1. Name Of The Medicinal Product

ISIB 60 XL Prolonged Release Tablets

and

CIBRAL 60 XL Prolonged Release Tablets

and

XISMOX 60 XL Prolonged Release Tablets

2. Qualitative And Quantitative Composition

Isosorbide mononitrate 60.0 mg

For excipients, see section 6.1.

3. Pharmaceutical Form

Prolonged Release Tablets

Light yellow, biconvex, oval-shaped, prolonged release tablets, scored on both sides and marked "DX 31" on one side.

4. Clinical Particulars 4.1 Therapeutic Indications

Prophylaxis of angina pectoris

4.2 Posology And Method Of Administration

Adults: The recommended dose is one 60 mg tablet once daily to be taken in the morning. The dose may be increased to 120 mg (two tablets) daily, both to be taken once daily in the morning. The dose can be titrated, by initiating treatment with 30 mg (half tablet) for the first 2-4 days to minimize the possibility of headache.

Children: The safety and efficacy in children has not been established.

Elderly: No evidence of a need for routine dosage adjustment in the elderly has been found, but special care may be needed in those with increased susceptibility to hypotension or marked hepatic or renal insufficiency.

There is a risk of tolerance developing when nitrate therapy is given. For this reason it is important that the tablets are taken once a day to achieve an interval with low nitrate concentration, thereby reducing the risk of tolerance development.

When necessary the product may be used in combination with beta-adrenoreceptor blockers and calcium antagonists. Dose adjustments of either class of agent may be necessary.

The tablets must not be chewed or crushed. They should be swallowed with half a glass of water.

4.3 Contraindications

Hypersensitivity to isosorbide mononitrate, or to any of the excipients.

Sildenafil has been shown to potentiate the hypotensive effects of nitrates, and its co-administration with nitrates or nitric oxide donors is therefore contra-indicated.

Isosorbide mononitrate is contraindicated in constrictive pericarditis and pericardial tamponade.

4.4 Special Warnings And Precautions For Use

Use with extreme caution in hypotension with or without other signs of shock and in cases of cerebrovascular insufficiency.

Other special warnings and precautions with Isosorbide mononitrate:

Significant aortic or mitral valve stenosis.

Hypertrophic obstructive cardiomyopathy.

Anaemia. Hypoxaemia, Hypothyroidism.

The tablets are not indicated for relief of acute angina attacks.

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

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Isosorbide mononitrate may act as a physiological antagonist to noradrenaline, acetylcholine, histamine and many other agents. The effect of anti-hypertensive drugs may be enhanced. Alcohol may enhance the hypotensive effects of isosorbide mononitrate.

The hypotensive effects of nitrates are potentiated by concurrent administration of sildenafil.

4.6 Pregnancy And Lactation

The tablets should not be used during pregnancy and lactation.

4.7 Effects On Ability To Drive And Use Machines

Patients experiencing headache or dizziness following initial treatment with the tablets should become stabilised on treatment before driving or using machines.

4.8 Undesirable Effects

Most of the adverse reactions are pharmacodynamically mediated and dose dependent. Headache may occur when treatment is initiated but usually disappears after continued treatment. Hypotension with symptoms such as dizziness and nausea has occasionally been reported. These symptoms generally disappear during long-term treatment. Less common are vomiting and diarrhoea. Uncommon is fainting.

Skin rashes (dry rash, exfoliative dermatitis) and pruritus have been reported rarely with isosorbide mononitrate. Myalgia has been reported very rarely.

4.9 Overdose

Symptoms: Pulsing headache. More serious symptoms are excitation, flushing, cold perspiration, nausea, vomiting, vertigo, syncope, tachycardia and a fall in blood pressure. Very large doses may give rise to methaemoglobinaemia (Very rare).

Treatment: Induction of emesis, activated charcoal. In case of pronounced hypotension the patient should first be placed in the supine position with legs raised. If necessary, fluid should be administered intravenously. (In cases of cyanosis as a result of methaemoglobinaemia, methyl thionine (methylene blue) 1 -2mg/Kg, slow intravenous delivery). Expert advice should be sought.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Organic nitrates, ATC code: C01D A14.

Isosorbide mononitrate is an organic nitrate, the major active metabolite of isosorbide dinitrate and an active vasodilator in its own right. The mechanism of action of Isosorbide mononitrate, like other organic nitrates, is believed to involve peripheral vasodilation, both venous and arterial. Maximal venous dilatation is usually achieved with lower doses of the nitrate, while higher doses cause progressive dilatation of the arterial vasculature. Nitrates thus lead to pooling of blood in the veins and reduced left ventricular and diastolic pressure. As arterial vascular resistance is also decreased, arterial blood pressure is reduced. Isosorbide mononitrate is an effective antianginal agent because it improves exertional angina by reducing myocardial oxygen demand, secondary to reduced preload and afterload. Organic nitrates release nitric oxide (NO), which induces protein phosphorylations, finally resulting in vascular smooth muscle relaxation.

In comparison to an immediate release product taken on a multiple dose basis, this prolonged release product has the advantage of both lowering the incidence of tolerance and increasing patient compliance.

5.2 Pharmacokinetic Properties

Isosorbide mononitrate is completely absorbed after oral administration. The absorption is not affected by simultaneous food intake. Contrary to many other nitrates, Isosorbide mononitrate is not subject to first pass metabolism and its oral bioavailability is therefore close to 100%. This feature probably contributes to the relatively small intersubject variability in plasma levels that are achieved following ingestion of the drug. Peak plasma concentrations of Isosorbide mononitrate after oral ingestion of a prolonged release tablet usually occur within 3.1-4.5 hours. Isosorbide mononitrate's volume of distribution is about 0.6 litres/kg, and its plasma protein binding is negligible (about 4%). Isosorbide mononitrate is metabolised to form several inactive compounds. Elimination is primarily by denitration and conjugation in the liver. The metabolites are excreted mainly via the kidneys. About 2% of the dose is excreted intact via the kidneys. The half-life of Isosorbide mononitrate in the plasma of healthy volunteers as well as in most patients is about 6.5 hours after administration of prolonged release tablets. Neither renal nor hepatic disease influence the pharmacokinetic of isosorbide mononitrate. The tablets are a prolonged release formulation. The active substance is released independently of pH.

5.3 Preclinical Safety Data

Isosorbide mononitrate is a well-established drug for which there is adequate published safety data.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Hypromellose 2208

Lactose monohydrate

Compressible Sugar (composed of Sucrose and Maltodextrin)

Magnesium stearate

Colloidal anhydrous silica

Iron oxide yellow.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life 5 years 6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

Blister pack PVDC- or ACLAR-coated-PVC/Aluminium 28, 30 or 98 tablets.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Dexcel-Pharma Ltd.

1 Cottesbrooke Park

Heartlands Business Park, Daventry

Northamptonshire NN1 1 8YL, England

8. Marketing Authorisation Number(S)

PL 14017/0096

9. Date Of First Authorisation/Renewal Of The Authorisation 27th October 2004. 10. Date Of Revision Of The Text

29 October 2009



Pronunciation: rif-AX-i-min



urea



1. Name Of The Medicinal Product

Xigris* 5mg powder for solution for infusion.

Xigris 20mg powder for solution for infusion.

2. Qualitative And Quantitative Composition

Xigris 5mg: Each vial contains 5mg of Drotrecogin alfa (activated).

After reconstitution with 2.5ml of Water for Injection each ml contains 2mg of Drotrecogin alfa (activated).

Excipient: Each vial contains approximately 17mg sodium.

Xigris 20mg: Each vial contains 20mg of drotrecogin alfa (activated).

After reconstitution with 10ml of Water for Injection, each ml contains 2mg of Drotrecogin alfa (activated).

Excipient: Each vial contains approximately 68mg sodium.

Drotrecogin alfa (activated) is a recombinant version of the endogenous activated Protein C and is produced by genetic engineering from an established human cell line.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder for solution for infusion. Xigris is supplied as a lyophilised, white to off-white powder.

4. Clinical Particulars 4.1 Therapeutic Indications

Xigris is indicated for the treatment of adult patients with severe sepsis with multiple organ failure when added to best standard care. The use of Xigris should be considered mainly in situations when therapy can be started within 24 hours after the onset of organ failure (for further information see section 5.1).

4.2 Posology And Method Of Administration

Xigris should be used by experienced doctors in institutions skilled in the care of patients with severe sepsis.

Treatment should be started within 48 hours, and preferably within 24 hours, of onset of the first documented sepsis-induced organ dysfunction (see section 5.1).

The recommended dose of Xigris is 24?g/kg/hr (based on actual body weight) given as a continuous intravenous infusion for a total duration of 96 hours. It is recommended that Xigris be infused with an infusion pump to accurately control the infusion rate. If the infusion is interrupted for any reason, Xigris should be restarted at the 24?g/kg/hr infusion rate and continued to complete the full recommended 96 hours of dosing administration. Dose escalation or bolus doses of Xigris are not necessary to account for the interruption in the infusion.

No dose adjustments are required in adult patients with severe sepsis with regard to age, gender, hepatic function (as measured by transaminase levels), renal function, obesity or co-administration of prophylactic heparin. The pharmacokinetics of drotrecogin alfa (activated) have not been studied in patients with severe sepsis and pre-existing end-stage renal disease and chronic hepatic disease.

Paediatrics: Data from a placebo-controlled clinical trial, which was stopped for futility after 477 patients 0 to 17 years old had received the study treatment, did not establish efficacy of Xigris in paediatric patients and showed a higher rate of central nervous system bleeding in the Xigris versus placebo group. Xigris is contraindicated in children below the age of 18 (see sections 4.3 and 5.1).

4.3 Contraindications

Hypersensitivity to the active substance, to any of the excipients, or to bovine thrombin (a trace residue from the manufacturing process).

Drotrecogin alfa (activated) is contraindicated in children below the age of 18 years (see section 5.1).

Because drotrecogin alfa (activated) may increase the risk of bleeding, Xigris is contraindicated in the following situations:

• Active internal bleeding.

• Patients with intracranial pathology; neoplasm or evidence of cerebral herniation.

• Concurrent heparin therapy

• Known bleeding diathesis except for acute coagulopathy related to sepsis.

• Chronic severe hepatic disease.

• Platelet count <30,000 x 106 /l, even if the platelet count is increased after transfusions.

• Patients at increased risk for bleeding (for example):

a) Any major surgery, defined as surgery that requires general or spinal anaesthesia, performed within the 12-hour period immediately preceding drug infusion, or any postoperative patient who demonstrates evidence of active bleeding, or any patient with planned or anticipated surgery during the drug infusion period.

b) History of severe head trauma that required hospitalisation, intracranial or intraspinal surgery, or haemorrhagic stroke within the previous 3 months, or any history of intracerebral arteriovenous malformation, cerebral aneurysm, or central nervous system mass lesion; patients with an epidural catheter or who are anticipated to receive an epidural catheter during drug infusion.

c) History of congenital bleeding diatheses.

d) Gastro-intestinal bleeding within the last 6 weeks that has required medical intervention unless definitive surgery has been performed.

e) Trauma patients at increased risk of bleeding.

 

4.4 Special Warnings And Precautions For Use

No further study has confirmed the efficacy results of the single pivotal trial.

Patients With Single Organ Dysfunction and Recent Surgery

Xigris is not approved for the treatment of patients with single organ dysfunction and should not be used in this particular subgroup of patients, especially if they had recent surgery (within 30 days). In each of two randomised, placebo-controlled trials, PROWESS and ADDRESS (see section 5.1), 28-day and in-hospital mortality were higher in patients treated with drotrecogin alfa (activated) compared to placebo for the sub-population of patients with single organ dysfunction and recent surgery (n = 98 in PROWESS and n = 636 in ADDRESS).

Bleeding

Drotrecogin alfa (activated) increases the risk of bleeding. In the following conditions, the risks of the administration of Xigris should be weighed against the anticipated benefits:

• Recent administration (within 3 days) of thrombolytic therapy.

• Recent administration (within 7 days) of oral anticoagulants.

• Recent administration (within 7 days) of aspirin or other platelet inhibitors.

• Recent (within 3 months) ischaemic stroke.

• Any other condition in which the physician considers significant bleeding is likely.

