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治療オプション:
Fedorchenko Olga Valeryevna 、薬局による医学的評価、 最終更新日:02.04.2022
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同じ成分を持つトップ20の薬:
⁇ евакорによる治療は、アテローム性動脈硬化性血管疾患のリスクがある脂質異常症の個人における複数の危険因子介入の構成要素であるべきです。. ⁇ евакорは、飽和脂肪とコレステロールが制限された食事に加えて、食事療法やその他の非薬理学的対策だけではリスクを低減するには不十分であった場合に、総CおよびLDL-Cを目標レベルに下げるための治療戦略の一部として使用する必要があります。.
冠状動脈性心臓病の一次予防。
症候性心血管疾患のない個人では、平均から中程度の上昇の合計CおよびLDL-C、および平均HDL-Cを下回る場合、 ⁇ евакорは次のリスクを減らすことが示されています。
- 心筋 ⁇ 塞。
- 不安定な狭心症。
- 冠血行再建術(参照。 臨床薬理学。, 臨床研究。.)
冠状動脈性心臓病。
⁇ евакорは、総CおよびLDL-Cを目標レベルに下げるための治療戦略の一環として、冠状動脈性心疾患患者の冠動脈硬化症の進行を遅らせることが示されています。.
高コレステロール血症。
脂質変化剤による治療は、高コレステロール血症によるアテローム性動脈硬化性血管疾患のリスクが大幅に増加している個人における複数の危険因子介入の構成要素であるべきです。. ⁇ евакорは、原発性高コレステロール血症(タイプIIaおよびIIb。2)、飽和脂肪とコレステロールで制限された食事への反応と他の非薬理学的対策だけへの反応が不十分であったとき。.
ヘテロ接合性家族性高コレステロール血症の青年期患者。
⁇ евакорは、適切な試験の後にheFHを使用して、少なくとも1年の死後の10〜17歳の思春期の少年と少女の総C、LDL-C、およびアポリポタンパク質Bレベルを下げるための食事療法の補助として示されています。次の所見が存在する食事療法の。
1。. LDL-Cは> 189 mg / dLまたは
タイプ。 | リポタンパク質が上昇。 | 脂質上昇。 | |
メジャー。 | マイナー。 | ||
I | カイロミクロン。 | TG | ⁇ →C。 |
I Ia。 | LDL。 | C | — |
私は。 | LDL、VLDL。 | C | TG |
III(まれ)。 | IDL。 | C / TG。 | — |
IV | VLDL。 | TG | ⁇ →C。 |
V(まれ)。 | カイロミクロン、VLDL。 | TG | ⁇ →C。 |
IDL =中間密度リポタンパク質。. |
2。. LDL-Cは> 160 mg / dLのままで、:。
- 早発性心血管疾患の家族歴が良好である。
- 青年期の患者には、他に2つ以上のCVDリスク要因が存在します。
一般的な推奨事項。
ロバスタチンによる治療を開始する前は、高コレステロール血症の二次的原因(例:. 糖尿病の制御不良。, 甲状腺機能低下症。, 腎症症候群。, ジスプロテイン血症。, 閉塞性肝疾患。, その他の薬物療法。, アルコール依存症。) 除外する必要があります。, トータルCを測定するために実行される脂質プロファイル。, HDL-C。, とTG。 TGが400 mg / dL未満の患者の場合。 ( <4.5 mmol / L。) LDL-Cは、次の式を使用して推定できます。
LDL-C = total-C – [0.2 ⁇ —(TG)+ HDL-C]。
TGレベルが400 mg / dLを超える場合(> 4.5 mmol / L)、この方程式は精度が低く、LDL-C濃度は超遠心分離によって決定する必要があります。. 高トリグリセリデミック患者では、総Cの上昇にもかかわらず、LDL-Cは低いか正常である可能性があります。このような場合、 ⁇ евакорは示されません。.
