregnancy

The routine use of diuretics in an otherwise healthy woman is inappropriate and exposes mother and fetus to unnecessary hazard (see PRECAUTIONS below).

Diuretics do not prevent development of toxemia of pregnancy, and there is no satisfactory evidence that they are useful in the treatment of developed toxemia.

Edema during pregnancy may arise from pathological causes or from the physiologic and mechanical consequences of pregnancy. Indapamide is indicated in pregnancy when edema is due to pathologic causes, just as it is in the absence of pregnancy (however, see PRECAUTIONS below). Dependent edema in pregnancy, resulting from restriction of venous return by the expanded uterus, is properly treated through elevation of the lower extremities and use of support hose; use of diuretics to lower intravascular volume in this case is illogical and unnecessary. There is hypervolemia during normal pregnancy which is not harmful to either the fetus or the mother (in the absence of cardiovascular disease), but which is associated with edema, including generalized edema in the majority of pregnant women. If this edema produces discomfort, increased recumbency will often provide relief. In rare instances, this edema may cause extreme discomfort which is not relieved by rest. In these cases, a short course of diuretics may provide relief and may be appropriate.

CONTRAINDICATIONS

Anuria. Known hypersensitivity to Indapamide or to other sulfonamide-derived drugs.

Warnings

WARNINGS

Severe cases of hyponatremia, accompanied by hypokalemia have been reported with recommended doses of Indapamide. This occurred primarily in elderly females. (See PRECAUTIONS: Geriatric Use.) This appears to be dose related. Also, a large case-controlled pharmacoepidemiology study indicates that there is an increased risk of hyponatremia with Indapamide 2.5 mg and 5 mg doses. Hyponatremia considered possibly clinically significant (125 mEq/L) has not been observed in clinical trials with the 1.25 mg dosage (see PRECAUTIONS). Thus, patients should be started at the 1.25 mg dose and maintained at the lowest possible dose. (See DOSAGE AND ADMINISTRATION.)

Hypokalemia occurs commonly with diuretics (see ADVERSE REACTIONS: Hypokalemia), and electrolyte monitoring is essential, particularly in patients who would be at increased risk from hypokalemia, such as those with cardiac arrhythmias or who are receiving concomitant cardiac glycosides.

In general, diuretics should not be given concomitantly with lithium because they reduce its renal clearance and add a high risk of lithium toxicity. Read prescribing information for lithium preparations before use of such concomitant therapy.

Precautions

PRECAUTIONSGeneralHypokalemia, Hyponatremia, and Other Fluid and Electrolyte Imbalances

Periodic determinations of serum electrolytes should be performed at appropriate intervals. In addition, patients should be observed for clinical signs of fluid or electrolyte imbalance, such as hyponatremia, hypochloremic alkalosis, or hypokalemia. Warning signs include dry mouth, thirst, weakness, fatigue, lethargy, drowsiness, restlessness, muscle pains or cramps, hypotension, oliguria, tachycardia, and gastrointestinal disturbance. Electrolyte determinations are particularly important in patients who are vomiting excessively or receiving parenteral fluids, in patients subject to electrolyte imbalance (including those with heart failure, kidney disease, and cirrhosis), and in patients on a salt-restricted diet.

The risk of hypokalemia secondary to diuresis and natriuresis is increased when larger doses are used, when the diuresis is brisk, when severe cirrhosis is present and during concomitant use of corticosteroids or ACTH. Interference with adequate oral intake of electrolytes will also contribute to hypokalemia. Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis, such as increased ventricular irritability.

Dilutional hyponatremia may occur in edematous patients; the appropriate treatment is restriction of water rather than administration of salt, except in rare instances when the hyponatremia is life threatening. However, in actual salt depletion, appropriate replacement is the treatment of choice. Any chloride deficit that may occur during treatment is generally mild and usually does not require specific treatment except in extraordinary circumstances as in liver or renal disease. Thiazide-like diuretics have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.

Hyperuricemia and Gout

Serum concentrations of uric acid increased by an average of 0.69 mg/100 mL in patients treated with Indapamide 1.25 mg, and by an average of 1 mg/100 mL in patients treated with Indapamide 2.5 mg and 5 mg, and frank gout may be precipitated in certain patients receiving Indapamide (see ADVERSE REACTIONS below). Serum concentrations of uric acid should, therefore, be monitored periodically during treatment.

Renal Impairment

Indapamide, like the thiazides, should be used with caution in patients with severe renal disease, as reduced plasma volume may exacerbate or precipitate azotemia. If progressive renal impairment is observed in a patient receiving Indapamide, withholding or discontinuing diuretic therapy should be considered. Renal function tests should be performed periodically during treatment with Indapamide.

Impaired Hepatic Function

Indapamide, like the thiazides, should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Glucose Tolerance

Latent diabetes may become manifest and insulin requirements in diabetic patients may be altered during thiazide administration. A mean increase in glucose of 6.47 mg/dL was observed in patients treated with Indapamide 1.25 mg, which was not considered clinically significant in these trials. Serum concentrations of glucose should be monitored routinely during treatment with Indapamide.

Calcium Excretion

Calcium excretion is decreased by diuretics pharmacologically related to Indapamide. After 6 to 8 weeks of Indapamide 1.25 mg treatment and in long-term studies of hypertensive patients with higher doses of Indapamide, however, serum concentrations of calcium increased only slightly with Indapamide. Prolonged treatment with drugs pharmacologically related to Indapamide may in rare instances be associated with hypercalcemia and hypophosphatemia secondary to physiologic changes in the parathyroid gland; however, the common complications of hyperparathyroidism, such as renal lithiasis, bone resorption, and peptic ulcer, have not been seen. Treatment should be discontinued before tests for parathyroid function are performed. Like the thiazides, Indapamide may decrease serum PBI levels without signs of thyroid disturbance.

Interaction with Systemic Lupus Erythematosus

Thiazides have exacerbated or activated systemic lupus erythematosus and this possibility should be considered with Indapamide as well.

Drug Interactions

Drug InteractionsOther Antihypertensives

Indapamide may add to or potentiate the action of other antihypertensive drugs. In limited controlled trials that compared the effect of Indapamide combined with other antihypertensive drugs with the effect of the other drugs administered alone, there was no notable change in the nature or frequency of adverse reactions associated with the combined therapy.

Lithium

See WARNINGS.

Post-Sympathectomy Patient

The antihypertensive effect of the drug may be enhanced in the post-sympathectomized patient.

Norepinephrine

Indapamide, like the thiazides, may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Both mouse and rat lifetime carcinogenicity studies were conducted. There was no significant difference in the incidence of tumors between the Indapamide-treated animals and the control groups.

PREGNANCY

PregnancyTeratogenic EffectsPregnancy Category B

Reproduction studies have been performed in rats, mice and rabbits at doses up to 6,250 times the therapeutic human dose and have revealed no evidence of impaired fertility or harm to the fetus due to Indapamide. Postnatal development in rats and mice was unaffected by pretreatment of parent animals during gestation. There are, however, no adequate and well controlled studies in pregnant women. Moreover, diuretics are known to cross the placental barrier and appear in cord blood. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. There may be hazards associated with this use such as fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in the adult.

Usage in Pregnancy

The routine use of diuretics in an otherwise healthy woman is inappropriate and exposes mother and fetus to unnecessary hazard.

Diuretics do not prevent development of toxemia of pregnancy, and there is no satisfactory evidence that they are useful in the treatment of developed toxemia.

Edema during pregnancy may arise from pathological causes or from the physiologic and mechanical consequences of pregnancy. Indapamide is indicated in pregnancy when edema is due to pathologic causes, just as it is in the absence of pregnancy (however, see PRECAUTIONS below). Dependent edema in pregnancy, resulting from restriction of venous return by the expanded uterus, is properly treated through elevation of the lower extremities and use of support hose; use of diuretics to lower intravascular volume in this case is illogical and unnecessary. There is hypervolemia during normal pregnancy which is not harmful to either the fetus or the mother (in the absence of cardiovascular disease), but which is associated with edema, including generalized edema in the majority of pregnant women. If this edema produces discomfort, increased recumbency will often provide relief. In rare instances, this edema may cause extreme discomfort which is not relieved by rest. In these cases, a short course of diuretics may provide relief and may be appropriate.