For procedures with an inherent bleeding risk, discontinue Xigris for 2 hours prior to the start of the procedure. Xigris may be restarted 12 hours after major invasive procedures or surgery if adequate haemostasis has been achieved. The incidence of serious bleeding events with Xigris was higher in patients with recent (within 30 days) surgery than in “medical” patients without surgery (see section 4.8). Bleeding risk should be taken into account when considering the risk benefit for individual patients. Xigris may be restarted immediately after uncomplicated less invasive procedures if adequate haemostasis has been achieved.

As a component of routine care, measures of haemostasis (e.g., activated partial thromboplastin time [APTT], prothrombin time [PT], and platelet count) should be obtained during the infusion of Xigris. If sequential tests of haemostasis indicate an uncontrolled or worsening coagulopathy that significantly increases the risk of bleeding, the benefits of continuing the infusion must be weighed against the potential increased risk of bleeding for that patient.

Laboratory Tests

Drotrecogin alfa (activated) has minimal effect on the PT. Prolongation of the APTT in patients with severe sepsis receiving Xigris may be due to the underlying coagulopathy, the pharmacodynamic effect of drotrecogin alfa (activated), and/or the effect of other concurrent medicinal products. The pharmacodynamic effect of drotrecogin alfa (activated) on the APTT assay is dependent on the reagent and instrument used to perform the assay and the time that elapses between sample acquisition and assay performance. Drotrecogin alfa (activated) that is present in a blood or plasma sample drawn from a patient who is being infused with the drug will be gradually neutralised by endogenous plasma protease inhibitors present in the sample. Virtually no measurable activity of drotrecogin alfa (activated) is present 2 hours after obtaining the blood sample. Due to these biological and analytical variables, the APTT should not be used to assess the pharmacodynamic effect of drotrecogin alfa (activated). In addition, approximately 2 hours after terminating the infusion of the drug, there is virtually no measurable activity of drotrecogin alfa (activated) remaining in the circulation of the patient; blood samples drawn for APTT determination after this point are no longer affected by the drug. The interpretation of sequential determinations of the PT and/or APTT should take these variables into consideration.

Because drotrecogin alfa (activated) may affect the APTT assays, drotrecogin alfa (activated) present in plasma samples may interfere with one-stage coagulation assays based on the APTT (such as Factor VIII, IX, and XI assays). Drotrecogin alfa (activated) present in plasma samples does not interfere with one-stage factor assays based on the PT (such as Factor II, V, VII and X assays).

If sequential measures of coagulopathy (including platelet count) indicate severe or worsening coagulopathy, the risk of continuing the infusion should be weighed against the expected benefit.

Immunogenicity

In adult patients in severe sepsis clinical studies, the frequency of anti-human Activated Protein C IgA/IgG/IgM antibodies or neutralising antibodies is low and is similar between drotrecogin alfa (activated) and placebo-treated patients tested. In patients developing antibodies, adverse events were not more frequent in drotrecogin alfa (activated) than in placebo patients. There was no evidence that the antibodies detected represented a specific immune response to drotrecogin alfa (activated) therapy.

There have been no clinical trials in severe sepsis specifically studying drotrecogin alfa (activated) re-administration. However, a small number of patients in severe sepsis controlled clinical trials received a prior course of drotrecogin alfa (activated). No hypersensitivity reactions were reported in these patients. Samples available were subsequently tested and all were negative for anti-human Activated Protein C antibody.

No anti-activated Protein C antibody formation was detected in healthy subjects, even after repeat administration.

However, the possibility of allergic reactions to constituents of the preparation cannot be completely excluded in certain predisposed patients. If allergic or anaphylactic reactions occur, treatment should be discontinued immediately and appropriate therapy initiated. If Xigris is readministered to patients, caution should be employed.

Xigris 5mg: This medicinal product contains approximately 17mg sodium per vial. To be taken into consideration by patients on a controlled sodium diet.

Xigris 20mg: This medicinal product contains approximately 68mg sodium per vial. To be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Caution should be employed when Xigris is used with other drugs that affect haemostasis (see sections 4.3 and 4.4), including Protein C, thrombolytics (e.g., streptokinase, tPA, rPA and urokinase), oral anticoagulants (e.g., warfarin), hirudins, antithrombin, aspirin and other anti-platelets agents, e.g., non-steroidal anti-inflammatory drugs, ticlopidine and clopidogrel, glycoprotein IIb/IIIa antagonists (such as abciximab, eptifibatide, tirofiban) and prostacyclins, such as iloprost.

Co-administration of Low-dose Heparin for Prophylaxis of Venous Thrombotic Events (VTE)

Low-dose heparin for VTE prophylaxis may be co-administered with drotrecogin alfa (activated). In a randomised study of heparin versus placebo (XPRESS) in 1,935 adult severe sepsis patients, all treated with drotrecogin alfa (activated), prophylactic heparin did not adversely affect mortality (heparin 28.3% versus placebo 31.9% in the overall ITT population, and heparin 30.3% versus placebo 26.9% in patients with multiple organ dysfunction treated within 24 hours of their first sepsis-induced organ dysfunction (n=890)). In the subgroup of 885 patients who were already receiving prophylactic heparin at study entry, mortality was 26.9% in the group randomised to continue heparin versus 35.6% in the group whose randomisation (to placebo) led to the discontinuation of heparin. However, the reasons for this difference are unknown and could be related to other factors. Additionally, there was no increased risk of serious bleeding, including central nervous system (CNS) bleeding. Prophylactic heparin increased the risk of non-serious bleeding (see section 4.8). There was no statistical difference in the rates of VTE between study arms.

4.6 Pregnancy And Lactation

Animal studies with respect to effects on pregnancy, embryonal/foetal development, parturition, and post-natal development have not been conducted with Xigris. Therefore, the potential risk for humans is unknown. Xigris should not be used during pregnancy unless clearly necessary.

It is not known whether Xigris is excreted in human milk or if there is a potential effect on the breast-fed infant. Therefore, the patient should not breast-feed whilst treated with Xigris.

4.7 Effects On Ability To Drive And Use Machines

Not relevant.

4.8 Undesirable Effects

Xigris increases the risk of bleeding.

The Phase 3 international, multi-centre, randomised, double-blind, placebo-controlled clinical trial (PROWESS) involved 850 drotrecogin alfa (activated)-treated and 840 placebo-treated patients. The percentage of patients experiencing at least one bleeding event in the two treatment groups was 24.9% and 17.7%, respectively. In both treatment groups, the majority of bleeding events were ecchymosis or gastro-intestinal tract bleeding. The difference in the incidence of serious bleeding events between the two treatment groups occurred primarily during study drug administration.

A total of 2,378 adult patients with severe sepsis received drotrecogin alfa (activated) in a Phase 3b, international, single-arm, open-label clinical trial (ENHANCE).

The incidence of serious bleeding events in the PROWESS and ENHANCE studies is provided below. In these studies, serious bleeding events included any intracranial haemorrhage, any life-threatening or fatal bleed, any bleeding event requiring the administration of

A Phase 3b, international, multi-centre, randomised, double-blind, placebo-controlled clinical trial (ADDRESS) of adult severe sepsis patients at low risk of death involved 1,317 drotrecogin alfa (activated)-treated and 1,293 placebo-treated patients. The percentage of patients experiencing at least one bleeding event in the two treatment groups was 10.9% and 6.4%, respectively (P <0.001). Bleeding events included serious bleeding events, bleeding events assessed as possibly study drug related by the investigator, bleeding events associated with the need for a red blood cell transfusion, and bleeding events that led to permanent discontinuation of the study drug. In the ADDRESS trial, serious bleeding events included any fatal bleed, any life-threatening bleed, any CNS bleed, or any bleeding event assessed as serious by the investigator.

Serious Bleeding Events During the Infusion Period

The following table lists the percentage of patients in PROWESS and ENHANCE experiencing serious bleeding events by site of haemorrhage during the study drug infusion period (defined as the duration of infusion plus the next full calendar day following the end of the infusion).

Site of Haemorrhage

Drotrecogin Alfa

(Activated)

[PROWESS]

n = 850

Placebo

[PROWESS]

n = 840

Drotrecogin Alfa

(Activated)

[ENHANCE]

n = 2,378

Gastro-intestinal

5 (0.6%)

4 (0.5%)

19 (0.8%)

Intra-abdominal

2 (0.2%)

3 (0.4%)

18 (0.8%)

Intra-thoracic

4 (0.5%)

0

11 (0.5%)

Retroperitoneal

3 (0.4%)

0

4 (0.2%)

Central nervous system (CNS)1

2 (0.2%)

0

15 (0.6%)

Genito-urinary

2 (0.2%)

0

0

Skin/soft tissue

1 (0.1%)

0

16 (0.7%)

Nasopharyngeal

0

0

4 (0.2%)

Joint/bone

0

0

1 (0.04%)

Site unknown2

1 (0.1%)

1 (0.1%)

6 (0.3%)

Total

20 (2.4%)

8 (1.0%)

853 (3.6%)

 

1 CNS bleeding is defined as any bleed in the central nervous system, including the following types of haemorrhage: petechial, parenchymal, subarachnoid, subdural, and stroke with haemorrhagic transformation.

2 Patients requiring the administration of

3 In ENHANCE, six patients experienced multiple serious bleeding events during the study drug infusion period (94 events observed in 85 patients).

     

During the infusion period in PROWESS and ENHANCE, the incidence of serious bleeding events with Xigris was numerically higher in patients with recent (within 30 days) surgery than in patients without surgery (PROWESS: 3.3% versus 2.0%; ENHANCE: 5.0% versus 3.1% respectively. Placebo rates in PROWESS 0.4% versus 1.2% respectively).

In ADDRESS, the percentage of treated patients experiencing a serious bleeding event by site of haemorrhage was similar to that observed in PROWESS. The incidence of serious bleeding events during infusion (defined as study day 0 through study day 6) was 31 (2.4%) and 15 (1.2%) in drotrecogin alfa (activated)-treated and placebo-treated patients, respectively (P = 0.02). The incidence of CNS bleeds during infusion was 4 (0.3%) and 3 (0.2%) for drotrecogin alfa (activated)-treated and placebo-treated patients, respectively. Recent surgery (within 30 days prior to study entry) was associated with a numerically higher risk of serious bleeding during infusion in both the Xigris-treated and the placebo-treated patients (Xigris: 3.6% in patients with recent surgery versus 1.6% in patients without recent surgery; placebo: 1.6% versus 0.9%, respectively).

In XPRESS, a randomised study of prophylactic heparin versus placebo in adult severe sepsis patients, all treated with drotrecogin alfa (activated), serious bleeding rates were consistent with those observed in previous studies over the treatment period of 0-6 days, and prophylactic heparin did not increase the risk of serious bleeding compared to placebo (2.3% versus 2.5%, respectively), including CNS bleeding (0.3% on both arms). However, prophylactic heparin increased the risk of non-serious bleeding compared with placebo (8.7% versus 5.7%, respectively; P = 0.0116).

Serious Bleeding Events During the 28-Day Study Period

In PROWESS, the incidence of serious bleeding events during the 28-day study period was 3.5% and 2.0% in drotrecogin alfa (activated)-treated and placebo-treated patients, respectively. The incidence of CNS bleeds during the 28-day study period was 0.2% and 0.1% for drotrecogin alfa (activated)-treated and placebo-treated patients, respectively. The risk of CNS bleeding may increase with severe coagulopathy and severe thrombocytopenia (see sections 4.3 and 4.4).

In the open-label ENHANCE study, the incidence of serious bleeding events during the 28-day study period was 6.5%, and the incidence of CNS bleeds during the 28-day study period was 1.5%.

In the placebo-controlled ADDRESS study, the incidence of serious bleeding events during the 28-day study period was 51 (3.9%) and 28 (2.2%) in drotrecogin alfa (activated)-treated and placebo-treated patients, respectively (P = 0.01). The incidence of CNS bleeds during the 28-day study period was 6 (0.5%) and 5 (0.4%) for drotrecogin alfa (activated)-treated and placebo-treated patients, respectively.

In XPRESS, serious bleeding rates were consistent with those observed in previous studies during the 28-day study period (days 0-28). Prophylactic heparin did not increase the risk of serious bleeding compared to placebo (3.9% versus 5.2%, respectively), including CNS bleeding (1.0% versus 0.7%, respectively).

In the Phase 1 studies, adverse events with a frequency of

4.9 Overdose

In clinical trials and in post-marketing experience there have been reports of accidental overdosing. In the majority of cases, no reactions have been observed. For the other reports, the observed events were consistent with known undesirable effects of the drug (see section 4.8), effects of the drug on laboratory tests (see section 4.4), or consequences of the underlying condition of sepsis.

