03 Oct 2012

TREDAPTIVE 1000 (nicotinic acid, laropiprant) - United Kingdom

Updated: 03 Oct 2012

TREDAPTIVE 1000 mg/20 mg modified release tablets

Tredaptive is indicated for the treatment of dyslipidaemia, particularly in adult patients with combined mixed dyslipidaemia (characterised by elevated levels of LDL-cholesterol and triglycerides and low HDL-cholesterol) and in adults patients with primary hypercholesterolaemia (heterozygous familial and non-familial).

Tredaptive should be used in patients in combination with HMG-CoA reductase inhibitors (statins), when the cholesterol lowering effect of HMG-CoA reductase inhibitor monotherapy is inadequate. It can be used as monotherapy only in patients in whom HMG-CoA reductase inhibitors are considered inappropriate or not tolerated. Diet and other non-pharmacological treatments (e.g. exercise, weight reduction) should be continued during therapy with Tredaptive.

TREDAPTIVE 1000 Description, Presentation and Dosage

TREDAPTIVE 1000 Description

TREDAPTIVE 1000 Drug Class Description

nicotinic acid and derivatives - ATC code: C10AD52

TREDAPTIVE 1000 Drug Description

Each modified-release tablet contains 1000 mg of nicotinic acid and 20 mg of laropiprant.

Excipient(s) with known effect:

Each modified-release tablet contains 128.4 mg of lactose monohydrate.

TREDAPTIVE 1000 Generic Name

nicotinic acid, laropiprant

TREDAPTIVE 1000 Presentation

TREDAPTIVE 1000 Presentation

Modified-release tablet.

Capsule-shaped, white to off-white tablet, with “552” debossed on one side..

Free Medical Education Resources

TREDAPTIVE 1000 Dosage

TREDAPTIVE 1000 Adult Dosage

Posology

The starting dose is one modified-release tablet (1,000 mg nicotinic acid/20 mg laropiprant) once a day. After four weeks, it is recommended that patients be advanced to the maintenance dose of 2,000 mg/40 mg taken as two modified-release tablets (1,000 mg/20 mg each) once daily. Daily doses greater than 2,000 mg/40 mg have not been studied and therefore are not recommended.

If Tredaptive is missed for less than 7 consecutive days, patients can resume therapy at the last administered dose. If Tredaptive is missed for 7 or more consecutive days, therapy should be resumed at the 1,000 mg/20 mg dose for 1 week, before advancing to the maintenance dose of 2,000 mg/40 mg.

Those patients switching from 2,000 mg or more of prolonged-release nicotinic acid can initiate Tredaptive at the 2,000 mg/40 mg dose. Patients switching from less than 2,000 mg of prolonged-release nicotinic acid should initiate therapy at the starting dose of 1,000 mg/20 mg and advance to the 2,000 mg/40 mg maintenance dose after four weeks. For patients switching from immediate-release nicotinic acid to Tredaptive, therapy should be initiated at the 1,000 mg/20 mg dose and advanced to the 2,000 mg/40 mg maintenance dose after four weeks.

Elderly patients

No dose adjustment is required for elderly patients.

Paediatric population

Safety and effectiveness of Tredaptive in paediatric patients under the age of 18 years have not been established. No data are available.

Patients with hepatic or renal insufficiency

Use of Tredaptive in patients with hepatic or renal insufficiency has not been studied. Like other nicotinic acid medicinal products, Tredaptive is contraindicated in patients with significant or unexplained hepatic dysfunction. It should be used with caution in patients with renal insufficiency, because nicotinic acid and its metabolites are primarily excreted by the kidneys.

Concomitant therapy

Acetylsalicylic acid provides no additional reduction of flushing beyond that achieved by Tredaptive. Therefore, treatment with acetylsalicylic acid to alleviate flushing symptoms is not necessary.

Because co-administration of bile acid sequestrants may reduce the bioavailability of acidic medicinal products such as nicotinic acid, it is recommended that Tredaptive be administered > 1 hour before or > 4 hours after administration of a bile acid sequestrant.

Method of administration

The tablets should be taken whole, with food, in the evening or at bedtime. To preserve the modified-release properties, the tablets must not be split, broken, crushed, or chewed before swallowing. To reduce the possibility of flushing, drinking alcohol or hot drinks or eating spicy foods should be avoided at the time of ingestion of the medicinal product.

TREDAPTIVE 1000 Precautions, Reactions and Contraindications

TREDAPTIVE 1000 Special Precautions

TREDAPTIVE 1000 Special Precautions

When Tredaptive is co-administered with a statin, please refer to the Summary of Product Characteristics for that particular medicinal product.