全米コレステロール教育プログラム(NCEP)治療ガイドラインを以下にまとめます。
NCEP治療ガイドライン:LDL-Cの目標と、さまざまなリスクカテゴリにおける治療ライフスタイルの変化と薬物療法のカットポイント。
リスクカテゴリ。 | LDL目標(mg / dL)。 | 治療的ライフスタイルの変化を開始するLDLレベル(mg / dL)。 | 薬物療法を検討するLDLレベル(mg / dL)。 |
CHD *またはCHDリスク同等物(10年リスク> 20%)。 | <100。 | ≥100。 | ≥130(100-129:薬物オプション ⁇ 。 |
2+リスク要因(10年リスク≤20%)。 | <130。 | ≥130。 | 10年リスク10-20%:≥130 10年リスク<10%:≥160。 |
0-1リスク要因 ⁇ 。 | <160。 | ≥160。 | > 190(160-189:LDL低下薬はオプション)。 |
⁇ CHD、冠状動脈性心臓病。 ⁇ 一部の当局は、LDL-Cレベルが100 mg / dL未満の場合、治療ライフスタイルの変化によってLDL-Cレベルを達成できない場合は、このカテゴリーでのLDL低下薬の使用を推奨しています。. 他の人は、主にトリグリセリドとHDL-Cを変更する薬物の使用を好みます。.、ニコチン酸またはフィブラート。. 臨床判断では、このサブカテゴリーで薬物療法の延期を求める場合もあります。. ⁇ リスクファクターが0〜1のほとんどすべての人のリスクは10%未満です。したがって、リスクファクターが0〜1の人を対象とした10年間のリスク評価は必要ありません。. |
LDL-Cの目標が達成された後、TGがまだ200 mg / dL以上である場合、非HDL-C(合計C-HDLC)が治療の二次ターゲットになります。. 非HDL-C目標は、各リスクカテゴリのLDL-C目標より30 mg / dL高く設定されています。.
急性冠動脈イベントの入院時に、LDL-Cが130 mg / dL以上の場合、退院時に薬物療法を開始することを検討できます(参照)。 上記のNCEPガイドライン。).
治療の目標はLDL-Cを下げることであるため、NCEPはLDL-Cレベルを使用して治療反応を開始および評価することを推奨しています。. LDL-Cレベルが利用できない場合のみ、total-Cを使用して治療を監視する必要があります。.
⁇ евакорは、高コレステロール血症と高トリグリセリド血症が組み合わさった患者のLDL-Cレベルの上昇を低下させるのに役立つ可能性がありますが、高コレステロール血症が主要な異常(タイプIIb高脂タンパク質血症)ですが、主要な異常がカイロミクロンの上昇である条件では研究されていません、VLDLまたはIDL(すなわち.、高リポタンパク血症タイプI、III、IV、またはV)。.2 高コレステロール血症または早期心血管疾患の家族歴がある小児患者のコレステロール値のNCEP分類は、以下に要約されています。
カテゴリー。 | Total-C(mg / dL)。 | LDL-C(mg / dL)。 |
許容範囲。 | <170。 | <110。 |
ボーダーライン。 | 170-199。 | 110-129。 |
ハイ。 | ≥200。 | ≥130。 |
思春期にロバスタチンで治療された子供は、成人期に再評価され、LDL-Cの成人の目標を達成するためにコレステロール低下レジメンに適切な変更が加えられるべきです。
患者は、 ⁇ евакорを投与する前に標準的なコレステロール低下食を摂取し、 ⁇ евакорによる治療中もこの食生活を継続する必要があります(参照)。 食事療法の詳細については、NCEP治療ガイドライン。)。. ⁇ евакорは食事とともに与えられるべきです。.
成人患者。
通常の推奨開始用量は、夕食とともに1日1回20 mgです。. ロバスタチンの推奨投与範囲は、単回または2回の分割投与で10〜80 mg /日です。最大推奨用量は80 mg /日です。. 用量は、治療の推奨目標に従って個別化する必要があります(参照)。 NCEPガイドライン。 と。 臨床薬理学。)。. 目標を達成するために20%以上のLDLCの削減を必要とする患者(参照。 適応と使用法。)は、20 mg /日の ⁇ евакорから開始する必要があります。. より少ない削減を必要とする患者では、10 mgのロバスタチンの開始用量が考慮される場合があります。. 調整は4週間以上の間隔で行う必要があります。. 10 mgの投与量は情報提供のみを目的としています。. ロバスタチン錠10 mgは市場で入手できますが、 ⁇ евакорは10 mgの強度で販売されなくなりました。.
コレステロールレベルは定期的に監視する必要があり、コレステロール値が目標範囲を大幅に下回る場合は、 ⁇ евакорの投与量を減らすことを考慮する必要があります。.
ダナゾール、ジルチアゼム、ドロネダロンまたはベラパミルを服用している患者の投与量。
ダナゾール、ジルチアゼム、ドロネダロン、またはベラパミルをロバスタチンと併用している患者では、治療は10 mgのロバスタチンから始まり、20 mg /日を超えてはなりません(参照)。 臨床薬理学。, 薬物動態。, 警告。, ミオパシー/横紋筋融解症。, 注意:。 薬物相互作用。, その他の薬物相互作用。).
アミオダロンを服用している患者の投与量。
アミオダロンを ⁇ евакорと同時に服用している患者では、用量は40 mg /日を超えてはなりません(参照)。 警告。, ミオパシー/横紋筋融解症。 と。 注意:。 薬物相互作用。, その他の薬物相互作用。).
