Lo-Lip

Hiperkolesterolemi

Diyet ve diğer farmakolojik olmayan tedavilere yanıt verirken, diyete ek olarak primer hiperkolesterolemi veya karışık dislipideminin tedavisi (ör. egzersiz, kilo verme) yetersizdir.

Homozigot ailesel hiperkolesteroleminin (HoFH) diyete ve diğer lipit düşürücü tedavilere ek olarak tedavisi (ör. LDL aferez) veya bu tür tedaviler uygun değilse.

Kardiyovasküler önleme

Diğer risk faktörlerinin ve diğer kardiyoprotektif tedavinin düzeltilmesine ek olarak, normal veya artmış kolesterol seviyeleri olan belirgin aterosklerotik kardiyovasküler hastalık veya diabetes mellituslu hastalarda kardiyovasküler mortalite ve morbiditenin azaltılması.

Pozoloji

Dozaj aralığı, akşamları tek bir doz olarak oral olarak verilen 5-80 mg / gün Lo-Lip'tir. Gerekirse dozaj ayarlamaları, akşamları tek bir doz olarak verilen 4 haftadan az olmayan aralıklarla, maksimum 80 mg / gün'e yapılmalıdır. 80 mg doz sadece şiddetli hiperkolesterolemisi olan ve düşük dozlarda tedavi hedeflerine ulaşmamış olan ve faydaların potansiyel risklerden daha ağır basması beklenen kardiyovasküler komplikasyonlar için yüksek risk altındaki hastalarda önerilir.

Hiperkolesterolemi

Hasta standart bir kolesterol düşürücü diyete konulmalı ve Lo-Lip tedavisi sırasında bu diyete devam etmelidir. Normal başlangıç dozu, akşamları tek bir doz olarak verilen 10-20 mg / gündür. LDL-C'de (% 45'ten fazla) büyük bir azalmaya ihtiyaç duyan hastalar, akşamları tek bir doz olarak verilen 20-40 mg / gün'de başlatılabilir. Gerekirse dozaj ayarlamaları yukarıda belirtildiği gibi yapılmalıdır.

Homozigot ailesel hiperkolesterolemi

Kontrollü bir klinik çalışmanın sonuçlarına dayanarak, önerilen başlangıç dozu akşam 40 mg / gün Lo-Lip'tir. Lo-Lip diğer lipit düşürücü tedavilere ek olarak kullanılmalıdır (örn. LDL aferezi) bu hastalarda veya bu tür tedaviler mevcut değilse.

Lo-Lip ile birlikte lomitapid alan hastalarda, Lo-Lip dozu 40 mg / günü geçmemelidir.

Kardiyovasküler önleme

Genel Lo-Lip dozu, yüksek koroner kalp hastalığı riski olan hastalarda (hiperlipidemili veya hiperlipidemisiz KKH) akşamları tek bir doz olarak verilen 20 ila 40 mg / gündür. Tıbbi ürün tedavisi, diyet ve egzersizle aynı anda başlatılabilir. Gerekirse dozaj ayarlamaları yukarıda belirtildiği gibi yapılmalıdır.

Eşzamanlı tedavi

Lo-Lip tek başına veya safra asidi sekestranları ile kombinasyon halinde etkilidir. Dozlama, safra asidi sekestranının uygulanmasından> 2 saat önce veya> 4 saat sonra yapılmalıdır.

Lo-Lip'i gemfibrozil veya fenofibrat dışında fibratlarla birlikte alan hastalarda, Lo-Lip dozu 10 mg / günü geçmemelidir. Amiodaron, amlodipin, verapamil, diltiazem veya Lo-Lip ile birlikte elbasvir veya grazoprevir içeren ürünler alan hastalarda, Lo-Lip dozu 20 mg / günü geçmemelidir.

Böbrek yetmezliği

Orta derecede böbrek yetmezliği olan hastalarda dozaj modifikasyonu gerekli olmamalıdır.

Şiddetli böbrek yetmezliği olan hastalarda (kreatinin klerensi <30 ml / dak), 10 mg / gün üzerindeki dozajlar dikkatle düşünülmeli ve gerekli görülürse dikkatli bir şekilde uygulanmalıdır.

Yaşlı

Doz ayarlaması gerekmez.