NURSING MOTHERS

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because most drugs are excreted in human milk, if use of this drug is deemed essential, the patient should stop nursing.

PEDIATRIC USE

Pediatric Use

Safety and effectiveness of Indapamide in pediatric patients have not been established.

GERIATRIC USE

Geriatric Use

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

Severe cases of hyponatremia, accompanied by hypokalemia have been reported with recommended doses of Indapamide in elderly females (see WARNINGS).

Adverse Reactions

ADVERSE REACTIONS

Most adverse effects have been mild and transient.

The clinical adverse reactions listed in Table 1 represent data from Phase II and III placebo-controlled studies (306 patients given Indapamide 1.25 mg). The clinical adverse reactions listed in Table 2 represent data from Phase II placebo-controlled studies and long-term controlled clinical trials (426 patients given Indapamide 2.5 mg or 5 mg). The reactions are arranged into two groups: 1) a cumulative incidence equal to or greater than 5 percent; 2) a cumulative incidence less than 5 percent. Reactions are counted regardless of relation to drug.

TABLE 1: Adverse Reactions from Studies of 1.25 mg

*OTHER All other clinical adverse reactions occurred at an incidence of greater then 1percent.
Incidence less than 5 percent	Incidence greater then 5 percent *
BODY AS A WHOLE
Headache	Asthenia
Infection	Flu Syndrome
Pain	Abdominal Pain
Back Pain	Chest Pain
GASTROINTESTINAL SYSTEM
	Constipation
	Diarrhea
	Dyspepsia
	Nausea
METABOLIC SYSTEM
	Peripheral Edema
CENTRAL NERVOUS SYSTEM
Dizziness	Nervousness
	Hypertonia
RESPIRATORY SYSTEM
Rhinitis	Cough
	Pharyngitis
	Sinusitis
SPECIAL SENSES
	Conjunctivitis

Approximately 4 percent of patients given Indapamide 1.25 mg compared to 5 percent of the patients given placebo discontinued treatment in the trials of up to 8 weeks because of adverse reactions.

In controlled clinical trials of 6 to 8 weeks in duration, 20 percent of patients receiving Indapamide 1.25 mg, 61 percent of patients receiving Indapamide 5 mg, and 80 percent of patients receiving Indapamide 10 mg had at least one potassium value below 3.4 mEq/L. In the Indapamide 1.25 mg group, about 40 percent of those patients who reported hypokalemia as a laboratory adverse event returned to normal serum potassium values without intervention. Hypokalemia with concomitant clinical signs or symptoms occurred in 2 percent of patients receiving Indapamide 1.25 mg.

TABLE 2: Adverse Reactions from Studies of 2.5 mg and 5 mg

Incidence less then 5 percent	Incidence greater then 5 percent
CENTRAL NERVOUS SYSTEM/ NEUROMUSCULAR
Headache	Lightheadedness
Dizziness	Drowsiness
Fatigue, weakness, loss of energy, lethargy, tiredness, or malaise	Vertigo Insomnia
Muscle cramps or spasm, or numbness of the extremities	Depression Blurred Vision
Nervousness, tension, anxiety, irritability, or agitation
GASTROINTESTINAL SYSTEM
	Constipation Nausea Vomiting Diarrhea Gastric irritation Abdominal pain or cramps Anorexia
CARDIOVASCULAR SYSTEM
	Orthostatic hypotension Premature ventricular contractions Irregular heart beat Palpitations
GENITOURINARY SYSTEM
	Frequency of urination Nocturia Polyuria
DERMATOLOGIC/HYPERSENSITIVITY
	Rash Hives Pruritus Vasculitis
OTHER
	Impotence or reduced libido Rhinorrhea Flushing Hyperuricemia Hyperglycemia Hyponatremia Hypochloremia Increase in serum urea nitrogen (BUN) or creatinine Glycosuria Weight loss Dry mouth Tingling of extremities

Because most of these data are from long-term studies (up to 40 weeks of treatment), it is probable that many of the adverse experiences reported are due to causes other than the drug. Approximately 10 percent of patients given Indapamide discontinued treatment in long-term trials because of reactions either related or unrelated to the drug.

Hypokalemia with concomitant clinical signs or symptoms occurred in 3 percent of patients receiving Indapamide 2.5 mg q.d. and 7 percent of patients receiving Indapamide 5 mg q.d. In long-term controlled clinical trials comparing the hypokalemic effects of daily doses of Indapamide and hydrochlorothiazide, however, 47 percent of patients receiving Indapamide 2.5 mg, 72 percent of patients receiving Indapamide 5 mg, and 44 percent of patients receiving hydrochlorothiazide 50 mg had at least one potassium value (out of a total of 11 taken during the study) below 3.5 mEq/L. In the Indapamide 2.5 mg group, over 50 percent of those patients returned to normal serum potassium values without intervention.

In clinical trials of 6 to 8 weeks, the mean changes in selected values were as shown in the tables below.

Mean Changes From Baseline After 8 Weeks Of Treatment - 1.25 mg
	Serum Electrolytes (mEq/L)	Serum Uric Acid (mg/dL)	BUN (mg/dL)
	Potassium	Sodium	Chloride
Indapamide 1.25 mg (n 255 to 257)	0.28	0.63	2.60	0.69	1.46
Placebo (n 263 to 266)	0.00	0.11	0.21	0.06	0.06

No patients receiving Indapamide 1.25 mg experienced hyponatremia considered possibly clinically significant (less then 125 mEq/L).

Indapamide had no adverse effects on lipids.

Mean Changes from Baseline after 40 Weeks of Treatment - 2.5 mg and 5 mg
	Serum Electrolytes (mEq/L)	Serum Uric Acid (mg/dL)	BUN (mg/dL)
	Potassium	Sodium	Chloride
Indapamide 2.5 mg (n 76)	0.4	0.6	3.6	0.7	0.1
Indapamide 5 mg (n 81)	0.6	0.7	5.1	1.1	1.4

The following reactions have been reported with clinical usage of Indapamide: jaundice (intrahepatic cholestatic jaundice), hepatitis, pancreatitis and abnormal liver function tests. These reactions were reversible with discontinuance of the drug.

Also reported are erythema multiforme, Stevens-Johnson Syndrome, bullous eruptions, purpura, photosensitivity, fever, pneumonitis, anaphylactic reactions, agranulocytosis, leukopenia, thrombocytopenia and aplastic anemia. Other adverse reactions reported with antihypertensive/diuretics are necrotizing angiitis, respiratory distress, sialadenitis, xanthopsia.

Overdosage

OVERDOSAGE

Symptoms of overdosage include nausea, vomiting, weakness, gastrointestinal disorders and disturbances of electrolyte balance. In severe instances, hypotension and depressed respiration may be observed. If this occurs, support of respiration and cardiac circulation should be instituted. There is no specific antidote. An evacuation of the stomach is recommended by emesis and gastric lavage after which the electrolyte and fluid balance should be evaluated carefully.

DOSAGE & ADMINISTRATION

DOSAGE AND ADMINISTRATIONHypertension

The adult starting Indapamide dose for hypertension is 1.25 mg as a single daily dose taken in the morning. If the response to 1.25 mg is not satisfactory after 4 weeks, the daily dose may be increased to 2.5 mg taken once daily. If the response to 2.5 mg is not satisfactory after 4 weeks, the daily dose may be increased to 5 mg taken once daily, but adding another antihypertensive should be considered.

Edema of Congestive Heart Failure

The adult starting Indapamide dose for edema of congestive heart failure is 2.5 mg as a single daily dose taken in the morning. If the response to 2.5 mg is not satisfactory after one week, the daily dose may be increased to 5 mg taken once daily.

