MSD-SP LTD

The quantity of lactose monohydrate has been added for each tablet strength.

In section 4.1 the statement "Studies to demonstrate the efficacy of Inegy or ezetimibe in the prevention of complications of atherosclerosis have not been completed." has been deleted and replaced with "A beneficial effect of INEGY or ezetimibe on cardiovascular morbidity and mortality has not yet been demonstrated."

Section 4.2 Posology and method of administration

Under the sub-section "Hypercholesterolaemia" and second paragraph, the text has been changed as follows: "…..The 10/80 mg dose is only recommended in patients with severe hypercholesterolaemia and high risk for cardiovascular complications who have not achieved their treatment goals on lower doses and when the benefits are expected to outweigh the potential risks (see section 4.4 and 5.1). who have not achieved their treatment goals on the 10/40 mg dose (see section 4.4)."

At the end of the third paragraph the following has been added "The tablet should not be split."

Under the sub-section "Co-administration with other medicines" The following paragraph has been added:

"In patients taking diltiazem or amlodipine concomitantly with Inegy the dose of Inegy should not exceed 10/40 mg/day (see section 4.4 and 4.5)"

Also added: "In patients taking lipid-lowering doses (³ 1 g/day) of niacin concomitantly with Inegy, the dose of Inegy should not exceed 10/20 mg/day (see section 4.4 and 4.5)."

 The following paragraph has been revised "In patients taking ciclosporin or danazol or lipid lowering doses

(³ 1 g/day) of niacin concomitantly with Inegy, the dose of Inegy should not exceed 10/10 mg /day (see sections 4.4 and 4.5)."

Section 4.4 Special warnings and precautions for use
Under the sub-section "myopathy/rhabdomyolysis" the third paragraph has been updated with number of patients and incidence of myopathy.

" As with HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose related for simvastatin. In clinical trial database in which 41,050 41,413 patients were treated with simvastatin with 24,747 (approximately 60%) of whom were enrolled in studies with a median follow-up of treated for at least 4 years, the incidence of myopathy was approximately 0.02 0.03%, 0.08% and 0.53 0.61% at 20, 40 and 80 mg/day, respectively….."

Also under this section a new paragraph has been added regarding a clinical trial in patients with a history of myocardial infarction:

"In a clinical trial in which patients with a history of myocardial infarction were treated with simvastatin 80 mg/day (mean follow-up 6.7 years), the incidence of myopathy was approximately 1.0% compared with 0.02% for patients on 20 mg/day. Approximately half of these myopathy cases occurred during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1%. (See sections 4.8 and 5.1.)"

Also in this section and under the sub-section "Before treatment" the list of patient groups requiring a reference baseline CK level has been updated to include elderly now over 65 years instead of 70 and females.

Under the sub-section "Whilst on treatment" the second paragraph has been updated as follows:

"Periodic CK determinations are recommended for patients titrating to the 10/80 mg dose. There is no assurance that such monitoring will prevent myopathy.

In the sub-section "Measures to reduce the risk of myopathy caused by medicinal product interactions (see also section 4.5)", the second paragraph has been updated as follows: "Due to the simvastatin component of Inegy, the risk of myopathy…. (see sections 4.2 and 4.5). There is also slight increase in The risk is increased when by concomitant use of diltiazem or amlodipine is used with Inegy 10 mg/80 mg (see sections 4.2 and 4.5). The risk of myopathy…"

Also in this sub-section, the fourth paragraph has been updated as follows: " The dose of Inegy should not exceed 10/10 mg daily in patients receiving concomitant medication with ciclosporin, or danazol or lipid lowering doses

(³ 1 g/day) of niacin. The benefits of the combined use of Inegy 10 mg/10 mg daily with ciclosporin or danzol or niacin should be carefully weighed against the potential risks of these combinations. (see section 4.2 and 4.5).

A new paragraph on the combined use of Inegy at doses higher than 10/20 mg daily with lipid-lowering doses

³ 1 g/day) of niacin has been added.

Also a new paragraph has been added on rare cases of myopathy/rhabdomyolysis being associated with concomitant administration of HMG-CoA reductase inhibitors and lipid-modifying doses 

(³ 1 g/day) of niacin. A further paragraph has been added that physicians contemplating combined therapy with simvastatin and lipid-modifying doses (³ 1 g/day) of niacin or products containing niacin should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs and symptoms of muscle pain etc.

Also added is a paragraph regarding the interim analysis of an ongoing study where a higher than expected incidence of myopathy in Chinese patients taking simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg and nicotinic acid/laropiprant 2000mg/40 mg was seen.

The paragraph on amlodipine has been revised to state that the combined use of Inegy at doses higher than 10/40 mg daily with diltiazem or amlodipine should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy.

 A new section on "Interstitial lung disease" has been added.

Section 4.5 Interaction with other medicinal products and other forms of interaction

In the first paragraph the following statement has been added: "Rare cases of myopathy/rhabdomyolysis have been associated with simvastatin co-administered with lipid modifying doses

(³ 1 g/day) of niacin (see section 4.4)."

The table on drug interactions has been updated. Niacin has been moved to the section "Do not exceed 10/20 mg Inegy daily" and amlodipine has been added to the section "Do not exceed 10/40 mg Inegy daily".

Also added to this section is a paragraph regarding a study in healthy adults given niacin and concomitant Inegy 10/20 mg daily for 7 days.

The paragraph on "amiodarone" has been updated to state that the dose of Inegy should not exceed 10/20 mg in patients receiving concomitant medication with amiodarone.

A new sub-section on calcium channel blockers has been made and information on verapamil and diltiazem has been revised. A new paragraph on amlodipine has been added.

Section 4.6 pregnancy and lactation
In this section the statements that "Inegy should not be used in women" or that "Inegy should be suspended for the duration of pregnancy" have been changed to "must".

Section 4.8 Undesirable effects
This section has been revised. Two tables have now been added to list all adverse reactions. The first one covers all adverse reactions with Inegy and at a greater incidence than placebo and the second covers adverse reactions with Inegy and at a greater incidence than statins. In addition, adverse events from clinical studies with Ezetrol not included in the clinical studies tables for Inegy and added are "cough", "gastritis", "decreased appetite", "hot flush", "hypertension", "pain" and "liver function test abnormal". The term "dyspneoa" and "erythema multiforme "have also been included for consistency with the Ezetrol SPC. Also added are "memory impairment" and "insomnia". A new paragraph has been added to cover adverse events that have been reported with some statins. These are "sleep disturbances, including insomnia and nightmares, sexual dysfunction, exceptional cases of interstitial lung disease, especially with long term therapy."

 Section 5.1 Pharmacodynamic properties
This section has been updated with information of the SEARCH trial.

Section 6.4 Special precautions for storage
This section has been updated to state that blisters should be "store in the original package in order to protect from moisture and light" and the bottles should be "Keep bottles tightly closed in order to protect from moisture and light."