Pediyatrik popülasyon

Heterozigot ailesel hiperkolesterolemili çocuklar ve ergenler (Tanner Evre II ve üstü çocuklar ve menarştan en az bir yıl, 10-17 yaş arası kızlar) için, önerilen normal başlangıç dozu akşamları günde bir kez 10 mg'dır. Çocuklar ve ergenler Lo-Lip tedavisine başlamadan önce standart kolesterol düşürücü bir diyete alınmalıdır; bu diyet Lo-Lip tedavisi sırasında devam etmelidir.

Önerilen doz aralığı 10-40 mg / gündür; önerilen maksimum doz 40 mg / gündür. Dozlar, pediatrik tedavi önerileri tarafından önerildiği gibi önerilen tedavi hedefine göre kişiselleştirilmelidir. Ayarlamalar 4 hafta veya daha uzun aralıklarla yapılmalıdır.

Tüy öncesi çocuklarda Lo-Lip deneyimi sınırlıdır.

Uygulama şekli

Lo-Lip oral uygulama içindir. Lo-Lip akşamları tek bir doz olarak uygulanabilir.

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- Aktif karaciğer hastalığı veya açıklanamayan kalıcı serum transaminaz yükselmeleri

- Gebelik ve emzirme

- Güçlü CYP3A4 inhibitörlerinin (AUC'yi yaklaşık 5 kat veya daha fazla artıran ajanlar) birlikte uygulanması (ör. itrakonazol, ketokonazol, posakonazol, vorikonazol, HIV proteaz inhibitörleri (ör. nelfinavir), boceprevir, telaprevir, eritromisin, klaritromisin, telitromisin, nefazodon ve kobikistat içeren tıbbi ürünler

- Gemfibrozil, siklosporin veya danazolün birlikte uygulanması

- HoFH hastalarında, lomitapidin> 40 mg Lo-Lip dozlarıyla birlikte uygulanması.

Myopathy/Rhabdomyolysis

Lo-Lip, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and very rare fatalities have occurred. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma.

As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose related. In a clinical trial database in which 41,413 patients were treated with Lo-Lip, 24,747 (approximately 60%) of whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was approximately 0.03%, 0.08% and 0.61% at 20, 40 and 80 mg/day, respectively. In these trials, patients were carefully monitored and some interacting medicinal products were excluded.

In a clinical trial in which patients with a history of myocardial infarction were treated with Lo-Lip 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 %..

The risk of myopathy is greater in patients on Lo-Lip 80 mg compared with other statin-based therapies with similar LDL-C- lowering efficacy.3 and 4.5).

In a clinical trial in which patients at high risk of cardiovascular disease were treated with Lo-Lip 40 mg/day (median follow-up 3.9 years), the incidence of myopathy was approximately 0.05 % for non-Chinese patients (n = 7367) compared with 0.24 % for Chinese patients (n = 5468). While the only Asian population assessed in this clinical trial was Chinese, caution should be used when prescribing Lo-Lip to Asian patients and the lowest dose necessary should be employed.

Reduced function of transport proteins

Reduced function of hepatic OATP transport proteins can increase the systemic exposure of Lo-Lip acid and increase the risk of myopathy and rhabdomyolysis. Reduced function can occur as the result of inhibition by interacting medicinal products (e.g. ciclosporin) or in patients who are carriers of the SLCO1B1 c.521T>C genotype.

Patients carrying the SLCO1B1 gene allele (c.521T>C) coding for a less active OATP1B1 protein have an increased systemic exposure of Lo-Lip acid and increased risk of myopathy. The risk of high dose (80 mg) Lo-Lip related myopathy is about 1 % in general, without genetic testing. Based on the results of the SEARCH trial, homozygote C allele carriers (also called CC) treated with 80 mg have a 15% risk of myopathy within one year, while the risk in heterozygote C allele carriers (CT) is 1.5%. The corresponding risk is 0.3% in patients having the most common genotype (TT). Where available, genotyping for the presence of the C allele should be considered as part of the benefit-risk assessment prior to prescribing 80 mg Lo-Lip for individual patients and high doses avoided in those found to carry the CC genotype. However, absence of this gene upon genotyping does not exclude that myopathy can still occur.

Creatine Kinase measurement

Creatine Kinase (CK) should not be measured following strenuous exercise or in the presence of any plausible alternative cause of CK increase as this makes value interpretation difficult. If CK levels are significantly elevated at baseline (> 5 x ULN), levels should be re-measured within 5 to 7 days later to confirm the results.

Before the treatment

All patients starting therapy with Lo-Lip, or whose dose of Lo-Lip is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness.