If the antihypertensive response to Indapamide is insufficient, Indapamide may be combined with other antihypertensive drugs, with careful monitoring of blood pressure. It is recommended that the usual dose of other agents be reduced by 50 percent during initial combination therapy. As the blood pressure response becomes evident, further dosage adjustments may be necessary.

In general, doses of 5 mg and larger have not appeared to provide additional effects on blood pressure or heart failure, but are associated with a greater degree of hypokalemia. There is minimal clinical trial experience in patients with doses greater than 5 mg once a day.

How is Indapamide Supplied

HOW SUPPLIED

Indapamide Tablets, USP are available containing 1.25 mg or 2.5 mg of Indapamide, USP.

The 1.25 mg tablets are pink film-coated, unscored, round tablets debossed with M on one side of the tablet and 69 on the other side. They are available as follows:

NDC 0378-0069-01

bottles of 100 tablets

NDC 0378-0069-05

bottles of 500 tablets

The 2.5 mg tablets are white film-coated, unscored, round tablets debossed with M on one side of the tablet and 80 on the other side. They are available as follows:

NDC 0378-0080-77

bottles of 90 tablets

NDC 0378-0080-01

bottles of 100 tablets

NDC 0378-0080-10

bottles of 1000 tablets

STORAGE AND HANDLING

Dispense in a tight, light-resistant

container as defined in the USP

using a child-resistant closure.

Keep container tightly closed.

Keep this and all medication

out of the reach of children.

Store at 20° to 25°C (68° to 77°F).

[See USP Controlled Room

Temperature.]

Avoid excessive heat.

Usual Dosage: See accompanying

prescribing information.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

DRUG: Indapamide

GENERIC: Indapamide

DOSAGE: TABLET

ADMINSTRATION: ORAL

NDC: 49349-015-02

STRENGTH:2;5 mg

COLOR: white

SHAPE: ROUND

SCORE: No score

SIZE: 7 mm

IMPRINT: M;80

QTY: 30

Indapamide  Indapamide  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 49349-015 (0378-0080-01) Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Indapamide (Indapamide) Indapamide 2.5 mg

Inactive Ingredients Ingredient Name Strength ANHYDROUS LACTOSE   HYDRATED SILICA   HYPROMELLOSE   MAGNESIUM STEARATE   CELLULOSE, MICROCRYSTALLINE   POLYDEXTROSE   POLYETHYLENE GLYCOL   MODIFIED CORN STARCH (1-OCTENYL SUCCINIC ANHYDRIDE)   PRASTERONE SODIUM SULFATE

Product Characteristics Color white Score no score Shape ROUND (TABLET) Size 7mm Flavor Imprint Code m;80 Contains

Packaging # NDC Package Description Multilevel Packaging 1 49349-015-02 30 TABLET In 1 BLISTER PACK None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA075659	09/16/2010

Labeler - REMEDYREPACK INC. (829572556)

Revised: 09/2010REMEDYREPACK INC.

More Indapamide resources

• Indapamide Side Effects (in more detail)
• Indapamide Dosage
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• Drug Images
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• Indapamide Professional Patient Advice (Wolters Kluwer)


• Indapamide MedFacts Consumer Leaflet (Wolters Kluwer)


• Indapamide Monograph (AHFS DI)


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Helixate NexGen 1000 IU

Helixate NexGen 1000 IU powder and solvent for solution for injection

Recombinant coagulation factor VIII (octocog alfa)

Read all of this leaflet carefully before you start using this medicine.

• Keep this leaflet. You may need to read it again.


• If you have any further questions, ask your doctor or your pharmacist.


• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.


• If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

• 1. What Helixate NexGen 1000 IU is and what it is used for


• 2. Before you use Helixate NexGen 1000 IU


• 3. How to use Helixate NexGen 1000 IU


• 4. Possible side effects


• 5. How to store Helixate NexGen 1000 IU


• 6. Further information

WHAT Helixate NexGen 1000 IU IS AND WHAT IT IS USED FOR

Helixate NexGen 1000 IU belongs to a pharmacotherapeutic group called blood coagulation Factor VIII (ATC-Code B02B D02).

Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency).

This preparation does not contain von Willebrand factor and is therefore not indicated in von Willebrand's disease.

One vial with powder for solution for injection nominally contains 1000 IU octocog alfa (IU equals International Units). After reconstitution with the appropriate volume of solvent (water for injections), each vial contains octocog alfa 400 IU/ml.

BEFORE YOU USE Helixate NexGen 1000 IU

Do not use Helixate NexGen 1000 IU if you are allergic (hypersensitive) to octocog alfa, to mouse or hamster protein or to any of the other ingredients of Helixate NexGen 1000 IU.

If you are unsure about this, ask your doctor.

Take special care with Helixate NexGen 1000 IU as there is a rare chance that you may experience an anaphylactic reaction (a severe, sudden allergic reaction). If you experience tightness in the chest, feeling dizzy, feeling sick or faint, or experience dizziness on standing, you may be experiencing an allergic reaction to Helixate NexGen 1000 IU. If this occurs, stop administering the product immediately and seek medical advice.

Your doctor may wish to carry out tests to ensure that your current dose of Helixate NexGen 1000 IU is sufficient to reach and maintain adequate factor VIII levels.

If your bleeding is not being controlled with Helixate NexGen 1000 IU, consult your doctor immediately. You may have developed factor VIII inhibitors and your doctor may wish to carry out tests to confirm this. Factor VIII inhibitors are antibodies in the blood which block the factor VIII you are using. This makes factor VIII less effective in controlling bleeding.

If you have previously developed a factor VIII inhibitor and you switch factor VIII products, you may be at risk of your inhibitor coming back.

Using other medicines

Interactions with other medicines are not known. However, please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

Pregnancy and breast-feeding

Based on the rare occurrence of haemophilia A in women, experience regarding the use of Helixate NexGen 1000 IU during pregnancy and breast-feeding is not available. Therefore, if you are pregnant or breast-feeding consult your doctor before using this product.

Driving and using machines

No effects on the ability to drive or use machines have been observed.

Important information about some of the ingredients of Helixate NexGen 1000 IU

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially “sodium-free”.

HOW TO USE Helixate NexGen 1000 IU

Helixate NexGen 1000 IU is intended for intravenous administration only and must be administered immediately after reconstitution. Aseptic conditions (meaning clean and germ free) are required during reconstitution and administration. Use only the medical devices for reconstitution and administration provided with each package of Helixate NexGen 1000 IU. Helixate NexGen 1000 IU must not be mixed with other infusion solutions. Do not use solutions containing visible particles or that are cloudy. Follow the directions given by your doctor closely and use the instructions below as a guide:

• 1. Wash hands thoroughly using soap and warm water.


• 2. Warm both unopened vials in your hands to a comfortable temperature (do not exceed 37 °C).


• 3. Ensure product and solvent vial flip caps are removed and the stoppers are treated with an aseptic solution and allowed to dry prior to opening the Mix2Vial package.

• 4. Open the Mix2Vial package by peeling away the lid. Do not remove the Mix2Vial from the blister package!

• 5. Place the solvent vial on an even, clean surface and hold the vial tight. Take the Mix2Vial together with the blister package and push the spike of the blue adapter end straight down through the solvent vial stopper.

• 6. Carefully remove the blister package from the Mix2Vial set by holding at the rim, and pulling vertically upwards. Make sure that you only pull away the blister package and not the Mix2Vial set.

• 7. Place the product vial on an even and firm surface. Invert the solvent vial with the Mix2Vial set attached and push the spike of the transparent adapter end straight down through the product vial stopper. The solvent will automatically flow into the product vial.

• 8. With one hand grasp the product-side of the Mix2Vial set and with the other hand grasp the solvent-side and unscrew the set carefully into two pieces. Discard the solvent vial with the blue Mix2Vial adapter attached.

• 9. Gently swirl the product vial with the transparent adapter attached until the substance is fully dissolved. Do not shake.

• 10. Draw air into an empty, sterile syringe. While the product vial is upright, connect the syringe to the Mix2Vial´s Luer Lock fitting. Inject air into the product vial.