There is no known antidote for drotrecogin alfa (activated). In case of overdose, immediately stop the infusion (see section 5.2).

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antithrombotic agents, enzymes. ATC code: B01AD10.

This medicinal product has been authorised under “Exceptional Circumstances”. This means that for scientific reasons it has not been possible to obtain complete information on this medicinal product. The European Medicines Agency (EMEA) will review any new information which may become available every year, and this SPC will be updated as necessary.

Mechanism of Action

Xigris is a recombinant version of the natural plasma-derived Activated Protein C, from which it differs only by unique oligosaccharides in the carbohydrate portion of the molecule. Activated Protein C is a crucial coagulation regulator. It limits thrombin formation by inactivating Factors Va and VIIIa, thereby providing negative feedback regulation of coagulation. Excessive coagulation activation in the microcirculatory bed plays a significant part in the pathophysiology of severe sepsis. Furthermore, Activated Protein C is an important modulator of the systemic response to infection and has antithrombotic and profibrinolytic properties. Xigris has similar properties to those of endogenous human Activated Protein C.

Pharmacodynamic Effects

In placebo-controlled clinical trials in patients with severe sepsis, Xigris exerted an antithrombotic effect by limiting thrombin generation and improved sepsis-associated coagulopathy, as shown by a more rapid improvement in markers of coagulation and fibrinolysis. Xigris caused a more rapid decline in thrombotic markers, such as D-dimer, prothrombin F1.2, and thrombin-antithrombin levels, and a more rapid increase in Protein C and antithrombin levels. Xigris also restored endogenous fibrinolytic potential, as evidenced by a more rapid trend toward normalisation in plasminogen levels and a more rapid decline in plasminogen activator inhibitor-1 levels. Additionally, patients with severe sepsis treated with Xigris had a more rapid decline in interleukin-6 levels, a global marker of inflammation, consistent with a reduction in the inflammatory response.

Clinical Efficacy

Xigris was studied in one Phase 3, international, multi-centre, randomised, double-blind, placebo-controlled trial (PROWESS) in 1,690 patients with severe sepsis. Severe sepsis is defined as sepsis associated with acute organ dysfunction. Patients meeting the clinical diagnosis of severe sepsis had: a) known or suspected infection; b) clinical evidence of systemic response to infection, including fever or hypothermia, leucopenia or leucocytosis, tachycardia and tachypnoea; and c) acute organ dysfunction. Organ dysfunction was defined as shock, hypotension or the need for vasopressor support despite adequate fluid resuscitation, relative hypoxemia (ratio of partial pressure of oxygen in arterial blood in mmHg to the percentage of oxygen in the inspired air expressed as a decimal [PaO2/FiO2 ratio] <250), oliguria despite adequate fluid resuscitation, marked reduction in blood platelet counts, and/or elevated lactic acid concentrations.

Exclusion criteria encompassed patients at high risk of bleeding (see sections 4.3 and 4.4), patients who were not expected to survive for 28 days due to a pre-existing, non-sepsis related medical condition, HIV positive patients whose most recent CD4 count was 3, patients on chronic dialysis, and patients who had undergone bone marrow, lung, liver, pancreas, or small bowel transplantation, and patients with acute clinical pancreatitis without a proven source of infection.

In the PROWESS trial, treatment was initiated within 48 hours of onset of the first sepsis-induced organ dysfunction. The median duration of organ dysfunction prior to treatment was 18 hours. Patients were given a 96-hour constant rate infusion of Xigris at 24?g/kg/hr (n = 850) or placebo (n = 840). Xigris was added to best standard care. Best standard care includes adequate antibiotics, source control and supportive treatment (fluids, inotropes, vasopressors and support of failing organs, as required).

Patients treated with Xigris experienced improved 28-day survival compared to those treated with placebo. At 28 days, the overall mortality rates were 24.7% for the Xigris-treated group and 30.8% for the placebo-treated group (P = 0.005).

Significant absolute death reduction was limited to the subgroup of patients with greater disease severity, i.e., baseline APACHE II score

A consistent treatment effect on mortality with Xigris administration was observed across patient subgroups defined by age, gender, and infection type.

PROWESS Follow-Up Study

Survival status was assessed in a follow-up study of PROWESS survivors. In-hospital and 3-month survival status was reported for 98% and 94% of the 1,690 PROWESS subjects, respectively. In the overall population, the in-hospital mortality was significantly lower in patients on Xigris than in patients on placebo (29.4% versus 34.6%; P = 0.023). Survival through 3 months was also better in the Xigris group compared to placebo (log rank P = 0.048). These data confirmed that the benefit of Xigris is limited to the more severely affected sepsis patients, such as patients with multiple organ failure and shock.

Further Clinical Experience

In a Phase 3b, international, single-arm, open-label clinical trial (ENHANCE), 2,378 adult patients with severe sepsis received drotrecogin alfa (activated). The entry criteria were similar to those employed in PROWESS. Patients received drotrecogin alfa (activated) within 48 hours of onset of the first sepsis-induced organ dysfunction. The median duration of organ dysfunction prior to treatment was 25 hours. At 28 days, the mortality rate in the Phase 3b study was 25.3%. The mortality rate was lower for patients treated within 24 hours of organ dysfunction compared to those treated after 24 hours, even after adjustment for differences in disease severity.

A total of 2,640 adult patients with severe sepsis who were at low risk of death (e.g., patients with APACHE II <25 or with only one sepsis-induced organ failure) were enrolled in a randomised, double-blind, placebo-controlled trial (ADDRESS). The trial was stopped for futility after an interim analysis.

No benefit of drotrecogin alfa (activated) was observed in the subgroup of 872 patients at low risk of death with multiple organ dysfunction, so ADDRESS did not confirm the efficacy results of the PROWESS study.

In the multiple organ dysfunction subgroup of ADDRESS the 28-day placebo mortality was 21.9%, similar to the single organ dysfunction subgroup of PROWESS (21.2%), confirming the lack of efficacy in patients with severe sepsis who are at low risk of death.

Paediatric Patients

Xigris is contraindicated in children below the age of 18 years (see also sections 4.2 and 4.3).

Data from a placebo-controlled clinical trial (RESOLVE) did not establish efficacy of Xigris in paediatric patients suffering from severe sepsis, acute infection, systemic inflammation and respiratory and cardiovascular organ dysfunction. This trial was stopped for futility after 477 patients had received the study drug (out of 600 patients intended). A planned interim analysis (with 400 patients enrolled) showed a low likelihood of demonstrating a significant difference in the primary endpoint of “Composite Time to Complete Organ Failure Resolution” (CTCOFR score of 9.8 versus 9.7 mean days over 14 days). There was also no difference in 28-day mortality (17.1% versus 17.3% in the Xigris and placebo groups, respectively).

Investigators attributed 2 deaths in the Xigris group and 5 deaths in the placebo group to bleeding events. There was a higher rate of central nervous system (CNS) bleeding in the drotrecogin alfa (activated) versus the placebo group. Over the infusion period (study days 0-6) the number of patients experiencing CNS bleeding was 5 versus 1 (2.1% versus 0.4%) for the overall population (drotrecogin alfa (activated) versus placebo), with 4 of the 5 events in the drotrecogin alfa (activated) group occurring in patients

In placebo controlled clinical trials, the treatment effect was most evident at sites enrolling larger numbers of patients.

5.2 Pharmacokinetic Properties

Drotrecogin alfa (activated) and endogenous human Activated Protein C are inactivated in plasma by endogenous protease inhibitors, but the mechanism by which they are cleared from plasma is unknown. Plasma concentrations of endogenous Activated Protein C in healthy subjects and patients with severe sepsis are usually below detection limits (<5ng/ml) and do not significantly influence the pharmacokinetic properties of drotrecogin alfa (activated).

In healthy subjects, greater than 90% of the steady-state condition is attained within 2 hours following the start of a constant-rate intravenous infusion of Xigris. Following the completion of an infusion, the decline in plasma drotrecogin alfa (activated) concentrations is biphasic and is comprised of a rapid initial phase (t?? = 13 minutes) and a slower second phase (t?? = 1.6 hours). The short half-life of 13 minutes accounts for approximately 80% of the area under the plasma concentration curve and governs the initial rapid accrual of plasma drotrecogin alfa (activated) concentrations towards the steady-state. Plasma drotrecogin alfa (activated) steady-state concentrations are proportional to the infusion rate over a range of infusion rates from 12?g/kg/hr to 48?g/kg/hr. The mean steady-state plasma concentration of drotrecogin alfa (activated) in healthy subjects receiving 24?g/kg/hr is 72ng/ml.

In patients with severe sepsis, infusion of drotrecogin alfa (activated) from 12?g/kg/hr to 30?g/kg/hr rapidly produced steady-state plasma concentrations that were proportional to infusion rates. In the Phase 3 trial, the pharmacokinetics of drotrecogin alfa (activated) were evaluated in 342 patients with severe sepsis administered a 96-hour continuous infusion at 24µg/kg/hr. The pharmacokinetics of drotrecogin alfa (activated) were characterised by attainment of steady-state plasma concentration within 2 hours following the start of the infusion. In the majority of patients, measurements of Activated Protein C beyond 2 hours after termination of the infusion were below the quantifiable limit, suggesting rapid elimination of drotrecogin alfa (activated) from the systemic circulation. The plasma clearance of drotrecogin alfa (activated) is approximately 41.8 l/hr in sepsis patients as compared with 28.1 l/hr in healthy subjects.

In patients with severe sepsis, the plasma clearance of drotrecogin alfa (activated) was significantly decreased by renal impairment and hepatic dysfunction, but the magnitude of the differences in clearance (<30%) does not warrant any dosage adjustment.

5.3 Preclinical Safety Data

Changes observed in monkeys at, or in small excess of, the maximum human exposure during repeated dose studies were all related to the pharmacological effect of Xigris and include, beside the expected prolongation of APTT, decreases in haemoglobin, erythrocytes and haematocrit and increases in reticulocyte count and PT.

Drotrecogin alfa (activated) was not mutagenic in an in vivo micronucleus study in mice or in an in vitro chromosomal aberration study in human peripheral blood lymphocytes with or without rat liver metabolic activation.

Carcinogenicity studies and animal reproduction studies have not been conducted with Xigris. However, with respect to the latter, the potential risk for humans being unknown, Xigris should not be used during pregnancy unless clearly necessary (see section 4.6).

6. Pharmaceutical Particulars 6.1 List Of Excipients

Sucrose

Sodium chloride

Sodium citrate

Citric acid

Hydrochloric acid

Sodium hydroxide

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf Life

3 years.

After reconstitution, immediate use is recommended. However, the reconstituted solution in the vial may be held for up to 3 hours at room temperature (15?C- 30?C). After preparation, the intravenous infusion solution can be used at room temperature (15?C- 30?C) for a period up to 14 hours.

6.4 Special Precautions For Storage

Store in a refrigerator (2°C-8°C). Keep the vial in the outer carton in order to protect it from light.

6.5 Nature And Contents Of Container

Powder in Type I glass vial. Pack of 1 vial.

6.6 Special Precautions For Disposal And Other Handling

1.

Use appropriate aseptic technique during the preparation of Xigris for intravenous administration.

2.

Calculate the dose and the number of Xigris vials needed.

 

 

Xigris 5mg: Each Xigris vial contains 5mg of drotrecogin alfa (activated).

 

 

Xigris 20mg: Each Xigris vial contains 20mg of drotrecogin alfa (activated).

 

 

The vial contains an excess of drotrecogin alfa (activated) to facilitate delivery of the label amount.

3.

Xigris 5mg: Prior to administration, 5mg vials of Xigris must be reconstituted with 2.5ml of sterile water for injection, resulting in a solution with a concentration of approximately 2mg/ml drotrecogin alfa (activated).

 

 

Xigris 20mg: Prior to administration, 20mg vials of Xigris must be reconstituted with 10ml of sterile water for injection, resulting in a solution with a concentration of approximately 2mg/ml drotrecogin alfa (activated).

 

 

Slowly add the sterile water for injection to the vial and avoid inverting or shaking the vial. Gently swirl each vial until the powder is completely dissolved.

4.