Caution should be exercised in patients with pre-disposing factors for rhabdomyolysis. In order to establish a reference baseline value, a CK level should be measured before starting a treatment in the following situations:

- Elderly (age > 65 years)

- Female gender

- Renal impairment

- Uncontrolled hypothyroidism

- Personal or familial history of hereditary muscular disorders

- Previous history of muscular toxicity with a statin or fibrate

- Alcohol abuse.

In such situations, the risk of treatment should be considered in relation to possible benefit, and clinical monitoring is recommended. If a patient has previously experienced a muscle disorder on a fibrate or a statin, treatment with a different member of the class should only be initiated with caution. If CK levels are significantly elevated at baseline (> 5 x ULN), treatment should not be started.

Whilst on treatment

If muscle pain, weakness or cramps occur whilst a patient is receiving treatment 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. If muscular symptoms are severe and cause daily discomfort, even if CK levels are < 5 x ULN, treatment discontinuation may be considered. If myopathy is suspected for any other reason, treatment should be discontinued.

There have been very rare reports of an immune-mediated necrotizing myopathy (IMNM) during or after treatment with some statins. IMNM is clinically characterized by persistent proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment.

If symptoms resolve and CK levels return to normal, then re-introduction of the statin or introduction of an alternative statin may be considered at the lowest dose and with close monitoring.

A higher rate of myopathy has been observed in patients titrated to the 80 mg dose. Periodic CK measurements are recommended as they may be useful to identify subclinical cases of myopathy. However, there is no assurance that such monitoring will prevent myopathy.

Therapy with Lo-Lip should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.

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The risk of myopathy and rhabdomyolysis is significantly increased by concomitant use of Lo-Lip with potent inhibitors of CYP3A4 (such as itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, nefazodone, medicinal products containing cobicistat), as well as gemfibrozil, ciclosporin and danazol. Use of these medicinal products is contraindicated.

The risk of myopathy and rhabdomyolysis is also increased by concomitant use of amiodarone, amlodipine, verapamil, or diltiazem with certain doses of Lo-Lip. The risk of myopathy, including rhabdomyolysis, may be increased by concomitant administration of fusidic acid with statins. For patients with HoFH, this risk may be increased by concomitant use of lomitapide with Lo-Lip.

Consequently, regarding CYP3A4 inhibitors, the use of Lo-Lip concomitantly with itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and medicinal products containing cobicistat is contraindicated. If treatment with potent CYP3A4 inhibitors (agents that increase AUC approximately 5 fold or greater)is unavoidable, therapy with Lo-Lip must be suspended (and use of an alternative statin considered) during the course of treatment. Moreover, caution should be exercised when combining Lo-Lip with certain other less potent CYP3A4 inhibitors: fluconazole, verapamil, diltiazem. Concomitant intake of grapefruit juice and Lo-Lip should be avoided.

The use of Lo-Lip with gemfibrozil is contraindicated. Due to the increased risk of myopathy and rhabdomyolysis, the dose of Lo-Lip should not exceed 10 mg daily in patients taking Lo-Lip with other fibrates, except fenofibrate.. Caution should be used when prescribing fenofibrate with Lo-Lip, as either agent can cause myopathy when given alone.

Lo-Lip must not be co-administered with systemic formulations of fusidic acid or within 7 days of stopping fusidic acid treatment. In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving fusidic acid and statins in combination. The patient should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness.

Statin therapy may be re-introduced seven days after the last dose of fusidic acid.

In exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g., for the treatment of severe infections, the need for co-administration of Lo-Lip and fusidic acid should only be considered on a case by case basis and under close medical supervision.

The combined use of Lo-Lip at doses higher than 20 mg daily with amiodarone, amlodipine, verapamil, or diltiazem should be avoided. In patients with HoFH, the combined use of Lo-Lip at doses higher than 40 mg daily with lomitapide must be avoided.

Patients taking other medicinal products labelled as having a moderate inhibitory effect on CYP3A4 concomitantly with Lo-Lip, particularly higher Lo-Lip doses, may have an increased risk of myopathy.

When coadministering Lo-Lip with a moderate inhibitor of CYP3A4 (agents that increase AUC approximately 2- 5 fold), a dose adjustment of Lo-Lip may be necessary. For certain moderate CYP3A4 inhibitors e.g. diltiazem, a maximum dose of 20 mg Lo-Lip is recommended.

