Abbott Healthcare Products Limited

Abbott Laboratories Ltd., Abbott House, Vanwall Business Park, Vanwall Road,Maidenhead, Berkshire,SL6 4XE,United Kingdom.

4.8  Undesirable effects

Flush

In the placebo-controlled clinical trials, flushing episodes (i.e., warmth, redness, itching and/or tingling) were the most common treatment-emergent adverse events for Niaspan (reported by 88% of patients). In these studies fewer than 6% of Niaspan patients discontinued due to flushing.

In comparisons of immediate-release (IR) nicotinic acid and Niaspan, although the number of patients who flushed was similar, fewer flushing episodes were reported by patients who received Niaspan. Following four weeks of maintenance therapy with Niaspan at daily doses of 1500 mg, the frequency of flushing over the four week period averaged 1.88 events per patient.

Flushing reactions generally occur during early treatment and the dose titration phase. They are thought to be mediated by the release of prostaglandin D2 and tolerance to flushing usually develops over the course of several weeks.

Spontaneous reports suggest that in rare cases, flushing may be more severe and accompanied by symptoms of dizziness, tachycardia, palpitations, dyspnoea, sweating, chills, and/or oedema, which in rare cases may lead to syncope. Medical treatment should be administered as necessary.

Hypersensitivity reactions

Hypersensitivity reactions have been reported very rarely. These may be characterised by symptoms such as generalised exanthema, flush, urticaria, vesiculobullous rash, angioedema, laryngospasm, dyspnoea, hypotension, and circulatory collapse. Medical treatment should be administered as necessary.

The following adverse reactions have been observed in clinical studies or in routine patient management, in patients receiving the recommended daily maintenance doses (1000, 1500, and 2000 mg) of Niaspan. They are presented by system organ class and frequency grouping (very common >1/10; common >1/100, <1/10; uncommon >1/1,000, <1/100; rare >1/10,000, <1/1,000; very rare <1/10,000, including isolated reports).

In general, the incidence of adverse reactions was higher in women compared to men. (Please refer to Table 2 below)

Table 2: Adverse reactions

Adverse reactions from postmarketing experience:

The following adverse reactions have been reported in postmarketing experience with nicotinic acid prolonged release.  Adverse reactions are presented by system organ class.

Nervous system disorders: Burning sensation, skin burning sensation

Eye disorders:  Blurred vision

Hepatobiliary disorders: Hepatitis

Skin and subcutaneous tissue disorders: Skin discolouration, skin burning sensation, erythema  

General disorders and administration site conditions:  Feeling hot

4.4     Special warnings and precautions for use

Niaspan must not be replaced with other nicotinic acid preparations.  When switching from other nicotinic acid preparations to Niaspan, therapy with Niaspan must be initiated with the recommended dose escalation schedule, see section 4.2.

Liver

Nicotinic acid preparations have been associated with abnormal liver tests.  Severe hepatic toxicity, including fulminant hepatic necrosis, has occurred in patients who have taken long-acting nicotinic acid products in place of immediate-release nicotinic acid.  Since the pharmacokinetics of Niaspan are different to other nicotinic acid preparations, Niaspan must not be replaced with other preparations.  The prescribing information of the HMG-CoA reductase inhibitor should also be consulted for warnings and precautions for use.

Caution is advised when Niaspan is used in patients who consume substantial quantities of alcohol and/or have a past history of liver disease.

Elevated liver transaminases have been observed with Niaspan therapy.  However, transaminase elevations were reversible upon discontinuation of Niaspan.

Liver tests including AST and ALT must be performed periodically in all patients during therapy with Niaspan and prior to treatment in case of history and/or symptoms of hepatic dysfunction (e.g. jaundice, nausea, fever, and/or malaise).  If the transaminase levels show evidence of progression, particularly if they rise to three times the upper limit of normal, the drug must be discontinued.

Skeletal muscle

Single rReports onf rhabdomyolysis in patients on combined therapy with Niaspan and HMG-CoA reductase inhibitors have been received from spontaneous reporting.  Physicians contemplating combined therapy with HMG-CoA reductase inhibitors and Niaspan should carefully weigh the potential benefits and risks and should carefully monitor patients for any symptoms of rhabdomyolysis e.g. muscle pain, tenderness or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug.  Periodic serum creatine phosphokinase (CPK) and potassium determinations should be considered in such situations.

A CPK level should be measured before starting such a combination in patients with pre-disposing factors for rhabdomyolysis, as follows:

·       renal impairment

·       hypothyroidism

·       alcohol abuse

·       age > 70 years

·       personal or family history of hereditary muscular disorders

·       previous history of muscular toxicity with fibrate or HMG-CoA reductase inhibitor

Muscle damage must be considered in any patient presenting with diffuse myalgia, muscle tenderness and/or marked increase in muscle CK levels ( > 5 x ULN); under these conditions treatment must be discontinued.

The prescribing information of the HMG-CoA reductase inhibitors should be consulted.

Glucose Intolerance

Diabetic or potentially diabetic patients should be observed closely since there may be a dose-related increase in glucose intolerance.  Adjustment of diet and/or oral antidiabetics and/or insulin therapy may become necessary.

Unstable angina and acute myocardial infarction

Caution is advised when Niaspan is used in patients with unstable angina or in the acute phase of myocardial infarction, particularly when such patients are also receiving vasoactive drugs such as nitrates, calcium channel blockers, or adrenergic blocking agents.

Uric acid

Elevated uric acid levels have occurred with Niaspan therapy.  Monitoring of patients predisposed to gout is recommended.

Coagulation

Niaspan may affect platelet count and prothrombin time, see section 4.5.  Patients undergoing surgery should be carefully evaluated.  Caution is also advised when Niaspan is administered concomitantly with anti-coagulants; patients receiving anti-coagulants must be monitored closely for prothrombin time and platelet count.

Hypophosphataemia

Niaspan has been associated with reductions in phosphorous levels.  Although these reductions were transient, monitoring of phosphorous levels is recommended in patients at risk of hypophosphataemia.

Other

Patients with a history of jaundice, hepatobiliary disease, or peptic ulcer should be observed closely during Niaspan therapy.

10.  DATE OF REVISION OF THE TEXT

15^th  January 200929 June 2010