The solution of reconstituted Xigris must be further diluted with sterile 0.9% sodium chloride injection to a final concentration of between 100?g/ml and 200?g/ml. Slowly withdraw the appropriate amount of reconstituted drotrecogin alfa (activated) solution from the vial. Add the reconstituted drotrecogin alfa (activated) into a prepared infusion bag of sterile 0.9% sodium chloride injection. When adding the reconstituted drotrecogin alfa (activated) into the infusion bag, direct the stream to the side of the bag to minimise the agitation of the solution. Gently invert the infusion bag to obtain a homogeneous solution. Do not transport the infusion bag between locations using mechanical delivery systems.

5.

After reconstitution, immediate use is recommended. However, the reconstituted solution in the vial may be held for up to 3 hours at room temperature (15 to 30?C).

 

 

After preparation, the intravenous infusion solution can be used at room temperature (15 to 30?C) for a period up to 14 hours.

6.

Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration.

7.

It is recommended that Xigris be infused with an infusion pump to accurately control the infusion rate. The solution of reconstituted Xigris should be diluted into an infusion bag containing sterile 0.9% sodium chloride injection to a final concentration of between 100µg/ml and 200µg/ml.

8.

When administering drotrecogin alfa (activated) at low flow rates (less than approximately 5ml/hr), the infusion set must be primed for approximately 15 minutes at a flow rate of approximately 5ml/hr.

9.

Xigris should be administered via a dedicated intravenous line or a dedicated lumen of a multi-lumen central venous catheter. The ONLY other solutions that can be administered through the same line are 0.9% sodium chloride injection, lactated Ringer's injection, dextrose, or dextrose and saline mixtures.

10.

Avoid exposing drotrecogin alfa (activated) solutions to heat and/or direct sunlight. No incompatibilities have been observed between drotrecogin alfa (activated) and glass infusion bottles or infusion bags made of polyvinylchloride, polyethylene, polypropylene, or polyolefin. The use of other types of infusion sets could have a negative impact on the amount and potency of drotrecogin alfa (activated) administered.

11.

Care should be taken to administer Xigris at the appropriate rate, calculated based on kg of bodyweight and infused for the correct duration. It is recommended that the bag be labelled accordingly.

7. Marketing Authorisation Holder

Eli Lilly Nederland BV, Grootslag 1-5, 3991 RA Houten, The Netherlands.

8. Marketing Authorisation Number(S)

5mg vial:

EU/1/02/225/001

20mg vial:

EU/1/02/225/002

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation:

22 August 2002

Date of latest renewal:



Pronunciation: car-bay-ta-PEN-tane/gwye-FEN-e-sin



Pronunciation: la-TAN-oh-prost



Generic Name: denosumab



Generic Name: guaifenesin and hydrocodone (gwye FEN e sin and HYE droe KOE done)



ihemophilic factor (recombinant, plasma/albumin-free)



1. Name Of The Medicinal Product

Xiapex 0.9 mg powder and solvent for solution for injection.

2. Qualitative And Quantitative Composition

Each vial of powder contains 0.9 mg of collagenase clostridium histolyticum*.

*A formulation of two collagenase enzymes co-expressed and harvested from anaerobic fermentation of a phenotypically selected strain of Clostridium histolyticum bacterium.

Excipients:

Sodium injected per joint:

Metacarpophalangeal (MP) joints: 0.9 mg.

Proximal interphalangeal (PIP) joints: 0.7 mg.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder and solvent for solution for injection.

(Powder for injection).

The powder is a white lyophilised powder.

The solvent is a clear colourless solution.

4. Clinical Particulars 4.1 Therapeutic Indications

Xiapex is indicated for the treatment of Dupuytren's contracture in adult patients with a palpable cord.

4.2 Posology And Method Of Administration

Xiapex must be administered by a physician appropriately trained in the correct administration of the product and experienced in the diagnosis and management of Dupuytren's disease.

Posology

The recommended dose of Xiapex is 0.58 mg per injection into a palpable Dupuytren's cord. The volume of reconstituted Xiapex to be administered into the Dupuytren's cord differs depending on the type of joint being treated (see Table 1).

Approximately 24 hours after injection, a finger extension procedure may be performed, as necessary, to facilitate cord disruption. If a satisfactory response has not been achieved, the injection and finger extension procedures may be repeated after approximately 4 weeks. Injections and finger extension procedures may be administered up to 3 times per cord at approximately 4-week intervals. Only one cord must be treated at a time. If the disease has resulted in multiple contractures, treatment of each cord must be undertaken in a sequential order, as determined by the physician. Clinical study experience with Xiapex is currently limited to up to 3 injections per cord and up to 8 injections in total.

Patients should be instructed to return to see their physician the next day for an examination of the injected hand and a finger extension procedure to disrupt the cord.

Special population

Elderly

Due to the lack of quantifiable systemic exposure of Xiapex no dose adjustment is necessary. No overall differences in safety or effectiveness were observed between elderly and younger patients.

Hepatic Impairment

Due to the lack of quantifiable systemic exposure, no dose adjustment is necessary.

Renal Impairment

Due to the lack of quantifiable systemic exposure, no dose adjustment is necessary.

Paediatric population

There is no relevant use of Xiapex in the paediatric population aged 0-18 years for the treatment of Dupuytren's contracture.

Method of administration

Intralesional use.

For single use only

Volume for reconstitution

Xiapex must only be reconstituted with the solvent provided and to the appropriate volume prior to use:

- For metacarpophalangeal (MP) joints use 0.39 ml of solvent.

- For proximal interphalangeal (PIP) joints use 0.31 ml of solvent (see Table 1).

Volume for injection

- For cords affecting MP joints each dose is administered in an injection volume of 0.25 ml.

- For cords affecting PIP joints, each dose is administered in an injection volume of 0.20 ml.

Table 1. Volumes needed for reconstitution and administration

   

Joint to be treated

Solvent required for reconstitution

Injection volume to deliver Xiapex 0.58 mg dose†

MP joints

0.39 ml

0.25 ml

PIP joints

0.31 ml

0.20 ml

†Note that injection volume for delivery of a 0.58 mg dose is less than the total volume of solvent used for reconstitution.

   

Patients should be instructed:

• Not to flex or extend the fingers of the injected hand to reduce extravasation of Xiapex out of the cord until the finger extension procedure is completed.

• Not to attempt to disrupt the injected cord by self manipulation at any time.

• To elevate the injected hand as much as possible until the day after the finger extension procedure.

Detailed instructions for the physician in the preparation of the medicinal product for injection (reconstitution procedure) are provided in section 6.6.

4.3 Contraindications

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

4.4 Special Warnings And Precautions For Use

Allergic reactions

In the double blind portion of the three phase 3 placebo-controlled clinical studies, 17% of Xiapex-treated patients had mild allergic reactions (i.e. pruritus). Although there were no severe allergic reactions observed in the Xiapex studies (e.g., those associated with respiratory impairment, hypotension, or end-organ dysfunction) physicians must be prepared to address any severe local or systemic allergic reactions including the potential for anaphylaxis that may occur following injection. Whilst there is no evidence from the clinical data of an increased risk of serious allergic reactions upon repeated injections, the potential for such reactions following repeated use cannot be excluded.

Tendon rupture or other serious injury to the injected extremity

Xiapex must only be injected into the Dupuytren's cord. Because Xiapex lyses collagen, care must be taken to avoid injecting into tendons, nerves, blood vessels, or other collagen-containing structures of the hand. Injection of Xiapex into collagen containing structures may result in damage to those structures, and possible permanent injury such as tendon rupture or ligament damage. When injecting a cord affecting a PIP joint of the fifth finger, the needle insertion must not be more than 2 to 3 mm in depth and not more than 4 mm distal to the palmar digital crease. Patients should be instructed to promptly contact the physician if there is trouble bending the finger after the swelling goes down (symptoms of tendon rupture).

Patients with Dupuytren's contractures that adhere to the skin may be at higher risk of skin lesions as a result of the pharmacological effect of Xiapex and the finger extension procedure on the skin overlying the targeted cord.

Use in patients with coagulation disorders

Xiapex must be used with caution in patients with coagulation disorders or those taking anticoagulants. In the three double-blind, placebo-controlled phase 3 studies, 73% of Xiapex-treated patients reported an ecchymosis or a contusion and 38% reported a haemorrhage at the injection site. The efficacy and safety of Xiapex in patients receiving anticoagulant medicinal products other than up to 150 mg acetylsalicylic acid per day prior to Xiapex administration is not known. Use of Xiapex in patients who have received anticoagulants (with the exception of up to 150 mg acetylsalicylic acid daily) within 7 days prior to receiving an injection of Xiapex is not recommended.

Immunogenicity

As with any non-human protein medicinal product, patients may develop antibodies to the therapeutic protein. During clinical studies, blood samples from patients with Dupuytren's contracture were tested at multiple time points for antibodies to the protein components of the medicinal product (AUX-I and AUX-II). At 30 days post the first injection, 92% of patients had circulating antibodies detected against AUX-I and 86% of patients against AUX-II. After a third or fourth injection, all subjects developed positive antibodies to both AUX-I and AUX-II. No apparent correlation of antibody development to clinical response or adverse reactions was observed. Since the enzymes in XIAPEX have some sequence homology with human matrix metalloproteinases (MMPs), anti-drug antibodies (ADA) could theoretically interfere with human MMPs. No safety concerns related to the inhibition of endogenous MMPs have been observed, in particular no adverse events indicating the development or exacerbation of autoimmune diseases or the development of a musculoskeletal syndrome (MSS). Whilst there is no clinical evidence from the current safety data of a musculoskeletal syndrome developing following the administration of XIAPEX, the potential for it to occur cannot be excluded. If this syndrome were to develop, it would occur progressively and is characterized by one or more of the following signs and symptoms: arthralgia, myalgia, joint stiffness, stiffness of the shoulders, hand oedema, palmar fibrosis and thickening or nodules forming in the tendons.

Long-term safety

Long-term safety of Xiapex is not fully characterised. The impact of treatment with Xiapex on subsequent surgery, if needed, is not known.

Excipients

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

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Due to the lack of quantifiable systemic exposure, no formal medicinal product interaction studies with Xiapex have been performed.

Whilst there is no clinical evidence of an interaction between tetracycline and anthracycline/anthraquinolone antibiotics and anthraquinone derivatives and Xiapex, such derivatives have been shown to inhibit matrix metalloproteinase-mediated collagen degradation at pharmacologically relevant concentrations in vitro. Therefore, use of Xiapex in patients who have received tetracycline antibiotics (e.g. doxycycline) within 14 days prior to receiving an injection of Xiapex is not recommended.

4.6 Pregnancy And Lactation

Pregnancy and fertility

For Xiapex no clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to fertility, pregnancy, or embryonal/ foetal development, (see section 5.3). Parturition or postnatal development studies in animals were not conducted since human pharmacokinetic studies show that Xiapex levels are not quantifiable in the systemic circulation following injection into a Dupuytren's cord (see section 5.1). Patients develop ADAs after repeated administration, the cross-reactivity of which versus endogenous MMPs involved in pregnancy and labour cannot be excluded. The potential risk for humans on parturition and postnatal development is unknown. Therefore the use of Xiapex is not recommended in pregnancy and treatment should be postponed until after pregnancy.

Breast-feeding

No effect on the breastfed newborn/infant is anticipated since the systemic exposure of the breast-feeding woman to Xiapex is negligible. Xiapex can be used during breast-feeding.

4.7 Effects On Ability To Drive And Use Machines

Xiapex may have a major influence on the ability to drive and use machines due to the swelling and pain which may impair the use of the treated hand. Other minor influences on the ability to drive and use machines include dizziness, paresthesia, hypoesthesia, and headache that have also been reported following injection of Xiapex. Patients must be instructed to avoid potentially hazardous tasks such as driving or using machines until it is safe to do so or as advised by the physician.

4.8 Undesirable Effects

Xiapex 0.58 mg was studied in patients with Dupuytren's contracture in three randomised, double-blind, placebo-controlled studies. The double-blind study population comprised 409 patients of whom 272 received Xiapex 0.58 mg and 137 received placebo. The mean age was 63 years (range 33 to 89 years) and 80% of patients were male.

The most frequently reported adverse reactions during the Xiapex clinical studies were local injection site reactions such as oedema peripheral (local to the injection site), contusion (including ecchymosis), injection site haemorrhage and injection site pain. Injection site reactions were very common, occurring in the vast majority of patients, were mostly mild to moderate in severity and generally subsided within 1-2 weeks post injection. Serious adverse reactions of tendon rupture (3 cases), tendonitis (1 case), other ligament injury (1 case) and complex regional pain syndrome (1 case) related to the medicinal product were reported.