Lo-Lip is a substrate of the Breast Cancer Resistant Protein (BCRP) efflux transporter. Concomitant administration of products that are inhibitors of BCRP (e.g., elbasvir and grazoprevir) may lead to increased plasma concentrations of Lo-Lip and an increased risk of myopathy; therefore, a dose adjustment of Lo-Lip should be considered depending on the prescribed dose. Co-administration of elbasvir and grazoprevir with Lo-Lip has not been studied; however, the dose of Lo-Lip should not exceed 20 mg daily in patients receiving concomitant medicinal products containing elbasvir or grazoprevir .

Rare cases of myopathy/rhabdomyolysis have been associated with concomitant administration of HMG-CoA reductase inhibitors and lipid-modifying doses (> 1 g/day) of niacin (nicotinic acid), either of which can cause myopathy when given alone.

In a clinical trial (median follow-up 3.9 years) involving patients at high risk of cardiovascular disease and with well-controlled LDL-C levels on Lo-Lip 40 mg/day with or without ezetimibe 10 mg, there was no incremental benefit on cardiovascular outcomes with the addition of lipid-modifying doses (>1 g/day) of niacin (nicotinic acid). Therefore, physicians contemplating combined therapy with Lo-Lip and lipid-modifying doses (> 1 g/day) of niacin (nicotinic acid) 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, tenderness, or weakness, particularly during the initial months of therapy and when the dose of either medicinal product is increased.

In addition, in this trial, the incidence of myopathy was approximately 0.24 % for Chinese patients on Lo-Lip 40 mg or ezetimibe/Lo-Lip 10/40 mg compared with 1.24 % for Chinese patients on Lo-Lip 40 mg or ezetimibe/Lo-Lip 10/40 mg coadministered with modified-release nicotinic acid/laropiprant 2000 mg/40 mg. While the only Asian population assessed in this clinical trial was Chinese, because the incidence of myopathy is higher in Chinese than in non-Chinese patients, coadministration of Lo-Lip with lipid-modifying doses (>1 g/day) of niacin (nicotinic acid) is not recommended in Asian patients.

Acipimox is structurally related to niacin. Although acipimox was not studied, the risk for muscle related toxic effects may be similar to niacin.

Hepatic effects

In clinical studies, persistent increases (to > 3 x ULN) in serum transaminases have occurred in a few adult patients who received Lo-Lip. When Lo-Lip was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pre-treatment levels.

It is recommended that liver function tests be performed before treatment begins and thereafter when clinically indicated. Patients titrated to the 80-mg dose should receive an additional test prior to titration, 3 months after titration to the 80-mg dose, and periodically thereafter (e.g., semi-annually) for the first year of treatment. Special attention should be paid to patients who develop elevated serum transaminase levels, and in these patients, measurements should be repeated promptly and then performed more frequently. If the transaminase levels show evidence of progression, particularly if they rise to 3 x ULN and are persistent, Lo-Lip should be discontinued. Note that ALT may emanate from muscle, therefore ALT rising with CK may indicate myopathy (see above Myopathy/Rhabdomyolysis).

There have been rare post-marketing reports of fatal and non-fatal hepatic failure in patients taking statins, including Lo-Lip. If serious liver injury with clinical symptoms and /or hyperbilirubinaemia or jaundice occurs during treatment with Lo-Lip, promptly interrupt therapy. If an alternate etiology is not found, do not restart Lo-Lip.

The product should be used with caution in patients who consume substantial quantities of alcohol.

As with other lipid-lowering agents, moderate (< 3 x ULN) elevations of serum transaminases have been reported following therapy with Lo-Lip. These changes appeared soon after initiation of therapy with Lo-Lip, were often transient, were not accompanied by any symptoms and interruption of treatment was not required.

Diabetes mellitus

Some evidence suggests that statins as a class raise blood glucose and in some patients, at high risk of future diabetes, may produce a level of hyperglycaemia where formal diabetes care is appropriate. This risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for stopping statin treatment. Patients at risk (fasting glucose 5.6 to 6.9 mmol/L, BMI > 30 kg/m², raised triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines.

Interstitial lung disease

Cases of interstitial lung disease have been reported with some statins, including Lo-Lip, especially with long term therapy. Presenting features can include dyspnoea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued.