• 11. While keeping the syringe plunger pressed, invert the system upside down and draw the solution into the syringe by pulling the plunger back slowly.

• 12. Now that the solution has been transferred into the syringe, firmly hold on to the barrel of the syringe (keeping the syringe plunger facing down) and disconnect the transparent Mix2Vial adapter from the syringe. Hold the syringe upright and push the plunger until no air is left in the syringe.


• 13. Apply a tourniquet.


• 14. Determine the point of injection and prepare antiseptically.


• 15. Puncture the vein and secure the venipuncture set with a plaster.


• 16 Let blood flow back to the open end of the venipuncture set and then attach the syringe with the solution. Make sure that no blood enters the syringe.


• 17. Remove tourniquet.


• 18. Inject the solution intravenously over several minutes, keeping an eye on the position of the needle. The rate of administration should be determined by the patient’s comfort (maximum rate of infusion: 2 ml/min).


• 19. If a further dose needs to be administered, use a new syringe with product reconstituted as described above.


• 20. If no further dose is required, remove the venipuncture set and syringe. Hold a swab firmly over the injection site on the outstretched arm for approx. 2 minutes. Finally, apply a small pressure dressing to the wound.

The amount of Helixate NexGen 1000 IU you should use and how often you use it depends on many factors such as your weight, the severity of your haemophilia, the site and extent of bleeding, the amount of factor VIII inhibitors that you may have and the factor VIII level required.

Your doctor will calculate the dose of Helixate NexGen 1000 IU and how frequently you should use it to get the necessary level of factor VIII activity in your blood. He will do this according to your particular needs using the formulae below.

I. Required IU = body weight (kg) × desired factor VIII rise as % of normal × 0.5

II. Expected factor VIII rise as % of normal = 2 × administered IU ÷ bodyweight in kg

The following information provides a guide for factor VIII minimum blood levels. In the case of the haemorrhagic events listed, the factor VIII activity should not fall below the given level (in % of normal) in the corresponding period:

Degree of haemorrhage : Factor VIII level required (% or IU/dl) : Frequency of doses in hours; duration of therapy in days

Early haemathrosis, muscle bleed or oral bleed : 20 to 40 : Repeat every 12 to 24 hours. At least 1 day, until the bleeding episode as indicated by pain is resolved or healing is achieved.

More extensive haemathrosis, muscle bleed or haematoma : 30 to 60 : Repeat infusion every 12 to 24 hours for 3 to 4 days or more until pain and disability are resolved.

Life-threatening bleeds such as intracranial bleed, throat bleed, severe abdominal bleed : 60 to 100 : Repeat infusion every 8 to 24 hours until threat is resolved.

Type of surgical procedure : Factor VIII level required (% or IU/dl) : Frequency of doses in hours; duration of therapy in days

Minor, including tooth extraction : 30 to 60 : Every 24 hours for at least 1 day until healing is achieved.

Major : 80 to 100 (pre-and post-operatively) : a) By bolus infusions. Repeat infusion every 8 to 24 hours until adequate wound healing occurs, then continue with therapy for at least another 7 days to maintain a factor VIII activity of 30 to 60 %. b) By continuous infusion. Raise factor VIII activity pre-surgery with an initial bolus infusion and immediately follow with continuous infusion (in IU/kg/h) adjusting according to patient’s daily clearance and desired factor VIII levels for at least 7 days.

Your doctor should always adapt the amount of Helixate NexGen 1000 IU to be administered and the frequency of administration according to the clinical effectiveness in your individual case. Under certain circumstances larger amounts than those calculated may be required, especially in the case of the initial dose.

If you are using Helixate NexGen 1000 IU to prevent bleeding (prophylaxis), your doctor will calculate the dose for you. This will usually be in the range of 20 to 60 IU of octocog alfa per kg of body weight, administered at intervals of 2 to 3 days. However, in some cases, especially younger patients, shorter dose intervals or higher doses may be necessary.

Although dosage can be estimated by the calculations presented above, it is strongly recommended that appropriate laboratory tests be performed on your plasma at suitable intervals to ensure that adequate factor VIII levels have been reached and are maintained. In the case of major surgical interventions in particular, a precise monitoring of the substitution therapy by means of coagulation analysis is indispensable.

If the factor VIII level of your plasma fails to reach expected levels, or if bleeding is not controlled after apparently adequate dosage, the presence of factor VIII inhibitors should be suspected. By appropriate laboratory procedures, the presence of factor VIII inhibitors must be checked and quantified by an experienced doctor.

If you have the impression that the effect of Helixate NexGen 1000 IU is too strong or too weak, talk to your doctor.

Patients with inhibitors

If you have been informed by your doctor that you have developed factor VIII inhibitors you will possibly be required to use a larger amount of Helixate NexGen than previously to control a bleeding. If this dose does not control your bleeding your doctor may consider the use of an additional product, factor VIIa concentrate or (activated) prothrombin complex concentrate. Do not increase the dose of Helixate NexGen you use to control your bleeding without consulting your doctor. Speak to your doctor if you would like further information on this.

These therapies should be directed by doctors with experience in the care of patients with haemophilia A.

Helixate NexGen 1000 IU should be injected intravenously over several minutes. The rate of administration should be determined by the patient’s comfort level (maximal rate of infusion: 2 ml/min).

Your doctor will tell you, how often and at what intervals Helixate NexGen 1000 IU is to be administered.

Usually, the substitution therapy with Helixate NexGen 1000 IU is a life-time treatment.

If you use more Helixate NexGen 1000 IU than you should

No symptoms of overdosage with recombinant coagulation factor VIII have been reported.

If you have used more Helixate NexGen 1000 IU than you should, please inform your doctor.

If you forget to use Helixate NexGen 1000 IU

• Proceed with the next administration immediately and continue at regular intervals as advised by your doctor.


• Do not take a double dose to make up for a forgotten dose.

If you stop using Helixate NexGen 1000 IU

Do not stop using Helixate NexGen 1000 IU without consulting your doctor.

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

Possible Side Effects

Like all medicines, Helixate NexGen 1000 IU can cause side effects, although not everybody gets them.

The frequency of possible side effects listed below is defined using the following convention:

very common (affects more than 1 user in 10)

common (affects 1 to 10 users in 100)

uncommon (affects 1 to 10 users in 1,000)

rare (affects 1 to 10 users in 10,000)

very rare (affects less than 1 user in 10,000)

not known (frequency cannot be estimated from the available data).

Side effects where frequency is common:

You may notice any of the following side effects after administration of Helixate NexGen 1000 IU:

• rash/itchy rash


• local reactions at the injection site (e.g. burning sensation, temporary redness)

Side effects where frequency is rare:

You may notice any of the following side effects after administration of Helixate NexGen 1000 IU:

• hypersensitivity reactions (e.g. tightness of the chest/general feeling of being unwell, dizziness and nausea and mildly reduced blood pressure, which may make you feel faint upon standing)


• fever.

Furthermore, the possibility of an anaphylactic shock cannot be completely excluded. If you notice any of the following symptoms during injection/infusion:

• chest tightness/general feeling of being unwell


• dizziness


• mild hypotension (mildly reduced blood pressure, which may make you feel faint upon standing)


• nausea

this can constitute an early warning for hypersensitivity and anaphylactic reactions. If allergic or anaphylactic reactions occur, the injection/infusion should be stopped immediately. Please consult your doctor immediately.

During studies, no patient developed clinically relevant antibody titres against the trace amounts of mouse protein and hamster protein present in the preparation. However, the possibility of allergic reactions to constituents, e.g. trace amounts of mouse and hamster protein in the preparation exists in certain predisposed patients.

The formation of neutralising antibodies to factor VIII (inhibitors) is a known complication in the management of individuals with haemophilia A. In studies with recombinant factor VIII preparations, development of inhibitors is predominantly observed in previously untreated haemophiliacs.

You should be carefully monitored for the development of inhibitors by appropriate clinical observations and laboratory tests.