Table 2 presents adverse reactions listed by system organ class and frequency categories, using the following convention: very common (

Table 2: Tabulated list of adverse reactions.

System organ class

Very common

Common

Uncommon

Infections and infestations

   

injection site cellulitis

Blood and lymphatic system disorders

lymphadenopathy

lymph node pain

thrombocytopenia

Immune system disorders

   

hypersensitivity

Psychiatric disorders

   

disorientation

agitation

insomnia

irritability

restlessness

Nervous system disorders

 

paresthesia

hypoesthesia

burning sensation

dizziness

headache

complex regional pain syndrome

monoplegia

syncope vasovagal

tremor

Eye disorders

   

eyelid oedema

Vascular disorders

   

haematoma

hypotension

Respiratory, thoracic and mediastinal disorders

   

dyspnoea

hyperventilation

Gastrointestinal disorders

 

nausea

diarrhoea

vomiting

abdominal pain upper

Skin and subcutaneous tissue disorders

pruritus

ecchymosis

blood blister

blister

rash

erythema

hyperhidrosis

rash erythematous

rash macular

eczema

swelling face

pain of skin

skin exfoliation

skin lesion

skin disorder

scab

skin discoloration

skin tightness

Musculoskeletal and connective tissue disorders

pain in extremity

arthralgia

joint swelling

myalgia

axillary mass

chest wall pain

groin pain

joint crepitation

joint stiffness

limb discomfort

muscle spasms

muscular weakness

musculoskeletal discomfort

musculoskeletal stiffness

neck pain

shoulder pain

Reproductive system and breast disorders

   

breast tenderness

hypertrophy breast

General disorders and administration site conditions

oedema peripheral*

injection site haemorrhage

injection site pain

injection site swelling

tenderness

axillary pain

inflammation

injection site inflammation

swelling

injection site erythema

injection site pruritus

injection site warmth

injection site vesicles

local swelling

pyrexia

pain

discomfort

fatigue

feeling hot

influenza like illness

injection site anaesthesia

injection site desquamation

injection site discoloration

injection site irritation

injection site nodule

injection site reaction

malaise

Investigations

   

lymph node palpable

alanine aminotransferase increased

aspartate aminotransferase increased

body temperature increased

Injury, poisoning and procedural complications

contusion

skin laceration

tendon rupture

ligament injury

limb injury

open wound

wound dehiscence

* “oedema peripheral” includes “injection site oedema” and “oedema”

4.9 Overdose

Administration of Xiapex at greater than recommended doses is expected to be associated with increased local reactions at the site of injection. Routine supportive care and symptomatic treatment must be provided in the case of overdose.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other Drugs For Disorders of the Musculo-Skeletal System – Enzymes, ATC code: M09AB02

Xiapex is a lyophilized product for parenteral administration containing collagenase clostridium histolyticum which is comprised of two collagenases in a defined mass ratio. These collagenases, referred to as AUX-I and AUX-II, are representative of the two major collagenase classes (Class I and Class II) produced by Clostridium histolyticum. AUX-I and AUX-II are single polypeptide chains consisting of approximately 1000 amino acids of known sequence with a molecular weight of 114 kDa and 113 kDa respectively as determined by mass spectrometry. The two polypeptides are purified by chromatographic steps customary for the separation and isolation of biotherapeutic proteins to yield a consistent, well characterized and controlled mixture of two collagenase enzymes.

Because the collagen lysis process following Xiapex administration is localized and does not require or result in quantifiable systemic levels of AUX-I and AUX-II, the primary pharmacodynamic activity of Xiapex cannot be evaluated in subjects and therefore, such studies have not been undertaken.

Mechanism of action

Collagenases are proteinases that hydrolyze collagen under physiological conditions. Injection of Xiapex into a Dupuytren's cord, which is comprised mostly of interstitial collagen types I and III, results in enzymatic disruption of the cord. Xiapex is comprised of a mixture of Class I (AUX-I) and Class II (AUX-II) clostridial collagenases in a defined mass ratio. The two classes of collagenases have similar but complementary substrate specificity. Both collagenases effectively cleave interstitial collagen but at different sites on the molecule; additionally, they prefer different conformations (triple helical versus denatured or cleaved). These differences account for the ability of the two classes of enzymes to digest collagen in a complementary manner. Class I collagenases (?, ?, ?, and ?) are the products of the colG gene, they initiate collagen hydrolysis near the amino and carboxy termini of triple helical domains, and generate large proteolytic fragments. In contrast, the Class II collagenases (?, ?, and ?,) are products of colH gene, their initial cleavage sites are located within the interior of the collagen molecule, and generate smaller collagen fragments. Both classes of collagenases readily hydrolyze gelatin (denatured collagen) and small collagen peptides, whereas Class II has higher affinity for small collagen fragments. Class I cleaves insoluble triple helical collagen with higher affinity than Class II collagenase. Together, these collagenases work to provide broad hydrolytic activity towards collagen.

Clinical results

The efficacy of Xiapex 0.58 mg was evaluated in two pivotal randomized, double-blind, placebo-controlled studies, CORD I (AUX-CC-857) and CORD II (AUX-CC-859), in adult patients with Dupuytren's contracture. At study entry, patients in the clinical studies had: (1) a finger flexion contracture with a palpable cord of at least one finger (other than the thumb) of 20° to 100° in a MP joint or 20° to 80° in PIP joint and (2) a positive “table top test” defined as the inability to simultaneously place the affected finger(s) and palm flat against a table top. The cord affecting a selected primary joint received up to 3 injections of 0.58 mg of Xiapex or placebo. A finger extension procedure was performed if needed, approximately 24 hours after injection to facilitate disruption of the cord. Each injection was separated by approximately 4 weeks.

The primary endpoint of each study was to evaluate the proportion of patients who achieved a reduction in contracture of the selected primary joint (MP or PIP) to 5° or less of normal, approximately 4 weeks after the last injection of that joint. Other endpoints included

Xiapex demonstrated a clinically significant benefit compared to placebo in the proportion of patients achieving the primary endpoint of a reduction in the contracture of all joints treated to 5° or less, approximately 4 weeks after the last injection (MP plus PIP, MP only, PIP only). For patients who achieved a contracture of the selected joint to 5° or less, the mean number of injections required to achieve this was 1.5 in the 2 studies. Xiapex also demonstrated a clinically significant benefit compared to placebo in decreasing the degree of contracture and increasing both the range of motion from baseline for all joints treated (MP plus PIP, MP only, PIP only) and the subject global assessment of treatment satisfaction.

Table 3 provides demographic and baseline characteristics for the study population and Tables 4-5 provide the results of the major efficacy endpoints measured in the 2 double-blind placebo controlled studies CORD I (AUX-CC-857) and CORD II (AUX-CC-859).

Table 3.

Demographic and baseline characteristics

Phase 3 Double-Blind, Placebo controlled studies (CORD I, CORD II)

VARIABLE

Xiapex

(N=249)

Placebo

(N=125)

Age (years)

   

Mean

62.7

64.2

Age category (years), n (%)

   

< 45

9 (3.6)

5 (4.0)

45 – 54

33 (13.2)

17 (13.6)

55 – 64

103 (41.4)

44 (35.2)

65 – 74

82 (33.0)

40 (32.0)

22 (8.8)

19 (15.2)

Gender, n (%)

   

Male

210 (84.3)

91 (72.8)

Female

39 (15.7)

34 (27.2)

Family history of Dupuytren's disease, n (%)

   

Yes

107 (43.0)

62 (49.6)

No

142 (57.0)

63 (50.4)

Physician Rating of Severity at Baseline

 

 

Mild

38 (15.4 %)

21 (16.8 %)

Moderate

148 (59.9 %)

71 (56.8 %)

Severe

61 (24.7 %)

33 (26.4 %)

Missing1

2 (0.8 %)

-

Note: Includes all patients who received at least 1 injection of double-blind study medicinal product (Xiapex 0.58 mg or placebo).

1 Not used to calculate physician rating of severity at baseline percentage – actual denominator of N=247 used.

   

Table 4.

Percentage of patients who achieved reduction in contracture to 5° or less

(Last injection)

TREATED PRIMARY JOINTS

CORD I

CORD II

   

Xiapex

Placebo

Xiapex

Placebo

 

All Joints

p-value

N=203c

N=103c

N=45

N=21

64.0 %

<0.001

6.8 %

-

44.4 %

<0.001

4.8 %

-

 

MP Jointsa

p-value

N=133

N=69

N=20

N=11

76.7 %

<0.001

7.2 %

-

65.0 %

0.003

9.1 %

-

 

PIP Jointsb

p-value

N=70

N=34

N=25

N=10

40.0 %

<0.001

5.9 %

-

28.0 %

0.069

0.0 %

-

 

a Metacarpophalangeal joint; b Proximal interphalangeal joint; c 2 primary joints were excluded from the efficacy analysis (1 joint from the placebo group was not evaluated and 1 joint from the Xiapex treated group had a baseline contracture of 0 degrees before treatment).

       

Table 5.

Mean increase in range of motion from baseline

(Last injection)

TREATED PRIMARY JOINTS

CORD I

CORD II

   

Xiapex

Placebo

Xiapex

Placebo

 

All Joints

N=203 c

N=103 c

N=45

N=21

Mean Baseline (SD)

Mean Final (SD)

Mean increase (SD)

43.9 (20.1)

80.7 (19.0)

36.7 (21.0)

45.3 (18.7)

49.5 (22.1)

4.0 (14.8)

40.3 (15.2)

75.8 (17.7)

35.4 (17.8)

44.0 (16.5)

51.7 (19.6)

7.6 (14.9)

MP Jointsa

N=133

N=69

N=20

N=11

Mean Baseline (SD)

Mean Final (SD)

Mean increase (SD)

42.6 (20.0)

83.7 (15.7)

40.6 (20.0)

45.7 (19.2)

49.7 (21.1)

3.7 (12.6)

39.5 (11.8)

79.5 (11.1)

40.0 (13.5)

41.4 (20.8)

50.0 (21.5)

8.6 (14.7)

PIP Jointsb

N=70

N=34

N=25

N=10

Mean Baseline (SD)

Mean Final (SD)

Mean increase (SD)

46.4 (20.4)

74.9 (23.1)

29.0 (20.9)

44.4 (17.9)

49.1 (24.4)

4.7 (18.5)

41.0 (17.7)

72.8 (21.3)

31.8 (20.1)

47.0 (10.3)

53.5 (18.3)

6.5 (15.8)

a Metacarpophalangeal joint; b Proximal interphalangeal joint; c 2 primary joints were excluded from the efficacy analysis (1 joint from the placebo group was not evaluated and 1 joint from the Xiapex treated group had a baseline contracture of 0 degrees before treatment).

All p-values < 0.001 for all comparisons between Xiapex and placebo, except for PIP joints in Study CORD II which was not eligible for statistical testing due to a hierarchical testing procedure.

       

Physician-rated change in contracture severity was reported as very much improved or much improved in 86% and 80% of the subjects in the Xiapex group compared to 3% and 5% of subjects in the placebo group for the CORD I and CORD II studies, respectively (p<0.001). Based on the Patient Global Assessment of Treatment Satisfaction, more than 85% of subjects in the CORD I and CORD II studies reported either being quite satisfied or very satisfied with their treatment with Xiapex versus



Generic Name: rivaroxaban (Oral route)

riv-a-ROX-a-ban

Oral route(Tablet)

Discontinuing rivaroxaban places patients at an increased risk of thrombotic events such as stroke. If anticoagulation with rivaroxaban must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant. Epidural or spinal hematomas, which may result in long-term or permanent paralysis, have occurred in patients treated with rivaroxaban who are receiving neuraxial anesthesia or undergoing spinal puncture. Factors that can increase the risk of developing these hematomas include: use of indwelling epidural catheters, concomitant use of drugs affecting hemostasis such as NSAIDs, platelet inhibitors, or other anticoagulants, or history of traumatic or repeated epidural or spinal puncture, spinal deformity, or spinal surgery. Monitor patients frequently for neurological impairment. If neurological compromise is noted, urgent treatment is necessary. Consider risks/benefits before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis .

Commonly used brand name(s)

In the U.S.