Paediatric population

Safety and effectiveness of Lo-Lip in patients 10-17 years of age with heterozygous familial hypercholesterolaemia have been evaluated in a controlled clinical trial in adolescent boys Tanner Stage II and above and in girls who were at least one year post-menarche. Patients treated with Lo-Lip had an adverse experience profile generally similar to that of patients treated with placebo. Doses greater than 40 mg have not been studied in this population. In this limited controlled study, there was no detectable effect on growth or sexual maturation in the adolescent boys or girls, or any effect on menstrual cycle length in girls.. Adolescent females should be counselled on appropriate contraceptive methods while on Lo-Lip therapy. In patients aged < 18 years, efficacy and safety have not been studied for treatment periods > 48 weeks' duration and long-term effects on physical, intellectual, and sexual maturation are unknown. Lo-Lip has not been studied in patients younger than 10 years of age, nor in pre-pubertal children and pre-menarchal girls.

Excipients

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

Lo-Lip'in araç ve makine kullanma yeteneği üzerinde hiçbir etkisi yoktur veya ihmal edilebilir bir etkisi yoktur. Bununla birlikte, araç veya makine kullanırken, pazarlama sonrası deneyimlerde baş dönmesinin nadiren bildirildiği dikkate alınmalıdır.

Klinik çalışmalar ve / veya pazarlama sonrası kullanım sırasında bildirilen aşağıdaki advers olayların sıklıkları, HPS ve 4S dahil olmak üzere büyük, uzun süreli, plasebo kontrollü klinik çalışmalarda insidans oranlarının değerlendirilmesine göre sınıflandırılır. sırasıyla 20.536 ve 4.444 hasta ile. HPS için, serum transaminazlarında ve CK'da sadece ciddi advers olayların yanı sıra miyalji artışları kaydedildi. 4S için, aşağıda listelenen tüm advers olaylar kaydedildi. Lo-Lip'teki insidans oranları bu çalışmalarda plasebodan daha düşük veya buna benzerse ve makul olarak nedensel olarak ilişkili benzer spontan rapor olayları varsa, bu advers olaylar “nadir” olarak sınıflandırılır.

40 mg / gün Lo-Lip (n = 10.269) veya plasebo (n = 10.267) ile tedavi edilen 20.536 hastayı içeren HPS'de, güvenlik profilleri Lo-Lip 40 mg ile tedavi edilen hastalar ile plasebo ile tedavi edilen hastalar arasında karşılaştırılabilirdi. çalışmanın ortalama 5 yılı. Olumsuz reaksiyonlara bağlı kesilme oranları karşılaştırılabilirdi (Lo-Lip 40 mg ile tedavi edilen hastalarda% 4.8, plasebo ile tedavi edilen hastalarda% 5.1). Lo-Lip 40 mg ile tedavi edilen hastalarda miyopati insidansı <% 0.1 idi. Plasebo ile tedavi edilen hastaların% 0.09'una (n = 9) kıyasla Lo-Lip 40 mg ile tedavi edilen hastaların% 0.21'inde (n = 21) yüksek transaminazlar (> 3 x ULN tekrar testi ile doğrulandı) meydana geldi.

Olumsuz olayların frekansları aşağıdakilere göre sıralanır:

Çok yaygın (> 1/10), Yaygın (> 1/100 ila <1/10), Yaygın olmayan (> 1/1000 ila <1/100), Nadir (> 1 / 10.000 ila <1/1000), Çok Nadir (<1 / 10.000), Veri bilinmiyor (.

* Bilişsel bozukluğun pazarlama sonrası nadir raporları vardır (ör. bellek kaybı, unutkanlık, amnezi, hafıza bozukluğu, karışıklık) Lo-Lip dahil statin kullanımı ile ilişkili. Raporlar genellikle zararlıdır ve statin kesildikten sonra, semptom başlangıcına (1 gün ila yıl) ve semptom çözünürlüğüne (3 haftalık medyan) değişken sürelerle geri dönüşümlüdür.

** Klinik bir çalışmada, 20 mg / gün ile tedavi edilen hastalara kıyasla 80 mg / gün Lo-Lip ile tedavi edilen hastalarda miyopati yaygın olarak meydana geldi (sırasıyla% 1.0'a karşı% 0.02).

*** Nadiren aşağıdaki özelliklerden bazılarını içeren belirgin bir aşırı duyarlılık sendromu bildirilmiştir: anjiyoödem, lupus benzeri sendrom, polimiyalji romatizması, dermatomiyozit, vaskülit, trombositopeni, eozinofili, ESR artışı, artrit ve artralji, ürtiker, ışığa duyarlılık, ateş, kızarma, dispne.