In clinical studies, Helixate NexGen has been used in the treatment of bleeding episodes in 37 previously untreated patients (PUPs) and 23 minimally treated pediatric patients (MTPs, defined as having equal to or less than 4 exposure days). Five out of 37 (14%) PUP and 4 out of 23 (17%) MTP patients treated with Helixate NexGen developed inhibitors: Overall 6 out of 60 (10%) with a titre above 10 BU and 3 out of 60 (5%) with a titre below 10 BU. The median number of exposure days at the time of inhibitor detection in these patients was 9 days (range 3 - 18 days).

The median number of exposure days in the clinical studies was 114 (range: 4-478). Four of the five patients, who had not achieved 20 exposure days at the end of the study, ultimately achieved more than 20 exposure days in post-study follow-up and one of them developed a low titre inhibitor. The fifth patient was lost to follow-up.

In clinical studies with 73 previously treated patients (PTP, defined as having more than 100 exposure days), followed over four years, no de-novo inhibitors were observed.

In extensive post-registration studies with Helixate NexGen, involving more than 1000 patients the following was observed: Less than 0.2% PTP developed de-novo inhibitors. In a subset defined as having less than 20 exposure days at study entry, less than 11% developed de-novo inhibitors.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

HOW TO STORE Helixate NexGen 1000 IU

Keep out of the reach and sight of children.

Store in a refrigerator (2°C - 8°C). Do not freeze. Keep the vials in the outer carton in order to protect from light.

You may store the product when kept in its outer carton at ambient room temperature (up to 25°C) for a single period of up to 3 months. In this case, the product expires at the end of this 3-month period; you must note the new expiry date on the top of the outer carton.

Do not refrigerate the solution after reconstitution. The reconstituted solution should be used immediately. This product is for single use only. Any unused solution must be discarded.

Do not use Helixate NexGen 1000 IU after the expiry date which is stated on labels and cartons. The expiry date refers to the last day of that month.

Do not use Helixate NexGen 1000 IU if you notice any particles or the solution is cloudy.

Further Information

What Helixate NexGen 1000 IU contains

Powder:

The active substance is recombinant coagulation factor VIII (octocog alfa).

The other ingredients are glycine, sodium chloride, calcium chloride, histidine, polysorbate 80, and sucrose.

Solvent:

Water for injections.

What Helixate NexGen 1000 IU looks like and content of the pack

Helixate NexGen 1000 IU is provided as a powder and solvent for solution for injection and is a dry white to slightly yellow powder or cake. After reconstitution the solution is clear. Medical devices for reconstitution and administration are provided with each package of Helixate NexGen 1000 IU.

Marketing Authorisation Holder:

Bayer Schering Pharma AG

13342 Berlin

Germany

Manufacturer:

Bayer HealthCare Manufacturing S.r.l.

Via delle Groane 126

20024 Garbagnate Milanese (MI)

Italy

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder.

United Kingdom

CSL Behring UK Limited

Tel:+44-(0)1444 447400

This leaflet was last approved in 03/2010

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu.

Hibiscrub (SSL International plc)

1. Name Of The Medicinal Product

'Hibiscrub'

2. Qualitative And Quantitative Composition

Chlorhexidine Gluconate 4% w/v (incorporated as Chlorhexidine Gluconate Solution Ph. Eur.)

3. Pharmaceutical Form

Liquid.

4. Clinical Particulars

4.1 Therapeutic Indications

'Hibiscrub' is an antimicrobial preparation for pre-operative surgical hand disinfection, antiseptic handwashing on the ward and pre-operative and post-operative skin antisepsis for patients undergoing elective surgery.

4.2 Posology And Method Of Administration

For external use only.

Pre-operative surgical hand disinfection Wet the hands and forearms, apply 5 ml of 'Hibiscrub' and wash for one minute cleaning the fingernails with a brush or scraper. Rinse, apply a further 5 ml of 'Hibiscrub' and continue washing for a further two minutes. Rinse thoroughly and dry.

Antiseptic handwash on the ward Wet the hands and forearms, apply 5 ml of 'Hibiscrub' and wash for one minute. Rinse thoroughly and dry.

Pre-operative skin antisepsis for the patient The patient washes his whole body in the bath or shower on at least two occasions, usually the day before and the day of operation, as follows:

The day before operation the patient washes with 25 ml of 'Hibiscrub' beginning with the face and working downwards paying particular attention to areas around the nose, axillae, umbilicus, groin and perineum. The body is then rinsed and the wash repeated with a further 25 ml, this time including the hair. Finally the patient rinses his entire body thoroughly and dries on a clean towel. This procedure should be repeated the following day. Patients confined to bed can be washed with 'Hibiscrub' using a standard bed-bath technique. Conventional disinfection of the operation site will then be performed when the patient is in theatre.

Post-operative skin antisepsis for the patient The patient washes his whole body, excluding the operation wound, in the bath or shower usually on the third day after operation using the procedure described above.

Children and Elderly Patients There are no special dosage recommendations for either elderly patients or children. The normal adult dose is appropriate unless recommended by the physician.

4.3 Contraindications

'Hibitane' preparations are contra-indicated for patients who have previously shown a hypersensitivity reaction to chlorhexidine. However, such reactions are extremely rare.

4.4 Special Warnings And Precautions For Use

For external use only. Keep out of the eyes and avoid contact with the brain, meninges and middle ear. In patients with head or spinal injuries or perforated ear drum, the benefit of use in pre-operative preparation should be evaluated against the risk of contact. If chlorhexidine solutions come into contact with the eyes, wash out promptly and thoroughly with water.

Do not inject or use in body cavities.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

See section 6.2.

4.6 Pregnancy And Lactation

There is no evidence of any adverse effects on the foetus arising from the use of 'Hibiscrub' as a handwash during pregnancy and lactation. Therefore no special precautions are recommended.

4.7 Effects On Ability To Drive And Use Machines

None have been reported or are known.

4.8 Undesirable Effects

Irritative skin reactions to chlorhexidine preparations can occasionally occur. Generalised allergic reactions to chlorhexidine have also been reported but are extremely rare.

4.9 Overdose

This has not been reported. Accidental ingestion Chlorhexidine taken orally is poorly absorbed. Treat with gastric lavage using milk, raw egg, gelatin or mild soap. Employ supportive measures as appropriate.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Mode of action - chlorhexidine has a wide range of antimicrobial activity. Chlorhexidine is effective against a wide range of Gram negative and Gram positive vegetative bacteria, yeasts, dermatophyte fungi and lipophilic viruses. It is inactive against bacterial spores except at elevated temperatures. Because of its cationic nature, chlorhexidine binds strongly to skin, mucosa and other tissues and is thus very poorly absorbed. No detectable blood levels have been found in man following oral use and percutaneous absorption, if it occurs at all, is insignificant.

5.2 Pharmacokinetic Properties

Retention and uptake kinetics and factors influencing the pharmacokinetics. Chlorhexidine appears to be very poorly absorbed. No blood levels were detected during a 3-week simulated clinical use of 'Hibiscrub'.

5.3 Preclinical Safety Data

Chlorhexidine is a drug on which extensive clinical experience has been obtained. All relevant information for the prescriber is provided elsewhere in the Summary of Product Characteristics.

6. Pharmaceutical Particulars

6.1 List Of Excipients

D-glucono-delta-lactone; Isopropyl alcohol; Lauryl dimethyl amine oxide; Perfume (Herbacol 15.393/T); Polyoxyethylene-polyoxypropylene block copolymer; Ponceau 4R (E124); Sodium Hydroxide; Purified Water.

6.2 Incompatibilities

Chlorhexidine is incompatible with soap and other anionic agents. Hypochlorite bleaches may cause brown stains to develop in fabrics which have previously been in contact with preparations containing chlorhexidine.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

Do not store above 25^oC.

6.5 Nature And Contents Of Container

HDPE bottles containing 250ml, 500ml and 5 litres.

6.6 Special Precautions For Disposal And Other Handling

See section 4.4.