Xarelto

Available Dosage Forms:

Tablet

Therapeutic Class: Anticoagulant

Pharmacologic Class: Factor Xa Inhibitor

Uses For Xarelto

Rivaroxaban is used to prevent deep venous thrombosis, a condition in which harmful blood clots form in the blood vessels of the legs. These blood clots can travel to the lungs and can become lodged in the blood vessels of the lungs, causing a condition called pulmonary embolism. This medicine is used for several days after hip or knee replacement surgery while you are unable to walk. It is during this time that blood clots are most likely to form.

Rivaroxaban is also used to prevent stroke and blood clots in patients with certain heart rhythm problem (e.g., nonvalvular atrial fibrillation).

Rivaroxaban is a factor Xa inhibitor, an anticoagulant. It works by decreasing the clotting ability of the blood and helps preventing harmful clots from forming in the blood vessels.

This medicine is available only with your doctor's prescription.

Before Using Xarelto

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of rivaroxaban in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of rivaroxaban in the elderly. However, elderly patients are more likely to have bleeding and blood clotting problems and age-related kidney disease, which may require caution and an adjustment in the dose for patients receiving rivaroxaban.

Pregnancy Pregnancy Category Explanation All Trimesters C Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women. Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

Abciximab Acenocoumarol Alteplase, Recombinant Anistreplase Argatroban Aspirin Bivalirudin Bromfenac Carbamazepine Celecoxib Cilostazol Clopidogrel Conivaptan Dabigatran Etexilate Dalteparin Danaparoid Desirudin Dexamethasone Diclofenac Diflunisal Dipyridamole Drotrecogin Alfa Enoxaparin Eptifibatide Etodolac Flurbiprofen Fondaparinux Heparin Ibuprofen Ibuprofen Lysine Indomethacin Itraconazole Ketoconazole Ketoprofen Ketorolac Lepirudin Magnesium Salicylate Mefenamic Acid Meloxicam Nabumetone Naproxen Nelfinavir Nepafenac Oxaprozin Phenindione Phenobarbital Phenprocoumon Phenytoin Piroxicam Posaconazole Prasugrel Protein C, Human Reteplase, Recombinant Rifampin Rifapentine Ritonavir Salsalate Saquinavir St John's Wort Streptokinase Sulfinpyrazone Sulindac Tenecteplase Ticagrelor Ticlopidine Tinzaparin Tirofiban Tolmetin Urokinase Voriconazole Warfarin Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

Bleeding problems or Blood vessel problems or Catheter insertion in the spine or Stomach or intestinal ulcer or bleeding or Stroke, recent or history of or Surgery (e.g., eye, brain, or spine), recent or history of—Use with caution. The risk of bleeding may be increased. Kidney disease or Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body. Major bleeding, active—Should not be used in patients with this condition. Proper Use of Xarelto

Take this medicine only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. To do so may increase the chance of side effects.

You may take this medicine with or without food.

This medicine should come with a Medication Guide. Read and follow these instructions carefully. Ask your doctor if you have any questions.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

For oral dosage form (tablets): For prevention of deep venous thrombosis (hip replacement surgery): Adults—10 milligrams (mg) once a day for 35 days. The starting dose should be taken at least 6 to 10 hours after surgery. Children—Use and dose must be determined by your doctor. For prevention of deep venous thrombosis (knee replacement surgery): Adults—10 milligrams (mg) once a day for 12 days. The starting dose should be taken at least 6 to 10 hours after surgery. Children—Use and dose must be determined by your doctor. For prevention of stroke and blood clots in patients with nonvalvular atrial fibrillation: Adults—15 or 20 milligrams (mg) once a day, taken with the evening meal. Children—Use and dose must be determined by your doctor. Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using Xarelto

It is very important that your doctor check your progress at regular visits to make sure this medicine is working properly. Blood tests will be needed to check for unwanted effects. Be sure to keep all appointments.

You may bleed or bruise more easily while you are using this medicine. Stay away from rough sports or other situations where you could be bruised, cut, or injured. Be careful when using sharp objects, including razors and fingernail clippers. Avoid nose picking and forceful nose blowing.

Make sure any doctor or dentist who treats you knows that you are using this medicine. You may need to stop using this medicine several days before having surgery or medical tests.

This medicine may cause bleeding problems. This risk is higher if you have a catheter in your back for pain medicine or anesthesia (sometimes called an "epidural"), or if you have kidney problems. The risk of bleeding increases if your kidney problems get worse. Check with your doctor right away if you have any unusual bleeding or bruising; black, tarry stools; bleeding gums; blood in the urine or stools; tingling, numbness, or weakness of the lower legs; or pinpoint red spots on your skin.

Be careful when using a regular toothbrush, dental floss, or toothpick. Your medical doctor, dentist, or nurse may recommend other ways to clean your teeth and gums. Check with your medical doctor before having any dental work done.

Do not suddenly stop taking this medicine without first checking with your doctor. Doing so, may increase risk of having a stroke.

Make sure your doctor knows if you are pregnant or planning to become pregnant during treatment with this medicine.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal (e.g., St. John's wort) or vitamin supplements.

Xarelto Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common Back pain bleeding gums bloody stools bowel or bladder dysfunction burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings coughing up blood difficulty with breathing or swallowing dizziness headache increased menstrual flow or vaginal bleeding leg weakness nosebleeds numbness paralysis prolonged bleeding from cuts red or black, tarry stools red or dark brown urine shortness of breath vomiting of blood or material that looks like coffee grounds Less common Fainting pain in the arms or legs wound secretion Rare Burning while urinating difficult or painful urination Incidence not known Abdominal or stomach pain or swelling blistering, peeling, or loosening of the skin blurred vision chills clay-colored stools cough or hoarseness dark urine diarrhea fast or irregular heartbeat fever with or without chills general feeling of tiredness or weakness hives itching joint or muscle pain loss of appetite lower back or side pain nausea or vomiting puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue red skin lesions, often with a purple center red, irritated eyes severe headache skin rash sore throat sores, ulcers, or white spots in the mouth or on the lips tightness in the chest unpleasant breath odor unusual bleeding or bruising unusual tiredness or weakness wheezing yellow eyes or skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Less common Blisters muscle spasm

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: Xarelto side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More Xarelto resources Xarelto Side Effects (in more detail) Xarelto Use in Pregnancy & Breastfeeding Xarelto Drug Interactions Xarelto Support Group 0 Reviews for Xarelto - Add your own review/rating Xarelto Prescribing Information (FDA) Xarelto MedFacts Consumer Leaflet (Wolters Kluwer) Xarelto Consumer Overview Rivaroxaban Professional Patient Advice (Wolters Kluwer) Compare Xarelto with other medications Atrial Fibrillation Deep Vein Thrombosis Prophylaxis after Hip Replacement Surgery Deep Vein Thrombosis Prophylaxis after Knee Replacement Surgery Prevention of Thromboembolism in Atrial Fibrillation



Address Xanodyne Pharmaceuticals, Inc,



Pronunciation: lev-al-BYOO-ter-ol



Generic Name: alprazolam (Oral route)

al-PRA-zoe-lam

Commonly used brand name(s)

In the U.S.

Gabazolamine-0.5 Niravam Xanax Xanax XR

In Canada

Alti-Alprazolam

Available Dosage Forms:

Tablet Tablet, Disintegrating Solution Tablet, Extended Release

Therapeutic Class: Antianxiety

Pharmacologic Class: Benzodiazepine, Short or Intermediate Acting

Uses For Xanax XR

Alprazolam is used to relieve symptoms of anxiety, including anxiety caused by depression. It is also used to treat panic disorder in some patients.

Alprazolam is a benzodiazepine. Benzodiazepines belong to the group of medicines called central nervous system (CNS) depressants, which are medicines that slow down the nervous system.

This medicine is available only with your doctor's prescription.

Before Using Xanax XR

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of alprazolam in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of alprazolam in the elderly. However, severe drowsiness, dizziness, confusion, clumsiness, or unsteadiness are more likely to occur in the elderly, who are usually more sensitive than younger adults to the effects of alprazolam. Elderly patients may require a lower dose to help reduce unwanted effects.

Pregnancy Pregnancy Category Explanation All Trimesters D Studies in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy in a life threatening situation or a serious disease, may outweigh the potential risk. Breast Feeding

Studies in women breastfeeding have demonstrated harmful infant effects. An alternative to this medication should be prescribed or you should stop breastfeeding while using this medicine.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

Delavirdine Indinavir Itraconazole Ketoconazole

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

Alfentanil Amobarbital Anileridine Aprobarbital Boceprevir Butabarbital Butalbital Carisoprodol Chloral Hydrate Chlorzoxazone Codeine Dantrolene Digoxin Ethchlorvynol Fentanyl Fluconazole Fospropofol Hydrocodone Hydromorphone Levorphanol Meperidine Mephenesin Mephobarbital Meprobamate Metaxalone Methocarbamol Methohexital Morphine Morphine Sulfate Liposome Oxycodone Oxymorphone Pentobarbital Phenobarbital Primidone Propoxyphene Remifentanil Secobarbital Sodium Oxybate Sufentanil Tapentadol Thiopental Voriconazole Zolpidem

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

Amprenavir Aprepitant Carbamazepine Cimetidine Clarithromycin Desipramine Desogestrel Dienogest Drospirenone Erythromycin Estradiol Cypionate Estradiol Valerate Ethinyl Estradiol Ethynodiol Diacetate Etonogestrel Fluoxetine Fosaprepitant Imipramine Kava Levonorgestrel Medroxyprogesterone Acetate Mestranol Nefazodone Norelgestromin Norethindrone Norgestimate Norgestrel Rifapentine Ritonavir Roxithromycin Sertraline St John's Wort Telaprevir Theophylline Troleandomycin Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

Depression or Epilepsy or history of seizures or Lung disease—Use with caution. May make these conditions worse. Glaucoma, acute narrow angle—Should not be used in patients with this condition. Kidney disease or Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body. Proper Use of alprazolam

This section provides information on the proper use of a number of products that contain alprazolam. It may not be specific to Xanax XR. Please read with care.

Take this medicine only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.

Swallow the extended-release tablet whole with a full glass of water. Do not break, crush, or chew it.

If you are using the orally disintegrating tablet, make sure your hands are dry before you handle the tablet. Do not remove the tablets from the bottle until you are ready to take it. Place the tablet immediately on the top of your tongue. It should melt quickly and be swallowed with saliva.

If you are using the oral solution, measure the oral liquid with a marked measuring spoon, oral syringe, or medicine cup.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

For anxiety: For oral dosage forms (solution, tablets, or orally disintegrating tablets): Adults—At first, 0.25 to 0.5 milligram (mg) three times a day. Your doctor may increase your dose if needed. However, the dose is usually not more than 4 mg a day. Older adults—At first, 0.25 milligram (mg) two or three times a day. Your doctor may increase your dose if needed. Children—Use and dose must be determined by your doctor. For panic disorder: For oral dosage form (extended-release tablets): Adults—At first, 0.5 to 1 milligram (mg) taken in the morning once a day. Your doctor may increase your dose if needed. However, the dose is usually not more than 10 mg a day. Older adults—At first, 0.5 milligram (mg) taken in the morning once a day. Your doctor may increase your dose if needed. Children—Use and dose must be determined by your doctor. For oral dosage forms (solution, tablets, or orally disintegrating tablets): Adults—At first, 0.5 milligram (mg) three times a day. Your doctor may increase your dose if needed. However, the dose is usually not more than 10 mg a day. Older adults—At first, 0.25 milligram (mg) two or three times a day. Your doctor may increase your dose if needed. Children—Use and dose must be determined by your doctor. Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

It is very important to protect the orally disintegrating tablets from moisture. Remove and throw away any cotton packaging from the medicine bottle when you first use the medicine.

Precautions While Using Xanax XR

It is very important that your doctor check your progress at regular visits to make sure this medicine is working properly. Blood tests may be needed to check for any unwanted effects.

Using this medicine while you are pregnant can harm your unborn baby. Use an effective form of birth control to keep from getting pregnant. If you think you have become pregnant while using the medicine, tell your doctor right away.

Do not take itraconazole (Sporanox®) or ketoconazole (Nizoral®) while you are using this medicine. Using any of them together with this medicine may increase the chance of serious side effects.

If you develop any unusual and strange thoughts or behavior while you are taking alprazolam, be sure to discuss it with your doctor. Some changes that have occurred in people taking this medicine are like those seen in people who drink alcohol and then act in a manner that is not normal. Other changes may be more unusual and extreme, such as confusion, worsening of depression, hallucinations (seeing, hearing, or feeling things that are not there), suicidal thoughts, and unusual excitement, nervousness, or irritability.