**** Lo-Lip dahil statinlerle HbA1c ve açlık serum glikoz seviyelerinde artış bildirilmiştir.

***** Bazı statinlerle tedavi sırasında veya sonrasında bağışıklık aracılı nekrotizan miyopati (IMNM), otoimmün miyopati hakkında çok nadir raporlar vardır. IMNM klinik olarak şu şekilde karakterize edilir: statin tedavisinin kesilmesine rağmen devam eden kalıcı proksimal kas zayıflığı ve artmış serum kreatin kinaz; önemli iltihaplanma olmadan nekrotizan miyopati gösteren kas biyopsisi; immünosüpresif ajanlarla iyileşme.

Bazı statinlerle aşağıdaki ek advers olaylar bildirilmiştir:

- Kabuslar dahil uyku bozuklukları

- Cinsel işlev bozukluğu

- Diyabetes mellitus: Frekans, risk faktörlerinin varlığına veya yokluğuna bağlı olacaktır (kana glikozu> 5.6 mmol / L, BMI> 30kg / m², yükseltilmiş trigliseritler, hipertansiyon öyküsü).

Pediyatrik popülasyon

Çocukları ve ergenleri kapsayan 48 haftalık bir çalışmada (Tanner Aşama II ve üstü erkekler ve menarştan en az bir yıl sonra kızlar) Heterozigot ailesel hiperkolesterolemi ile 10-17 yaş arası (n = 175) Lo-Lip ile tedavi edilen grubun güvenlik ve tolere edilebilirlik profili genellikle plasebo ile tedavi edilen grubun güvenlik profiline benzerdi.

Fiziksel, entelektüel ve cinsel olgunlaşma üzerindeki uzun vadeli etkileri bilinmemektedir. Bir yıllık tedaviden sonra şu anda yeterli veri mevcut değildir.

Şüpheli advers reaksiyonların raporlanması

Tıbbi ürünün yetkilendirilmesinden sonra şüpheli advers reaksiyonların bildirilmesi önemlidir. Tıbbi ürünün fayda / risk dengesinin sürekli izlenmesine izin verir. Sağlık uzmanlarından şüpheli advers reaksiyonları Sarı Kart Şeması (www.mhra.gov.uk/yellowcard) aracılığıyla bildirmeleri veya Google play veya Apple App mağazasında MHRA Sarı Kart aramaları istenir.

Bugüne kadar, birkaç doz aşımı vakası bildirilmiştir; alınan maksimum doz 3.6 g idi. Tüm hastalar sekel olmadan iyileşti. Doz aşımı durumunda spesifik bir tedavi yoktur. Bu durumda, semptomatik ve destekleyici önlemler alınmalıdır.

Pharmacotherapeutic group: Lipid modifiying agents, plain, HMG-CoA reductase inhibitors, ATC-Code: C10A A01

Mechanism of action

After oral ingestion, Lo-Lip, which is an inactive lactone, is hydrolyzed in the liver to the corresponding active beta-hydroxyacid form which has a potent activity in inhibiting HMG-CoA reductase (3-hydroxy - 3-methylglutaryl-CoA reductase). This enzyme catalyses the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in the biosynthesis of cholesterol.

Lo-Lip has been shown to reduce both normal and elevated LDL-C concentrations. LDL is formed from very-low-density protein (VLDL) and is catabolised predominantly by the high affinity LDL receptor. The mechanism of the LDL-lowering effect of Lo-Lip may involve both reduction of VLDL-cholesterol (VLDL-C) concentration and induction of the LDL receptor, leading to reduced production and increased catabolism of LDL-C. Apolipoprotein B also falls substantially during treatment with Lo-Lip. In addition, Lo-Lip moderately increases HDL-C and reduces plasma TG. As a result of these changes the ratios of total- to HDL-C and LDL- to HDL-C are reduced.

Clinical efficacy and safety

High risk of coronary heart disease (CHD) or existing coronary heart disease

In the Heart Protection Study (HPS), the effects of therapy with Lo-Lip were assessed in 20,536 patients (age 40-80 years), with or without hyperlipidaemia, and with coronary heart disease, other occlusive arterial disease or diabetes mellitus. In this study, 10,269 patients were treated with Lo-Lip 40 mg/day and 10,267 patients were treated with placebo for a mean duration of 5 years. At baseline, 6,793 patients (33%) had LDL-C levels below 116 mg/dL; 5,063 patients (25%) had levels between 116 mg/dL and 135 mg/dL; and 8,680 patients (42%) had levels greater than 135 mg/dL.