7. Marketing Authorisation Holder

Tubifoam Limited, Toft Hall, Toft Road, Knutsford, Cheshire, WA16 9PD.

8. Marketing Authorisation Number(S)

PL 01652/0001

9. Date Of First Authorisation/Renewal Of The Authorisation

1^st February 2001 / 8^th October 2003.

10. Date Of Revision Of The Text

October 2003.

Efient 5mg & 10mg film-coated tablets (Eli Lilly and Company Ltd Daiichi Sankyo UK Limited)

1. Name Of The Medicinal Product

Efient* 5 mg film-coated tablets.

Efient 10 mg film-coated tablets.

2. Qualitative And Quantitative Composition

Each tablet contains 5 mg prasugrel (as hydrochloride).

Excipient: Each tablet contains 2.7 mg lactose.

Each tablet contains 10 mg prasugrel (as hydrochloride).

Excipient: Each tablet contains 2.1 mg lactose.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet (tablet).

Yellow and double-arrow-shaped tablets, debossed with “5 MG” on one side and “4760” on the other.

Film-coated tablet (tablet).

Beige and double-arrow-shaped tablets, debossed with “10 MG”on one side and “4759” on the other.

4. Clinical Particulars

4.1 Therapeutic Indications

Efient, co-administered with acetylsalicylic acid (ASA), is indicated for the prevention of atherothrombotic events in patients with acute coronary syndrome (i.e., unstable angina, non-ST segment elevation myocardial infarction [UA/NSTEMI] or ST segment elevation myocardial infarction [STEMI]) undergoing primary or delayed percutaneous coronary intervention (PCI).

For further information please refer to section 5.1.

4.2 Posology And Method Of Administration

Posology

Adults

Efient should be initiated with a single 60 mg loading dose and then continued at 10 mg once a day. Patients taking Efient should also take ASA daily (75 mg to 325 mg).

In patients with acute coronary syndrome (ACS) who are managed with PCI, premature discontinuation of any antiplatelet agent, including Efient, could result in an increased risk of thrombosis, myocardial infarction or death due to the patient's underlying disease. A treatment of up to 12 months is recommended, unless the discontinuation of Efient is clinically indicated (see sections 4.4 and 5.1).

Patients 75 years old

The use of Efient in patients

Patients weighing <60 kg

Efient should be given as a single 60 mg loading dose and then continued at a 5 mg once-daily dose. The 10 mg maintenance dose is not recommended. This is due to an increase in exposure to the active metabolite of prasugrel, and an increased risk of bleeding in patients with body weight <60 kg when given a 10 mg once-daily dose, compared with patients

Renal impairment

No dose adjustment is necessary for patients with renal impairment, including patients with end-stage renal disease (see section 5.2). There is limited therapeutic experience in patients with renal impairment (see section 4.4).

Hepatic impairment

No dose adjustment is necessary in subjects with mild to moderate hepatic impairment (Child-Pugh class A and B) (see section 5.2). There is limited therapeutic experience in patients with mild and moderate hepatic dysfunction (see section 4.4).

Children and adolescents

Efient is not recommended for use in children below age 18 due to a lack of data on safety and efficacy.

Method of administration

For oral use. Efient may be administered with or without food. Administration of the 60 mg prasugrel loading dose in the fasted state may provide most rapid onset of action (see section 5.2). Do not crush or break the tablet.

4.3 Contraindications

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

Active pathological bleeding.

History of stroke or transient ischaemic attack (TIA).

Severe hepatic impairment (Child-Pugh class C).

4.4 Special Warnings And Precautions For Use

Bleeding risk

In the phase 3 clinical trial, key exclusion criteria included an increased risk of bleeding; anaemia; thrombocytopaenia; a history of pathological intracranial findings. Patients with acute coronary syndromes undergoing PCI treated with Efient and ASA showed an increased risk of major and minor bleeding according to the TIMI classification system. Therefore, the use of Efient in patients at increased risk of bleeding should only be considered when the benefits in terms of prevention of ischaemic events are deemed to outweigh the risk of serious bleedings. This concern applies especially to patients:

•

• with a propensity to bleed (e.g., due to recent trauma, recent surgery, recent or recurrent gastrointestinal bleeding, or active peptic ulcer disease).

• with body weight <60 kg (see sections 4.2 and 4.8). In these patients the 10 mg maintenance dose is not recommended. A 5 mg maintenance dose should be used.

• with concomitant administration of medicinal products that may increase the risk of bleeding, including oral anticoagulants, clopidogrel, non-steroidal anti-inflammatory drugs (NSAIDs), and fibrinolytics.

For patients with active bleeding for whom reversal of the pharmacological effects of Efient is required, platelet transfusion may be appropriate.

The use of Efient in patients

Therapeutic experience with prasugrel is limited in patients with renal impairment (including ESRD) and in patients with moderate hepatic impairment. These patients may have an increased bleeding risk. Therefore, prasugrel should be used with caution in these patients.

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

Surgery

Patients should be advised to inform physicians and dentists that they are taking prasugrel before any surgery is scheduled, and before any new medicinal product is taken. If a patient is to undergo elective surgery, and an antiplatelet effect is not desired, Efient should be discontinued at least 7 days prior to surgery. Increased frequency (3-fold) and severity of bleeding may occur in patients undergoing CABG surgery within 7 days of discontinuation of prasugrel (see section 4.8). The benefits and risks of prasugrel should be carefully considered in patients in whom the coronary anatomy has not been defined, and urgent CABG is a possibility.

Hypersensitivity including angioedema

Hypersensitivity reactions including angioedema have been reported in patients receiving prasugrel, including in patients with a history of hypersensitivity reaction to clopidogrel. Monitoring for signs of hypersensitivity in patients with a known allergy to thienopyridines is advised (see section 4.8).

Thrombotic Thrombocytopenic Purpura (TTP)

TTP has been reported with the use of prasugrel. TTP is a serious condition and requires prompt treatment.

Lactose

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

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Warfarin: Concomitant administration of Efient with coumarin derivatives other than warfarin has not been studied. Because of the potential for increased risk of bleeding, warfarin (or other coumarin derivatives) and prasugrel should be co-administered with caution (see section 4.4).

Non-steroidal anti-inflammatory drugs (NSAIDs): Concomitant administration with chronic NSAIDs has not been studied. Because of the potential for increased risk of bleeding, chronic NSAIDs (including COX-2 inhibitors) and Efient should be co-administered with caution (see section 4.4).

Efient can be concomitantly administered with medicinal products metabolised by cytochrome P450 enzymes (including statins), or medicinal products that are inducers or inhibitors of cytochrome P450 enzymes. Efient can also be concomitantly administered with ASA, heparin, digoxin, and medicinal products that elevate gastric pH, including proton pump inhibitors and H₂ blockers. Although not studied in specific interaction studies, Efient has been co-administered in the phase 3 clinical trial with low molecular weight heparin, bivalirudin, and GP IIb/IIIa inhibitors (no information available regarding the type of GP IIb/IIIa inhibitor used) without evidence of clinically significant adverse interactions.

Effects of other medicinal products on Efient

Acetylsalicylic acid: Efient is to be administered concomitantly with acetylsalicylic acid (ASA). Although a pharmacodynamic interaction with ASA leading to an increased risk of bleeding is possible, the demonstration of the efficacy and safety of prasugrel comes from patients concomitantly treated with ASA.

Heparin: A single intravenous bolus dose of unfractionated heparin (100 U/kg) did not significantly alter the prasugrel-mediated inhibition of platelet aggregation. Likewise, prasugrel did not significantly alter the effect of heparin on measures of coagulation. Therefore, both medicinal products can be administered concomitantly. An increased risk of bleeding is possible when Efient is co-administered with heparin.

Statins: Atorvastatin (80 mg daily) did not alter the pharmacokinetics of prasugrel and its inhibition of platelet aggregation. Therefore, statins that are substrates of CYP3A are not anticipated to have an effect on the pharmacokinetics of prasugrel or its inhibition of platelet aggregation.