Alprazolam may cause some people, especially older persons, to become drowsy, dizzy or less alert than they are normally. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are dizzy, or are not alert or able to see well.

Do not stop taking this medicine without checking with your doctor first. Your doctor may want you to gradually reduce the amount you are using before stopping it completely. This may help prevent a worsening of your condition and reduce the possibility of withdrawal symptoms, such as convulsions (seizures), stomach or muscle cramps, sweating, tremors, vomiting, or unusual behavior.

This medicine will add to the effects of alcohol and other central nervous system (CNS) depressants. CNS depressants are medicines that slow down the nervous system, which may cause drowsiness or make you less alert. Some examples of CNS depressants are antihistamines or medicine for hay fever, allergies, or colds; sedatives, tranquilizers, or sleeping medicine; prescription pain medicine or narcotics; barbiturates (used for seizures); muscle relaxants; or anesthetics (numbing medicines), including some dental anesthetics. This effect may last for a few days after you stop taking this medicine. Check with your doctor before taking any of the above while you are using this medicine.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Xanax XR Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common Being forgetful changes in patterns and rhythms of speech clumsiness or unsteadiness difficulty with coordination discouragement drowsiness feeling sad or empty irritability lack of appetite lightheadedness loss of interest or pleasure relaxed and calm shakiness and unsteady walk sleepiness or unusual drowsiness slurred speech tiredness trouble concentrating trouble in speaking trouble performing routine tasks trouble sleeping unsteadiness, trembling, or other problems with muscle control or coordination unusual tiredness or weakness Less common Abdominal or stomach pain blurred vision body aches or pain burning, crawling, itching, numbness, prickling, "pins and needles, or tingling feelings changes in behavior chills clay-colored stools confusion about identity, place, and time cough dark urine decrease in frequency of urination decrease in urine volume diarrhea difficult or labored breathing difficulty in moving difficulty in passing urine (dribbling) difficulty with concentration dizziness, faintness, or lightheadedness when getting up from a lying or sitting position suddenly dry mouth ear congestion environment seems unreal fainting fear or nervousness feeling of unreality feeling warm fever general feeling of discomfort or illness headache hyperventilation inability to move eyes inability to sit still increased blinking or spasms of the eyelid irregular heartbeats itching joint pain lack or loss of self-control loss of bladder control loss of coordination loss of memory loss of voice mood or mental changes muscle aching or cramping muscle pain or stiffness muscle weakness nasal congestion nausea need to keep moving painful urination problems with memory rash restlessness runny nose seeing, hearing, or feeling things that are not there seizures sense of detachment from self or body shaking shivering shortness of breath sneezing sore throat sticking out of the tongue sweating swollen joints talkativeness tightness in the chest trouble in breathing, speaking, or swallowing trouble with balance twitching, twisting, or uncontrolled repetitive movements of the tongue, lips, face, arms, or legs uncontrolled twisting movements of the neck, trunk, arms, or legs unpleasant breath odor unusual drowsiness, dullness, tiredness, weakness, or feeling of sluggishness unusual facial expressions unusually deep sleep unusually long duration of sleep vomiting of blood wheezing yellow eyes or skin Rare Actions that are out of control attack, assault, or force chest pain continuing ringing or buzzing or other unexplained noise in ears decreased awareness or responsiveness deep or fast breathing with dizziness ear pain false or unusual sense of well-being fast, irregular, pounding, or racing heartbeat or pulse feeling jittery feeling unusually cold generalized slowing of mental and physical activity hearing loss hoarseness lack of feeling or emotion loss of control of the legs loss of strength or energy nightmares numbness of the feet, hands, and around mouth severe sleepiness shakiness in the legs, arms, hands, or feet sleep talking sleeplessness swelling talking, feeling, and acting with excitement thoughts of killing oneself unable to sleep uncaring unusual weak feeling voice changes Incidence not known General tiredness and weakness light-colored stools stomach pain, continuing upper right abdominal pain

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common Absent, missed, or irregular menstrual periods decreased appetite decreased interest in sexual intercourse decreased sexual performance or desire abnormal ejaculation difficulty having a bowel movement (stool) inability to have or keep an erection increased appetite increased in sexual ability, desire, drive, or performance increased interest in sexual intercourse increased weight loss in sexual ability, desire, drive, or performance stopping of menstrual bleeding watering of mouth weight loss Less common Abdominal bloating and cramping blistering, crusting, irritation, itching, or reddening of the skin change in taste bad unusual or unpleasant (after) taste cracked, dry, or scaly skin cramps double vision feeling of warmth heavy bleeding menstrual changes pain pelvic pain redness of the face, neck, arms, and occasionally, upper chest seeing double sudden sweating unexplained runny nose or sneezing Rare Acid or sour stomach belching bigger, dilated, or enlarged pupils (black part of eye) change in color vision difficulty seeing at night feeling of constant movement of self or surroundings feeling of relaxation heartburn hives or welts increased sensitivity of eyes to sunlight indigestion redness of skin runny nose sensation of spinning stomach discomfort, upset, or pain stuffy nose Incidence not known Blistering, peeling, or loosening of the skin red, irritated eyes red skin lesions, often with a purple center sores, ulcers, or white spots in the mouth or on the lips swelling of the breasts or breast soreness in both females and males unexpected or excess milk flow from breasts

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: Xanax XR side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More Xanax XR resources Xanax XR Side Effects (in more detail) Xanax XR Use in Pregnancy & Breastfeeding Drug Images Xanax XR Drug Interactions Xanax XR Support Group 24 Reviews for Xanax XR - Add your own review/rating Xanax XR Extended-Release Tablets MedFacts Consumer Leaflet (Wolters Kluwer) Xanax XR Prescribing Information (FDA) Xanax XR Consumer Overview Alprazolam Prescribing Information (FDA) Alprazolam Professional Patient Advice (Wolters Kluwer) Alprazolam Monograph (AHFS DI) Alprazolam MedFacts Consumer Leaflet (Wolters Kluwer) Niravam Prescribing Information (FDA) Niravam Orally Disintegrating Tablets MedFacts Consumer Leaflet (Wolters Kluwer) Xanax Prescribing Information (FDA) Xanax Consumer Overview Compare Xanax XR with other medications Anxiety Depression Dysautonomia Panic Disorder Tinnitus





1. Name Of The Medicinal Product

Xenical 120 mg hard capsules

2. Qualitative And Quantitative Composition

Each hard capsule contains 120 mg orlistat.

For a full list of excipients, see 6.1.

3. Pharmaceutical Form

Hard capsule.

The capsule has a turquoise cap and turquoise body bearing the imprint of “ROCHE XENICAL 120”.

4. Clinical Particulars 4.1 Therapeutic Indications

Xenical is indicated in conjunction with a mildly hypocaloric diet for the treatment of obese patients with a body mass index (BMI) greater or equal to 30 kg/m?, or overweight patients (BMI > 28 kg/m?) with associated risk factors.

Treatment with orlistat should be discontinued after 12 weeks if patients have been unable to lose at least 5 % of the body weight as measured at the start of therapy.

4.2 Posology And Method Of Administration

Adults

The recommended dose of orlistat is one 120 mg capsule taken with water immediately before, during or up to one hour after each main meal. If a meal is missed or contains no fat, the dose of orlistat should be omitted.

The patient should be on a nutritionally balanced, mildly hypocaloric diet that contains approximately 30 % of calories from fat. It is recommended that the diet should be rich in fruit and vegetables. The daily intake of fat, carbohydrate and protein should be distributed over three main meals.

Doses of orlistat above 120 mg three times daily have not been shown to provide additional benefit.

The effect of orlistat results in an increase in faecal fat as early as 24 to 48 hours after dosing. Upon discontinuation of therapy, faecal fat content usually returns to pre-treatment levels, within 48 to 72 hours.

Special populations

The effect of orlistat in patients with hepatic and/or renal impairment, children and elderly patients has not been studied.

There is no relevant indication for use of Xenical in children.

4.3 Contraindications

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

- Chronic malabsorption syndrome.

- Cholestasis.

- Breast-feeding.

4.4 Special Warnings And Precautions For Use

In clinical trials, the decrease in bodyweight with orlistat treatment was less in type II diabetic patients than in non-diabetic patients. Antidiabetic medicinal product treatment may have to be closely monitored when taking orlistat.

Co-administration of orlistat with ciclosporin is not recommended (see section 4.5).

Patients should be advised to adhere to the dietary recommendations they are given (see section 4.2).

The possibility of experiencing gastrointestinal adverse reactions (see section 4.8) may increase when orlistat is taken with a diet high in fat (e.g. in a 2000 kcal/day diet,> 30 % of calories from fat equates to> 67 g of fat). The daily intake of fat should be distributed over three main meals. If orlistat is taken with a meal very high in fat, the possibility of gastrointestinal adverse reactions may increase.

Cases of rectal bleeding have been reported with Xenical. Prescribers should investigate further in case of severe and/or persistent symptoms.

The use of an additional contraceptive method is recommended to prevent possible failure of oral contraception that could occur in case of severe diarrhoea (see section 4.5).

Coagulation parameters should be monitored in patients treated with concomitant oral anticoagulants (see section 4.5 and 4.8).

The use of orlistat may be associated with hyperoxaluria and oxalate nephropathy in patients with underlying chronic kidney disease and/or volume depletion (see section 4.8).

Rare occurrence of hypothyroidism and/or reduced control of hypothyroidism may occur. The mechanism, although not proven, may involve a decreased absorption of iodine salts and/or levothyroxine (see section 4.5).

Antiepileptics patient: Orlistat may unbalance anticonvulsivant treatment by decreasing the absorption of antiepileptic drugs, leading to convulsions (see section 4.5).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Ciclosporin

A decrease in ciclosporin plasma levels has been observed in a drug-drug-interaction study and also reported in several cases, when orlistat was administered concomitantly. This can lead to a decrease of immunosuppressive efficacy. Therefore the combination is not recommended (see section 4.4). However, if such concomitant use is unavoidable, more frequent monitoring of ciclosporin blood levels should be performed both after addition of orlistat and upon discontinuation of orlistat in ciclosporin treated patients. Ciclosporin blood levels should be monitored until stabilised.

Acarbose

In the absence of pharmacokinetic interaction studies, the concomitant administration of orlistat with acarbose should be avoided.

Oral anticoagulants

When warfarin or other anticoagulants are given in combination with orlistat, international normalised ratio (INR) values should be monitored (see section 4.4).

Fat soluble vitamins

Treatment with orlistat may potentially impair the absorption of fat-soluble vitamins (A, D, E and K).

The vast majority of patients receiving up to four full years of treatment with orlistat in clinical studies had vitamin A, D, E and K and beta-carotene levels that stayed within normal range. In order to ensure adequate nutrition, patients on a weight control diet should be advised to have a diet rich in fruit and vegetables and use of a multivitamin supplement could be considered. If a multivitamin supplement is recommended, it should be taken at least two hours after the administration of orlistat or at bedtime.

Amiodarone

A slight decrease in plasma levels of amiodarone, when given as a single dose, has been observed in a limited number of healthy volunteers who received orlistat concomitantly. In patients receiving amiodarone treatment, the clinical relevance of this effect remains unknown but may become clinically relevant in some cases. In patients receiving concomitant amiodarone treatment, reinforcement of clinical and ECG monitoring is warranted.

Convulsions have been reported in patients treated concomitantly with orlistat and antiepileptic drugs e.g. valproate, lamotrigine, for which a causal relationship to an interaction cannot be excluded. Therefore, these patients should be monitored for possible changes in the frequency and/or severity of convulsions.

Rare occurrence of hypothyroidism and/or reduced control of hypothyroidism may occur. The mechanism, although not proven, may involve a decreased absorption of iodine salts and/or levothyroxine (see section 4.4).

Lack of interactions

No interactions with amitriptyline, atorvastatin, biguanides, digoxin, fibrates, fluoxetine, losartan, phenytoin, phentermine, pravastatin, nifedipine Gastrointestinal Therapeutic System (GITS), nifedipine slow release, sibutramine or alcohol have been observed. The absence of these interactions has been demonstrated in specific drug-drug-interaction studies.

The absence of an interaction between oral contraceptives and orlistat has been demonstrated in specific drug-drug interaction studies. However, orlistat may indirectly reduce the availability of oral contraceptives and lead to unexpected pregnancies in some individual cases. An additional contraceptive method is recommended in case of severe diarrhoea (see section 4.4).