Treatment with Lo-Lip 40 mg/day compared with placebo significantly reduced the risk of all cause mortality (1328 [12.9%] for Lo-Lip-treated patients versus 1507 [14.7%] for patients given placebo; p = 0.0003), due to an 18% reduction in coronary death rate (587 [5.7%] versus 707 [6.9%]; p = 0.0005; absolute risk reduction of 1.2%). The reduction in non-vascular deaths did not reach statistical significance.

Lo-Lip also decreased the risk of major coronary events (a composite endpoint comprised of non-fatal MI or CHD death) by 27% (p < 0.0001). Lo-Lip reduced the need for undergoing coronary revascularization procedures (including coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) and peripheral and other non-coronary revascularization procedures by 30% (p < 0.0001) and 16% (p = 0.006), respectively. Lo-Lip reduced the risk of stroke by 25% (p < 0.0001), attributable to a 30% reduction in ischemic stroke (p < 0.0001). In addition, within the subgroup of patients with diabetes, Lo-Lip reduced the risk of developing macrovascular complications, including peripheral revascularization procedures (surgery or angioplasty), lower limb amputations, or leg ulcers by 21% (p = 0.0293). The proportional reduction in event rate was similar in each subgroup of patients studied, including those without coronary disease but who had cerebrovascular or peripheral artery disease, men and women, those aged either under or over 70 years at entry into the study, presence or absence of hypertension, and notably those with LDL cholesterol below 3.0 mmol/l at inclusion.

In the Scandinavian Lo-Lip Survival Study (4S), the effect of therapy with Lo-Lip on total mortality was assessed in 4,444 patients with CHD and baseline total cholesterol 212-309 mg/dL (5.5-8.0 mmol/L). In this multicentre, randomised, double-blind, placebo-controlled study, patients with angina or a previous myocardial infarction (MI) were treated with diet, standard care, and either Lo-Lip 20-40 mg/day (n = 2,221) or placebo (n = 2,223) for a median duration of 5.4 years. Lo-Lip reduced the risk of death by 30% (absolute risk reduction of 3.3%). The risk of CHD death was reduced by 42% (absolute risk reduction of 3.5%). Lo-Lip also decreased the risk of having major coronary events (CHD death plus hospital-verified and silent nonfatal MI) by 34%. Furthermore Lo-Lip significantly reduced the risk of fatal plus non-fatal cerebrovascular events (stroke and transient ischemic attacks) by 28%. There was no statistically significant difference between groups in non-cardiovascular mortality.

The Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) evaluated the effect of treatment with Lo-Lip 80 mg versus 20 mg (median follow-up 6.7 yrs) on major vascular events (MVEs; defined as fatal CHD, non-fatal MI, coronary revascularization procedure, non-fatal or fatal stroke, or peripheral revascularization procedure) in 12,064 patients with a history of myocardial infarction. There was no significant difference in the incidence of MVEs between the 2 groups; Lo-Lip 20 mg (n = 1553; 25.7 %) vs. Lo-Lip 80 mg (n = 1477; 24.5 %); RR 0.94, 95 % CI: 0.88 to 1.01. The absolute difference in LDL-C between the two groups over the course of the study was 0.35 ± 0.01 mmol/L. The safety profiles were similar between the two treatment groups except that the incidence of myopathy was approximately 1.0 % for patients on Lo-Lip 80 mg compared with 0.02 % for patients on 20 mg. 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 %.

Primary hypercholesterolaemia and combined hyperlipidaemia

In studies comparing the efficacy and safety of Lo-Lip 10, 20, 40 and 80 mg daily in patients with hypercholesterolaemia, the mean reductions of LDL-C were 30, 38, 41 and 47%, respectively. In studies of patients with combined (mixed) hyperlipidaemia on Lo-Lip 40 mg and 80 mg, the median reductions in triglycerides were 28 and 33% (placebo: 2%), respectively, and mean increases in HDL-C were 13 and 16% (placebo: 3%), respectively.