Medicinal products that elevate gastric pH: Daily co-administration of ranitidine (an H₂ blocker) or lansoprazole (a proton pump inhibitor) did not change the prasugrel active metabolite's AUC and T_max, but decreased the C_max by 14% and 29%, respectively. In the phase 3 clinical trial, Efient was administered without regard to co-administration of a proton pump inhibitor or H₂ blocker. Administration of the 60 mg prasugrel loading dose without concomitant use of proton pump inhibitors may provide most rapid onset of action.

Inhibitors of CYP3A: Ketoconazole (400 mg daily), a selective and potent inhibitor of CYP3A4 and CYP3A5, did not affect prasugrel-mediated inhibition of platelet aggregation or the prasugrel active metabolite's AUC and T_max, but decreased the C_max by 34% to 46%. Therefore, CYP3A inhibitors such as azol antifungals, HIV protease inhibitors, clarithromycin, telithromycin, verapamil, diltiazem, indinavir, ciprofloxacin, and grapefruit juice are not anticipated to have a significant effect on the pharmacokinetics of the active metabolite.

Inducers of cytochromes P450: Rifampicin (600 mg daily), a potent inducer of CYP3A and CYP2B6, and an inducer of CYP2C9, CYP2C19, and CYP2C8, did not significantly change the pharmacokinetics of prasugrel. Therefore, known CYP3A inducers such as rifampicin, carbamazepine, and other inducers of cytochromes P450 are not anticipated to have significant effect on the pharmacokinetics of the active metabolite.

Effects of Efient on other medicinal products

Digoxin: Prasugrel has no clinically significant effect on the pharmacokinetics of digoxin.

Medicinal products metabolised by CYP2C9: Prasugrel did not inhibit CYP2C9, as it did not affect the pharmacokinetics of S-warfarin. Because of the potential for increased risk of bleeding, warfarin and Efient should be co-administered with caution (see section 4.4).

Medicinal products metabolised by CYP2B6: Prasugrel is a weak inhibitor of CYP2B6. In healthy subjects, prasugrel decreased exposure to hydroxybupropion, a CYP2B6-mediated metabolite of bupropion, by 23%. This effect is likely to be of clinical concern only when prasugrel is co-administered with medicinal products for which CYP2B6 is the only metabolic pathway, and have a narrow therapeutic window (e.g., cyclophosphamide, efavirenz).

4.6 Pregnancy And Lactation

No clinical study has been conducted in pregnant or lactating women.

Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Because animal reproduction studies are not always predictive of a human response, Efient should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the foetus.

It is unknown whether prasugrel is excreted in human breast milk. Animal studies have shown excretion of prasugrel in breast milk. The use of prasugrel during breastfeeding is not recommended.

Prasugrel had no effect on fertility of male and female rats at oral doses up to an exposure 240-times the recommended daily human maintenance dose (based on mg/m²).

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on ability to drive and use machines have been performed. Prasugrel is expected to have no or negligible influence on the ability to drive and use machines.

4.8 Undesirable Effects

a. Summary of the safety profile

Safety in patients with acute coronary syndrome undergoing PCI was evaluated in one clopidogrel-controlled study (TRITON) in which 6741 patients were treated with prasugrel (60 mg loading dose and 10 mg once daily maintenance dose) for a median of 14.5 months (5802 patients were treated for over 6 months, 4136 patients were treated for more than 1 year). The rate of study drug discontinuation due to adverse events was 7.2% for prasugrel and 6.3% for clopidogrel. Of these, bleeding was the most common adverse reaction for both drugs leading to study drug discontinuation (2.5% for prasugrel and 1.4% for clopidogrel).

Bleeding

Non-Coronary Artery Bypass Graft (CABG) related bleeding

In TRITON, the frequency of patients experiencing a Non-CABG-related bleeding event is shown in Table 1. The incidence of Non-CABG-related TIMI major bleeding, including life-threatening and fatal, as well as TIMI minor bleeding, was statistically significantly higher in subjects treated with prasugrel compared to clopidogrel in the UA/NSTEMI and all ACS populations. No significant difference was seen in the STEMI population. The most common site of spontaneous bleeding was the gastrointestinal tract (1.7% rate with prasugrel and 1.3% rate with clopidogrel); the most frequent site of provoked bleeding was the arterial puncture site (1.3% rate with prasugrel and 1.2% with clopidogrel).

Table 1: Incidence of Non-CABG-related bleeding^a (% Patients)

Event	All ACS	UA/NSTEMI	STEMI
Prasugrelb +ASA (N=6741)	Clopidogrelb +ASA (N=6716)	Prasugrelb +ASA (N=5001)	Clopidogrelb +ASA (N=4980)	Prasugrelb +ASA (N=1740)	Clopidogrelb +ASA (N=1736)
TIMI major bleedingc	2.2	1.7	2.2	1.6	2.2	2.0
Life-threateningd	1.3	0.8	1.3	0.8	1.2	1.0
Fatal	0.3	0.1	0.3	0.1	0.4	0.1
Symptomatic ICHe	0.3	0.3	0.3	0.3	0.2	0.2
Requiring inotropes	0.3	0.1	0.3	0.1	0.3	0.2
Requiring surgical intervention	0.3	0.3	0.3	0.3	0.1	0.2
Requiring transfusion (	0.7	0.5	0.6	0.3	0.8	0.8
TIMI minor bleedingf	2.4	1.9	2.3	1.6	2.7	2.6

a Centrally adjudicated events defined by the Thrombolysis in Myocardial Infarction (TIMI) Study Group criteria.

b Other standard therapies were used as appropriate.

c Any intracranial haemorrhage or any clinically overt bleeding associated with a fall in haemoglobin

d Life-threatening bleeding is a subset of TIMI major bleeding and includes the types indented below. Patients may be counted in more than one row.

e ICH=intracranial haemorrhage.

f Clinically overt bleeding associated with a fall in haemoglobin of

Patients 75 years old

In the phase 3 clinical trial, Non-CABG-related TIMI major or minor bleeding rates for patients in two age groups were as follows:

Age	Prasugrel	Clopidogrel
	9.0% (1.0% fatal)	6.9% (0.1% fatal)
<75 years (N=11672)	3.8% (0.2% fatal)	2.9% (0.1% fatal)

Patients < 60 kg

In the phase 3 clinical trial, Non-CABG-related TIMI major or minor bleeding rates for patients in two weight groups were as follows:

Weight	Prasugrel	Clopidogrel
<60 kg (N=664)	10.1% (0% fatal)	6.5% (0.3% fatal)
	4.2% (0.3% fatal)	3.3% (0.1% fatal)

In patients and age <75 years, Non-CABG-related TIMI major or minor bleeding rates were 3.6% for prasugrel and 2.8% for clopidogrel; rates for fatal bleeding were 0.2% for prasugrel and 0.1% for clopidogrel.

CABG-related bleeding

In the phase 3 clinical trial, 437 patients underwent CABG during the course of the study. Of those patients, the rate of CABG-related TIMI major or minor bleeding was 14.1% for the prasugrel group and 4.5% in the clopidogrel group. The higher risk for bleeding events in subjects treated with prasugrel persisted up to 7 days from the most recent dose of study drug. For patients who received their thienopyridine within 3 days prior to CABG, the frequencies of TIMI major or minor bleeding were 26.7% (12 of 45 patients) in the prasugrel group, compared with 5.0% (3 of 60 patients) in the clopidogrel group. For patients who received their last dose of thienopyridine within 4 to 7 days prior to CABG, the frequencies decreased to 11.3% (9 of 80 patients) in the prasugrel group and 3.4% (3 of 89 patients) in the clopidogrel group. Beyond 7 days after drug discontinuation, the observed rates of CABG-related bleeding were similar between treatment groups (see section 4.4).

b. Tabulated summary of adverse reactions

Table 2 summarises haemorrhagic and non-haemorrhagic adverse reactions in TRITON, or that were spontaneously reported, classified by frequency and system organ class. Frequencies are defined as follows:

Very common (

Table 2: Haemorrhagic and Non-haemorrhagic adverse reactions

System Organ Class	Common	Uncommon	Rare	Not Known
Blood and Lymphatic system disorders	Anaemia		Thrombocytopaenia	Thrombotic thrombocytopaenic purpura (TTP) -see section 4.4
Immune system disorders		Hypersensitivity including angioedema
Eye disorders		Eye haemorrhage
Vascular disorders	Haematoma
Respiratory, thoracic and mediastinal disorders	Epistaxis	Haemoptysis
Gastrointestinal disorders	Gastrointestinal haemorrhage	Retroperitoneal haemorrhage Rectal haemorrhage Haematochezia Gingival bleeding
Skin and subcutaneous tissue disorders	Rash Ecchymosis
Renal and urinary disorders	Haematuria
General disorders and administration site conditions	Vessel puncture site haematoma Puncture site haemorrhage
Injury, poisoning and procedural complications	Contusion	Post-procedural haemorrhage	Subcutaneous haematoma

In patients with or without a history of TIA or stroke, the incidence of stroke in the phase 3 clinical trial was as follows (see section 4.4):

History of TIA or stroke	Prasugrel	Clopidogrel
Yes (N=518)	6.5% (2.3% ICH*)	1.2% (0% ICH*)
No (N=13090)	0.9% ( 0.2% ICH*)	1.0% (0.3% ICH*)

* ICH=intracranial haemorrhage.

4.9 Overdose

Overdose of Efient may lead to prolonged bleeding time and subsequent bleeding complications. No data are available on the reversal of the pharmacological effect of prasugrel; however, if prompt correction of prolonged bleeding time is required, platelet transfusion and/or other blood products may be considered.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Platelet aggregation inhibitors excluding heparin. ATC code: B01AC22.

Pharmacodynamics

Prasugrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y₁₂ class of ADP receptors on platelets. Since platelets participate in the initiation and/or evolution of thrombotic complications of atherosclerotic disease, inhibition of platelet function can result in the reduction of the rate of cardiovascular events such as death, myocardial infarction, or stroke.

Following a 60 mg loading dose of prasugrel, inhibition of ADP-induced platelet aggregation occurs at 15 minutes with 5 µM ADP and 30 minutes with 20 µM ADP. The maximum inhibition by prasugrel of ADP-induced platelet aggregation is 83% with 5 µM ADP and 79% with 20 µM ADP, in both cases with 89% of healthy subjects and patients with stable atherosclerosis achieving at least 50% inhibition of platelet aggregation by 1 hour. Prasugrel-mediated inhibition of platelet aggregation exhibits low between-subject (9%) and within-subject (12%) variability with both 5 µM and 20 µM ADP. Mean steady-state inhibition of platelet aggregation was 74% and 69% respectively for 5 µM ADP and 20 µM ADP, and was achieved following 3 to 5 days of administration of the 10 mg prasugrel maintenance dose preceded by a 60 mg loading dose. More than 98% of subjects had

Platelet aggregation gradually returned to baseline values after treatment in 7 to 9 days after administration of a single 60 mg loading dose of prasugrel, and in 5 days following discontinuation of maintenance dosing at steady-state.

Clopidogrel: Following administration of 75 mg clopidogrel once daily for 10 days, 40 healthy subjects were switched to prasugrel 10 mg once daily with or without a loading dose of 60 mg. Similar or higher inhibition of platelet aggregation was observed with prasugrel. Switching directly to prasugrel 60 mg loading dose resulted in the most rapid onset of higher platelet inhibition. Following administration of a 900 mg loading dose of clopidogrel (with ASA), 56 subjects with ACS were treated for 14 days with either prasugrel 10 mg once daily or clopidogrel 150 mg once daily, and then switched to either clopidogrel 150 mg or prasugrel 10 mg for another 14 days. Higher inhibition of platelet aggregation was observed in patients switched to prasugrel 10 mg compared with those treated with clopidogrel 150 mg. No data are available on switching from a clopidogrel loading dose directly to a prasugrel loading dose.

Efficacy and Safety in Acute Coronary Syndrome (ACS)

The phase 3 TRITON study compared Efient (prasugrel) with clopidogrel, both co-administered with ASA and other standard therapy. TRITON was a 13,608 patient, multi-centre international, randomised, double-blind, parallel group study. Patients had ACS with moderate to high risk UA, NSTEMI, or STEMI and were managed with PCI.

Patients with UA/NSTEMI within 72 hours of symptoms or STEMI between 12 hours to 14 days of symptoms were randomised after knowledge of coronary anatomy. Patients with STEMI within 12 hours of symptoms and planned for primary PCI could be randomised without knowledge of coronary anatomy. For all patients, the loading dose could be administered any time between randomisation and 1 hour after the patient left the catheterisation lab.

Patients randomised to receive prasugrel (60 mg loading dose followed by 10 mg once daily) or clopidogrel (300 mg loading dose followed by 75 mg once daily) were treated for a median of 14.5 months (maximum of 15 months with a minimum of 6 months follow-up). Patients also received ASA (75 mg to 325 mg once daily). Use of any thienopyridine within 5 days before enrolment was an exclusion criterion. Other therapies, such as heparin and GPIIb/IIIa inhibitors, were administered at the discretion of the physician. Approximately 40% of patients (in each of the treatment groups) received GPIIb/IIIa inhibitors in support of PCI (no information available regarding the type of GPIIb/IIIa inhibitor used). Approximately 98% of patients (in each of the treatment groups) received antithrombins (heparin, low molecular weight heparin, bivalirudin, or other agent) directly in support of PCI.

The trial's primary outcome measure was the time to first occurrence of cardiovascular (CV) death, non-fatal myocardial infarction (MI), or non-fatal stroke. Analysis of the composite endpoint in the All ACS population (combined UA/NSTEMI and STEMI cohorts) was contingent on showing statistical superiority of prasugrel versus clopidogrel in the UA/NSTEMI cohort (p<0.05).

All ACS population : Efient showed superior efficacy compared to clopidogrel in reducing the primary composite outcome events as well as the pre-specified secondary outcome events, including stent thrombosis (see Table 3). The benefit of prasugrel was apparent within the first 3 days and it persisted to the end of study. The superior efficacy was accompanied by an increase in major bleeding (see sections 4.4 and 4.8). The patient population was 92% Caucasian, 26% female, and 39%

The observed benefit of prasugrel in patients

Patients with a history of TIA or a history of ischaemic stroke more than 3 months prior to prasugrel therapy had no reduction in the primary composite endpoint.

Table 3: Patients with Outcome Events in TRITON Primary Analysis

Outcome Events	Prasugrel + ASA	Clopidogrel +ASA	Hazard Ratio (HR) (95% CI)	p-value
All ACS	(N=6813) %	(N=6795) %	0.812 (0.732, 0.902)	<0.001
Primary Composite Outcome Events Cardiovascular (CV) death, non-fatal MI, or non-fatal stroke	9.4	11.5
Primary Individual Outcome Events
CV death	2.0	2.2	0.886 (0.701, 1.118)	0.307
Non-fatal MI	7.0	9.1	0.757 (0.672, 0.853)	<0.001
Non-fatal stroke	0.9	0.9	1.016 (0.712, 1.451)	0.930
UA/NSTEMI Primary Composite Outcome Events	(N= 5044) %	(N=5030) %
CV death, non-fatal MI, or non-fatal stroke	9.3	11.2	0.820 (0.726, 0.927)	0.002
CV death	1.8	1.8	0.979 (0.732,1.309)	0.885
Non-fatal MI	7.1	9.2	0.761 (0.663,0.873)	<0.001
Non-fatal stroke	0.8	0.8	0.979 (0.633,1.513)	0.922
STEMI Primary Composite Outcome Events	(N= 1769) %	(N=1765) %
CV death, non-fatal MI, or non-fatal stroke	9.8	12.2	0.793 (0.649, 0.968)	0.019
CV death	2.4	3.3	0.738 (0.497,1.094)	0.129
Non-fatal MI	6.7	8.8	0.746 (0.588,0.948)