4.6 Pregnancy And Lactation

For orlistat no clinical data on exposed pregnancies are available.

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).

Caution should be exercised when prescribing to pregnant women.

As it is not known whether orlistat is secreted into human milk, orlistat is contra-indicated during breast-feeding.

4.7 Effects On Ability To Drive And Use Machines

Xenical has no influence on the ability to drive and use machines.

4.8 Undesirable Effects

Adverse reactions to orlistat are largely gastrointestinal in nature. The incidence of adverse events decreased with prolonged use of orlistat.

Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

The following table of undesirable effects (first year of treatment) is based on adverse events that occurred at a frequency of> 2 % and with an incidence

System organ class

Adverse reaction/event

Nervous system disorders

 

Very common:

Headache

Respiratory, thoracic and mediastinal disorders

 

Very common:

Upper respiratory infection

Common:

Lower respiratory infection

Gastrointestinal disorders

 

Very common:

Abdominal pain/discomfort

Oily spotting from the rectum

Flatus with discharge

Faecal urgency

Fatty/oily stool

Flatulence

Liquid stools

Oily evacuation

Increased defecation

Common:

Rectal pain/discomfort

Soft stools

Faecal incontinence

Abdominal distension*

Tooth disorder

Gingival disorder

Renal and urinary disorders

 

Common:

Urinary tract infection

Metabolism and nutrition disorders

 

Very common:

Hypoglycaemia*

Infections and infestations

 

Very common:

Influenza

General disorders and administration site conditions

 

Common:

Fatigue

Reproductive system and breast disorders

 

Common:

Menstrual irregularity

Psychiatric disorders

 

Common:

Anxiety

* only unique treatment adverse events that occurred at a frequency of> 2 % and with an incidence

In a 4 year clinical trial, the general pattern of adverse event distribution was similar to that reported for the 1 and 2 year studies with the total incidence of gastrointestinal related adverse events occurring in year 1 decreasing year on year over the four year period.

The following table of undesirable effects is based on post-marketing spontaneous reports, and therefore the frequency remains unknown:

System organ class

Adverse reaction

Investigations

 

Increase in liver transaminases and in alkaline phosphatase.

Decreased prothrombin, increased INR and unbalanced anticoagulant treatment resulting in variations of haemostatic parameters have been reported in patients treated with anticoagulants in association with orlistat (see section 4.4 and 4.5)

Gastrointestinal disorders

 

Rectal bleeding

Diverticulitis

Pancreatitis

Skin and subcutaneous tissue disorders

Bullous eruptions

Immune system disorders

Hypersensitivity (e.g. pruritus, rash, urticaria, angioedema, bronchospasm and anaphylaxis)

Hepatobiliary disorders

Cholelithiasis

Hepatitis that may be serious

Renal and urinary disorders

Oxalate nephropathy

4.9 Overdose

Single doses of 800 mg orlistat and multiple doses of up to 400 mg three times daily for 15 days have been studied in normal weight and obese subjects without significant adverse findings. In addition, doses of 240 mg tid have been administered to obese patients for 6 months. The majority of orlistat overdose cases received during post-marketing reported either no adverse events or adverse events that are similar to those reported with recommended dose.

Should a significant overdose of orlistat occur, it is recommended that the patient be observed for 24 hours. Based on human and animal studies, any systemic effects attributable to the lipase-inhibiting properties of orlistat should be rapidly reversible.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmaco-therapeutic group: Peripherally acting antiobesity agent, ATC code A08AB01.

Orlistat is a potent, specific and long-acting inhibitor of gastrointestinal lipases. It exerts its therapeutic activity in the lumen of the stomach and small intestine by forming a covalent bond with the active serine site of the gastric and pancreatic lipases. The inactivated enzyme is thus unavailable to hydrolyse dietary fat, in the form of triglycerides, into absorbable free fatty acids and monoglycerides.

In the 2-year studies and the 4-year study, a hypocaloric diet was used in association with treatment in both the orlistat and the placebo treated groups.

Pooled data from five 2 year studies with orlistat and a hypocaloric diet showed that 37 % of orlistat patients and 19 % of placebo patients demonstrated a loss of at least 5 % of their baseline body weight after 12 weeks of treatment. Of these, 49 % of orlistat treated patients and 40 % of placebo treated patients went on to lose

Data from the 4-year XENDOS clinical trial showed that 60 % of orlistat patients and 35 % of placebo patients demonstrated a loss of at least 5 % of their baseline body weight after 12 weeks of treatment. Of these, 62 % of orlistat treated patients and 52 % of placebo treated patients went on to lose

More patients on orlistat or placebo lost baseline body weight of at least 5 % at 12 weeks or 10 % at one year in the XENDOS study than in the five 2-year studies. The reason for this difference is that the five 2-year studies included a 4-week diet and placebo lead-in period during which patients lost on average 2.6 kg prior to commencing treatment.

Data from the 4-year clinical trial also suggested that weight loss achieved with orlistat delayed the development of type 2 diabetes during the study (cumulative diabetes cases incidences: 3.4 % in the orlistat group compared to 5.4 % in the placebo-treated group). The great majority of diabetes cases came from the subgroup of patients with impaired glucose tolerance at baseline, which represented 21 % of the randomised patients. It is not known whether these findings translate into long-term clinical benefits.

In obese type 2 diabetic patients insufficiently controlled by antidiabetic agents, data from four one-year clinical trials showed that the percentage of responders (

In a multi-centre (US, Canada), parallel-group, double-blind, placebo-controlled study, 539 obese adolescent patients were randomised to receive either 120 mg orlistat (n=357) or placebo (n=182) three times daily as an adjunct to a hypocaloric diet and exercise for 52 weeks. Both populations received multivitamin supplements. The primary endpoint was the change in body mass index (BMI) from baseline to the end of the study.

The results were significantly superior in the orlistat group (difference in BMI of 0.86 kg/m2 in favour of orlistat). 9.5 % of the orlistat treated patients versus 3.3 % of the placebo treated patients lost

5.2 Pharmacokinetic Properties

Absorption

Studies in normal weight and obese volunteers have shown that the extent of absorption of orlistat was minimal. Plasma concentrations of intact orlistat were non-measurable (< 5 ng/ml) eight hours following oral administration of orlistat.

In general, at therapeutic doses, detection of intact orlistat in plasma was sporadic and concentrations were extremely low (< 10 ng/ml or 0.02 µmol), with no evidence of accumulation, which is consistent with minimal absorption.

Distribution

The volume of distribution cannot be determined because the drug is minimally absorbed and has no defined systemic pharmacokinetics. In vitro orlistat is> 99 % bound to plasma proteins (lipoproteins and albumin were the major binding proteins). Orlistat minimally partitions into erythrocytes.

Metabolism

Based on animal data, it is likely that the metabolism of orlistat occurs mainly within the gastrointestinal wall. Based on a study in obese patients, of the minimal fraction of the dose that was absorbed systemically, two major metabolites, M1 (4-member lactone ring hydrolysed) and M3 (M1 with N-formyl leucine moiety cleaved), accounted for approximately 42 % of the total plasma concentration.

M1 and M3 have an open beta-lactone ring and extremely weak lipase inhibitory activity (1000 and 2500 fold less than orlistat respectively). In view of this low inhibitory activity and the low plasma levels at therapeutic doses (average of 26 ng/ml and 108 ng/ml respectively), these metabolites are considered to be pharmacologically inconsequential.

Elimination

Studies in normal weight and obese subjects have shown that faecal excretion of the unabsorbed drug was the major route of elimination. Approximately 97 % of the administered dose was excreted in faeces and 83 % of that as unchanged orlistat.

The cumulative renal excretion of total orlistat-related materials was < 2 % of the given dose. The time to reach complete excretion (faecal plus urinary) was 3 to 5 days. The disposition of orlistat appeared to be similar between normal weight and obese volunteers. Orlistat, M1 and M3 are all subject to biliary excretion.

5.3 Preclinical Safety Data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction.

In animal reproductive studies, no teratogenic effect was observed. In the absence of a teratogenic effect in animals, no malformative effect is expected in man. To date, active substances responsible for malformations in man have been found teratogenic in animals when well-conducted studies were performed in two species.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Capsule filling:

microcrystalline cellulose (E460)

sodium starch glycollate

povidone (E1201)

sodium lauryl sulphate

talc

Capsule shell:

gelatine

indigo carmine (E132)

titanium dioxide (E171)

edible printing ink (black iron oxide, ammonium hydroxide, potassium hydroxide, shellac)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

Blisters: Do not store above 25 °C. Store in original package in order to protect from moisture.

Bottles: Do not store above 30 °C. Keep the container tightly closed in order to protect from moisture.

6.5 Nature And Contents Of Container

PVC/PE/PVDC blisters containing 21, 42 and 84 hard capsules.

Glass bottles with desiccant containing 21, 42 and 84 hard capsules.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Roche Registration Limited

6 Falcon Way

Shire Park

Welwyn Garden City

AL7 1TW

United Kingdom

8. Marketing Authorisation Number(S)

EU/1/98/071/001-006

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 29 July 1998

Date of latest renewal: 29 July 2008

10. Date Of Revision Of The Text

25 March 2009

LEGAL STATUS

POM



Generic Name: collagenase clostridium histolyticum (Injection route)

KOL-a-jen-ase klos-TRID-ee-um his-toe-LIT-ik-um

Commonly used brand name(s)

In the U.S.

Xiaflex

Available Dosage Forms:

Powder for Solution

Pharmacologic Class: Collagenase

Uses For Xiaflex

Collagenase clostridium histolyticum injection is used to treat Dupuytren's contracture with a palpable cord in adults.

This medicine is to be administered only by or under the supervision of your doctor.

Before Using Xiaflex

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of collagenase clostridium histolyticum injection in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of collagenase clostridium histolyticum injection in the elderly.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

Blood clotting disorders—Use with caution. May make these conditions worse. Proper Use of Xiaflex

A nurse or other trained health professional will give you this medicine in a hospital. This medicine is given through a needle placed into the cord of the contracture of your hand.

Precautions While Using Xiaflex

It is very important that you return to your doctor the next day. This will allow your doctor to see the injected hand, and to do a possible finger extension procedure to disrupt the cord.

This medicine may cause serious types of allergic reactions, including anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Tell your doctor right away if you have itching, rash, hives, chest pain, dizziness or lightheadedness, trouble breathing, or any swelling of your hands, face, or mouth after you receive this medicine.

Using this medicine may cause injury to the blood vessels, tendons, or ligaments of the hand. Tell your doctor right away if you have pain or numbness in your hand or arm, trouble bending the finger after the swelling goes down, or bleeding at the injection site.

This medicine may cause infection. Tell your doctor right away if you have a fever, chills, or increasing redness or swelling of your hand.

It is very important that you elevate the fingers of the injected hand until bedtime to prevent swelling. Do not try to move or massage the cord, bend, or extend the fingers of the injected hand, or do heavy activity using your hand to prevent more injury.

Your doctor may put a splint on your hand after giving this medicine. Wear the splint at bedtime for up to 4 months. Do finger bending and extending exercises as instructed by your doctor.

Xiaflex Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

More common Bruising or bleeding at the injection site swelling of the hands tearing of the skin Incidence not known Bone pain lower back or side pain painful, swollen joints

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common Blistering, burning, coldness, discoloration of the skin, feeling of pressure, hives, infection, inflammation, lumps, numbness, rash, scarring, stinging, tingling, or ulceration at the injection site bruise flushing, redness of the skin or unusually warm skin at the injection site itching, pain, swelling, or tenderness at the injection site swollen, painful, or tender lymph glands in the neck or armpit

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: Xiaflex side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More Xiaflex resources Xiaflex Side Effects (in more detail) Xiaflex Use in Pregnancy & Breastfeeding Xiaflex Drug Interactions Xiaflex Support Group 0 Reviews for Xiaflex - Add your own review/rating Xiaflex Prescribing Information (FDA) Xiaflex MedFacts Consumer Leaflet (Wolters Kluwer) Xiaflex Consumer Overview Collagenase Clostridium Histolyticum Professional Patient Advice (Wolters Kluwer) Compare Xiaflex with other medications Dupuytren's contracture



Pronunciation: IN-koe-BOT-ue-LYE-num-TOX-in-AY



Pronunciation: al-PRA-zoe-lam



acyclovir and hydrocortisone



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