Paediatric population

In a double-blind, placebo-controlled study, 175 patients (99 boys Tanner Stage II and above and 76 girls who were at least one year post-menarche) 10-17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolaemia (HeFH) were randomized to Lo-Lip or placebo for 24 weeks (base study). Inclusion in the study required a baseline LDL-C level between 160 and 400 mg/dL and at least one parent with an LDL-C level > 189 mg/dL. The dosage of Lo-Lip (once daily in the evening) was 10 mg for the first 8 weeks, 20 mg for the second 8 weeks, and 40 mg thereafter. In a 24-week extension, 144 patients elected to continue therapy and received Lo-Lip 40 mg or placebo.

Lo-Lip significantly decreased plasma levels of LDL-C, TG, and Apo B. Results from the extension at 48 weeks were comparable to those observed in the base study.

After 24 weeks of treatment, the mean achieved LDL-C value was 124.9 mg/dL (range: 64.0-289.0 mg/dL) in the Lo-Lip 40 mg group compared to 207.8 mg/dL (range: 128.0-334.0 mg/dL) in the placebo group.

After 24 weeks of Lo-Lip treatment (with dosages increasing from 10, 20 and up to 40 mg daily at 8-week intervals), Lo-Lip decreased the mean LDL-C by 36.8 % (placebo: 1.1 % increase from baseline), Apo B by 32.4 % (placebo: 0.5 %), and median TG levels by 7.9 % (placebo: 3.2 %) and increased mean HDL-C levels by 8.3 % (placebo: 3.6 %). The long-term benefits of Lo-Lip on cardiovascular events in children with HeFH are unknown.

The safety and efficacy of doses above 40 mg daily have not been studied in children with heterozygous familial hypercholesterolaemia. The long-term efficacy of Lo-Lip therapy in childhood to reduce morbidity and mortality in adulthood has not been established.

Lo-Lip is an inactive lactone, which is readily hydrolyzed in vivo to the corresponding beta-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Hydrolysis takes place mainly in the liver; the rate of hydrolysis in human plasma is very slow.

The pharmacokinetic properties have been evaluated in adults. Pharmacokinetic data in children and adolescents are not available.

Absorption

In man Lo-Lip is well absorbed and undergoes extensive hepatic first-pass extraction. The extraction in the liver is dependent on the hepatic blood flow. The liver is the primary site of action of the active form. The availability of the beta-hydroxyacid to the systemic circulation following an oral dose of Lo-Lip was found to be less than 5% of the dose. Maximum plasma concentration of active inhibitors is reached approximately 1-2 hours after administration of Lo-Lip. Concomitant food intake does not affect the absorption.

The pharmacokinetics of single and multiple doses of Lo-Lip showed that no accumulation of medicinal product occurred after multiple dosing.

Distribution

The protein binding of Lo-Lip and its active metabolite is >95%.

Elimination

Lo-Lip is a substrate of CYP3A4. The major metabolites of Lo-Lip present in human plasma are the beta-hydroxyacid and four additional active metabolites. Following an oral dose of radioactive Lo-Lip to man, 13% of the radioactivity was excreted in the urine and 60% in the faeces within 96 hours. The amount recovered in the faeces represents absorbed medicinal product equivalents excreted in bile as well as unabsorbed medicinal product. Following an intravenous injection of the beta-hydroxyacid metabolite, its half-life averaged 1.9 hours. An average of only 0.3% of the IV dose was excreted in urine as inhibitors.

Lo-Lip acid is taken up actively into the hepatocytes by the transporter OATP1B1.

Lo-Lip is a substrate of the efflux transporter BCRP.

Special populations

SLCO1B1 polymorphism

Carriers of the SLCO1B1 gene c.521T>C allele have lower OATP1B1 activity. The mean exposure (AUC) of the main active metabolite, Lo-Lip acid is 120% in heterozygote carriers (CT) of the C allele and 221% in homozygote (CC) carriers relative to that of patients who have the most common genotype (TT). The C allele has a frequency of 18% in the European population. In patients with SLCO1B1 polymorphism there is a risk of increased exposure of Lo-Lip acid, which may lead to an increased risk of rhabdomyolysis.

Farmakodinamik, tekrarlanan doz toksisitesi, genotoksisite ve kanserojenite ile ilgili geleneksel hayvan çalışmalarına dayanarak, hasta için farmakolojik mekanizma nedeniyle beklenenden başka bir risk yoktur. Hem sıçan hem de tavşanda maksimum tolere edilen dozlarda Lo-Lip, fetal malformasyon üretmedi ve doğurganlık, üreme fonksiyonu veya yenidoğan gelişimi üzerinde hiçbir etkisi olmadı.

Uygulanamaz.

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