Hepatic effects

Switching from immediate-release (crystalline) nicotinic acid to Tredaptive has not been studied. However, cases of severe hepatic toxicity, including fulminant hepatic necrosis, have occurred in patients who have switched from immediate-release nicotinic acid to long-acting nicotinic acid at equivalent doses. Therefore, patients switching from immediate-release nicotinic acid to Tredaptive should be initiated at the 1000 mg/20 mg dose.

Tredaptive should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease.

Like other lipid-lowering therapies, nicotinic acid medicinal products have been associated with abnormal liver function tests. Transaminase elevations were reversible upon discontinuation of therapy.

Liver function tests are recommended before initiation, every 6 to 12 weeks for the first year, and periodically (e.g. semi-annually) thereafter. Patients who develop increased transaminase levels should be monitored until the abnormalities have resolved. Should an increase in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) of ≥ 3 X ULN persist, reduction of dose or withdrawal of Tredaptive is recommended.

Effect on skeletal muscle

Rare cases of myopathy/rhabdomyolysis have been associated with concomitant administration of lipid-altering doses (≥ 1000 mg/day) of nicotinic acid and HMG-CoA reductase inhibitors (statins).

Physicians contemplating combined therapy with statins and Tredaptive should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs and symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and when the dose of either medicinal product is increased. Periodic serum creatine kinase (CK) should be considered in such situations, but there is no assurance that such monitoring will prevent the occurrence of severe myopathy.

Caution should be exercised in patients with pre-disposing factors for rhabdomyolysis.

• Age > 70 years

• Renal impairment

• Uncontrolled hypothyroidism

• Personal or familial history of hereditary muscular disorders

• Previous history of muscular toxicity with a statin or fibrate

• Alcohol abuse.

If muscle pain, weakness or cramps occur while a patient is receiving Tredaptive with a statin, their CK levels should be measured. If these levels are found, in the absence of strenuous exercise, to be significantly elevated (> 5 x ULN), treatment should be stopped.

Race

In an interim analysis of an ongoing clinical outcome study, an independent safety monitoring committee identified a higher than expected incidence of myopathy in Chinese patients taking Tredaptive and simvastatin 40 mg. Therefore, caution should be used when treating Chinese patients with Tredaptive co-administered with simvastatin or ezetimibe/simvastatin (particularly simvastatin doses of 40 mg or higher). Because the risk of myopathy with statins is dose-related, the use of Tredaptive with simvastatin 80 mg or ezetimibe/simvastatin 10/80 mg is not recommended in Chinese patients. It is unknown whether there is an increased risk of myopathy in other Asian patients treated with Tredaptive co-administered with simvastatin or ezetimibe/simvastatin.

Renal dysfunction

Because nicotinic acid and its metabolites are excreted through the kidneys, Tredaptive should be used with caution in patients with renal dysfunction.

Effect on glucose

Nicotinic acid medicinal products have been associated with increases of fasting blood glucose levels. Diabetic or potentially diabetic patients should be observed closely. Adjustment of diet and/or hypoglycaemic therapy may be necessary.

Acute coronary syndrome

As with other nicotinic acid medicinal products, caution should be used when Tredaptive is used in patients with unstable angina or in the acute phase of an MI, particularly when such patients are also receiving vasoactive medicinal products such as nitrates, calcium channel blockers, or adrenergic blocking agents.

Haematologic effects

As with other nicotinic acid medicinal products, Tredaptive (2,000 mg/40 mg) was associated with small reductions in platelet count. Therefore, patients undergoing surgery should be carefully evaluated.

Effect on uric acid

As with other nicotinic acid medicinal products, Tredaptive (2,000 mg/40 mg) was associated with small increases in uric acid levels. Therefore, Tredaptive should be used with caution in patients with or predisposed to gout.

Hypophosphatemia

As with other nicotinic acid medicinal products, Tredaptive was associated with small decreases in phosphorus levels. Therefore, patients with a risk for hypophosphatemia should be closely followed.

Other information

As with other nicotinic acid medicinal products, patients with a history of jaundice, hepato-biliary disorder or peptic ulcer should be observed closely.

Excipient

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

TREDAPTIVE 1000 Adverse Reactions

TREDAPTIVE 1000 Adverse Reactions

In clinical trials, over 2,500 patients received Tredaptive alone or with an HMG-CoA reductase inhibitor. Adverse reactions have usually been mild and transient.

Flushing

Flushing is the most common adverse reaction of Tredaptive. Flushing is most prominent in the head, neck, and upper torso. In a pool of four active- or placebo-controlled clinical trials (N=4,747, n=2,548 taking Tredaptive), flushing was reported by the investigator as a possibly, probably, or definitely treatment-related adverse reaction in 12.3 % of patients taking Tredaptive. In these studies, the percentage of patients taking Tredaptive, nicotinic acid (pooled prolonged-release formulations) or pooled placebo/simvastatin who discontinued due to any flushing-related symptom (redness, warmth, itching and tingling) was 7.2 %, 16.6 %, and 0.4 %, respectively. Discontinuations due to other specific adverse reactions among patients taking Tredaptive were infrequent (< 1 %).

