Substances related to nicotinic acid

• Acipimox is a medicine used to treat disorders related to high levels of fat in the blood. Its uses and safety have been reviewed because of a study showing that a related medicine, nicotinic acid, increased the side effects and gave no additional benefit when it was taken together with other treatments for these disorders.
• The review has shown that acipimox can be useful as an additional or alternative treatment to lower high levels of triglycerides (a particular type of fat) in the blood of patients with high levels of these fats (with or without high cholesterol), who cannot be treated by means such as diet, exercise, or other medicines.
• Most patients taking acipimox are already using it in this way, but the product information is being updated to clarify the recommended use.
• Patients taking acipimox should have their treatment re-evaluated at their next regular appointment.
• Patients who have any questions should ask their doctor or pharmacist.

• Acipimox is indicated for the treatment of hypertriglyceridaemia with or without hypercholesterolaemia (Fredrickson type IIb or type IV hyperlipoproteinaemia).
• Based on the available data, the indications for acipimox should be restricted to alternative or adjunct treatment in patients who have not responded adequately to other treatments such as statin or fibrate treatment. Patients receiving acipimox should have their treatment reviewed at their next regular appointment.
• The main role of acipimox is to prevent the non-cardiovascular complications of hypertriglyceridaemia and acipimox should not be used for the prevention of cardiovascular disease in the absence of convincing LDL-C or outcome data.
• Although the review of acipimox-containing medicines was originally triggered by concerns arising from the HPS2-THRIVE study, the extended release nicotinic acid/laropiprant combination used in that study cannot be regarded as the same as mono-component acipimox and the concerns can therefore not be extrapolated to acipimox, in particular due to the possible confounding effect of laropiprant.
• However, based on the results from HPS2-THRIVE and the chemical similarity of acipimox and nicotinic acid, prescribers should be aware of the potential increased risk of myopathy when acipimox is used in combination with a statin.
  

The review of acipimox was based on the limited available efficacy and safety data on acipimox as well as data from the scientific literature relating to the structurally related compound nicotinic acid. In addition, the PRAC consulted an ad-hoc expert group of European experts on the use of acipimox.

• Based on the available data, the PRAC noted a number of clinical differences between acipimox and nicotinic acid, with acipimox having a longer duration of action and non-clinical studies showing that acipimox is consistently less potent than nicotinic acid as an agonist of the HCA2 receptor.
• Acipimox was considered to be efficacious in reducing triglyceride levels in patients with hypertriglyceridaemia (Fredrickson type IV hyperlipoproteinaemia) and significantly superior to placebo in patients with hypercholesterolaemia and hypertriglyceridaemia (Fredrickson type IIb hyperlipoproteinaemia). It was noted that acipimox was of particular use in patients who either do not tolerate statin or fibrates or who do not achieve triglyceride goals with statin or fibrate therapy alone and could therefore be used as an alternative or adjunct treatment to reduce triglyceride levels in these patients.
• Having reviewed the available safety data, including data on nicotinic acid obtained from HPS2-THRIVE, the PRAC considered the safety profile of acipimox to be well characterised. Flushing, rash and gastrointestinal effects (nausea, dyspepsia, diarrhoea and upper abdominal pain) are the most frequently reported adverse effects for acipimox and are listed in the acipimox product information, together with pruritus, erythema, urticaria and angioedema. The PRAC considered that the available data did not identify any new safety information which impacts the benefit-risk balance of acipimox, with the exception of a potential risk of muscle toxicity associated with the concomitant use of acipimox with statins, which was addressed by adding a warning to the product information.

The PRAC concluded that the benefit-risk balance of acipimox-containing products remains favourable under normal conditions of use, subject to the agreed changes to the product information. This was endorsed by the CMDh.

Acipimox is a substance closely related to nicotinic acid that has been available since 1984 as Olbetam and other trade names for the treatment of lipid disorders. In the EU, acipimox-containing medicines are currently marketed in Austria, Belgium, Denmark, Hungary, Italy, Luxembourg, the Netherlands and the United Kingdom.

Medicines containing nicotinic acid or related substances have been authorised in the EU via national procedures since the mid-1950s. Nicotinic acid is a naturally occurring substance used in low doses as a vitamin (known as niacin or vitamin B3). In higher doses, it reduces the levels of fat in the blood. Nicotinic acid was also authorised in combination with laropiprant. Laropiprant has no effect on cholesterol but it reduces flushing, which is a known side effect of nicotinic acid.

The review of nicotinic acid and its related substances acipimox and xantinol nicotinate was initiated on 27 February 2013 at the request of the Danish Health and Medicines Authority, under Article 31 of Directive 2001/83/EC. In July 2013 it was established that nicotinic acid and the related substance xantinol nicotinate were not currently marketed in the EU to treat lipid disorders (xantinol nicotinate is authorised in some EU countries for oral use as a vasodilator, a medicine that widens the blood vessels used to treat blood circulation problems) and the review was therefore restricted to acipimox only.

A review of these data was first conducted by the Pharmacovigilance Risk Assessment Committee (PRAC). The PRAC recommendations were sent to Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh), which adopted a final position.

As the CMDh position was adopted by majority vote, it was sent to the European Commission, which endorsed it and issued an EU-wide legally binding decision on 20 February 2014.