Overall adverse reactions with Tredaptive

In addition to flushing, clinical adverse reactions reported by the investigators as possibly, probably, or definitely related to Tredaptive in ≥ 1 % of patients treated with Tredaptive alone (n=947) or co-administered with statin (n=1,601) and clinically meaningful adverse reactions (< 1 %), for up to one year are listed below.

The frequencies of adverse reactions are ranked according to the following: Very common (≥ 1/10), Common (≥ 1/100 to < 1/10), Uncommon (≥ 1/1,000 to < 1/100), Rare (≥ 1/10,000 to < 1/1,000), Very rare (< 1/10,000).

System organ class

Adverse reaction

Frequency

Immune system disorders

Hypersensitivity reaction (see below)

Uncommon

Nervous system disorders

Dizziness, headache, paraesthesia

Common

Vascular disorders

Flushing

Very common

Gastrointestinal disorders

Diarrhoea, dyspepsia, nausea, vomiting

Common

Skin and subcutaneous tissue disorders

Erythema, pruritus, rash, urticaria

Common

General disorders and administration site conditions

Feeling hot

Common

Investigations

Elevations in ALT and/or AST (consecutive, ≥ 3 X ULN), fasting glucose, uric acid (see below)

Common

 

Elevations in CK (≥ 10 X ULN), total bilirubin, reductions in phosphorus and platelet counts (see below)

Uncommon

Hypersensitivity reactions

An apparent hypersensitivity reaction has been reported (< 1 %). This is characterised by multiple symptoms that may include: angio-oedema, pruritus, erythema, paraesthesia, loss of consciousness, vomiting, urticaria, flushing, dyspnoea, nausea, incontinence of urine and stool, cold sweats, shivering, chills, increased blood pressure, lip swelling, burning sensation, drug eruption, arthralgia, leg swelling, and tachycardia.

Investigations

Marked and persistent increases of serum transaminases have been reported infrequently. In controlled clinical studies, the incidence of clinically important elevations in serum transaminases (ALT and/or AST ≥ 3 X ULN, consecutive) was 1.0 % for patients treated with Tredaptive with or without a statin. These elevations were generally asymptomatic and returned to baseline after discontinuation of therapy or with continued treatment.

Clinically important elevations of CK (≥ 10 X ULN) were seen in 0.3 % of the patients treated with Tredaptive with or without a statin.

Other abnormal laboratory values reported were elevations in LDH, fasting glucose, uric acid, total bilirubin, and amylase, and reductions in phosphorus and platelet counts.

As with other nicotinic acid medicinal products, elevations in fasting glucose (a median increase of approximately 4 mg/dL), and uric acid (mean change from baseline of +14.7 %), and reductions in platelet counts (a mean change from baseline of -14.0 %) were reported in controlled clinical studies with Tredaptive (2,000 mg/40 mg). In diabetic patients a median increase in HbA1c of 0.2 % was observed (where modification of hypoglycaemic therapy was allowed).

Post-marketing Experience and Other Clinical Trial Experience

Additional adverse reactions that have been reported in post-marketing use with Tredaptive or other nicotinic acid medicinal products (with or without a statin) at unknown frequency or in clinical trials with Tredaptive (< 1 % of patients ) or other nicotinic acid medicinal products (with or without a statin) include the following:

Infections and infestations: Rhinitis.

Immune system disorders: Anaphylactic shock, angio-oedema, type I hypersensitivity.

Metabolism and nutrition disorders: Impaired glucose tolerance, gout.

Psychiatric disorders: Anxiety, insomnia.

Nervous system disorders: Migraine, syncope.

Eye disorders: Cystoid macular oedema, toxic amblyopia.

Cardiac disorders: Atrial fibrillation and other cardiac arrhythmias, palpitations, tachycardia.

Vascular disorders: Hypotension, orthostatic hypotension.

Respiratory, thoracic, and mediastinal disorders: Dyspnoea.

Gastrointestinal disorders: Abdominal pain, mouth oedema, eructation, peptic ulcer.

Hepatobiliary disorders: Jaundice.

Skin and subcutaneous tissue disorders: Acanthosis nigricans, dry skin, hyperpigmentation, macular rash, sweating (night or cold sweat), vesicular or vesiculobullous rash.

Musculoskeletal and connective tissue disorders: Muscular weakness, myalgia.

General disorders and administration site conditions: Asthaenia, chills, face oedema, generalised oedema, pain, peripheral oedema.

TREDAPTIVE 1000 Contraindications

TREDAPTIVE 1000 Contraindications

• Hypersensitivity to the active substances or to any of the excipients

• Significant or unexplained hepatic dysfunction.

• Active peptic ulcer disease.

• Arterial bleeding.

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