ヘテロ接合性家族性高コレステロール血症を伴う青年期患者(10〜17歳)。
ロバスタチンの推奨投与範囲は10〜40 mg /日です。最大推奨用量は40 mg /日です。. 用量は、治療の推奨目標に従って個別化する必要があります(参照)。 NCEP小児パネルガイドライン。4, 臨床薬理学。、および。 適応と使用法。)。. 目標を達成するためにLDL-Cを20%以上削減する必要がある患者は、20 mg /日の ⁇ евакорから開始する必要があります。. より少ない削減を必要とする患者では、10 mgのロバスタチンの開始用量が考慮される場合があります。. 調整は4週間以上の間隔で行う必要があります。.
脂質低下療法の併用。
⁇ евакорは単独で、または胆 ⁇ 酸隔離剤と併用すると効果的です(参照。 警告。, ミオパシー/横紋筋融解症。 と。 注意:。 薬物相互作用。).
腎不全患者の投与量。
重度の腎不全(クレアチニンクリアランス<30 mL / min)の患者では、20 mg /日を超える投与量の増加を慎重に検討し、必要と思われる場合は慎重に実施する必要があります(参照)。 臨床薬理学。 と。 警告。, ミオパシー/横紋筋融解症。).
この薬の任意の成分に対する過敏症。.
活動性肝疾患または原因不明の血清トランスアミナーゼの上昇(参照) 警告。).
強力なCYP3A4阻害剤との併用投与(例:.、イトラコナゾール、ケトコナゾール、ポサコナゾール、ボリコナゾール、HIVプロテアーゼ阻害剤、ボセプレビル、テラプレビル、エリスロマイシン、クラリスロマイシン、テリスロマイシン、ネファゾドン)(参照。 警告。, ミオパシー/横紋筋融解症。).
妊娠と授乳(参照。 注意。, 妊娠と授乳中の母親。)。. アテローム性動脈硬化症は慢性的なプロセスであり、妊娠中の脂質低下薬の中止は、原発性高コレステロール血症の長期治療の結果にほとんど影響を与えないはずです。. さらに、コレステロールとコレステロール生合成経路の他の製品は、ステロイドや細胞膜の合成を含む、胎児の発育に不可欠な要素です。. ⁇ евакорなどのHMG-CoAレダクターゼの阻害剤がコレステロールの合成およびおそらくコレステロール生合成経路の他の生成物を減少させる能力があるため、 ⁇ евакорは妊娠中および授乳中の母親では禁 ⁇ です。. ⁇ евакорは、そのような患者が妊娠する可能性が非常に低い場合にのみ、出産適齢期の女性に投与されるべきです。. この薬の服用中に患者が妊娠した場合は、すぐに ⁇ евакорを中止し、胎児への潜在的な危険を患者に知らせる必要があります(参照)。 注意。, 妊娠。).
WARNINGS
Myopathy/Rhabdomyolysis
Lovastatin, 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 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 study (EXCEL) in which patients were carefully monitored and some interacting drugs were excluded, there was one case of myopathy among 4933 patients randomized to lovastatin 20- 40 mg daily for 48 weeks, and 4 among 1649 patients randomized to 80 mg daily.
There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.
All patients starting therapy with Мевакор, or whose dose of Мевакор is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing Мевакор. Мевакор therapy should be discontinued immediately if myopathy is diagnosed or suspected. In most cases, muscle symptoms and CK increases resolved when treatment was promptly discontinued. Periodic CK determinations may be considered in patients starting therapy with Мевакор or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy.
Many of the patients who have developed rhabdomyolysis on therapy with lovastatin have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus. Such patients merit closer monitoring. Мевакор therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Мевакор therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.
The risk of myopathy/rhabdomyolysis is increased by concomitant use of lovastatin with the following:
Strong inhibitors of CYP3A4: Lovastatin, like several other inhibitors of HMG-CoA reductase, is a substrate of cytochrome P450 3A4 (CYP3A4). Certain drugs which inhibit this metabolic pathway can raise the plasma levels of lovastatin and may increase the risk of myopathy. These include itraconazole, ketoconazole, posaconazole, voriconazole, the macrolide antibiotics erythromycin and clarithromycin, the ketolide antibiotic telithromycin, HIV protease inhibitors, boceprevir, telaprevir, or the antidepressant nefazodone. Combination of these drugs with lovastatin is contraindicated. If short-term treatment with strong CYP3A4 inhibitors is unavoidable, therapy with lovastatin should be suspended during the course of treatment (see CONTRAINDICATIONS; PRECAUTIONS: DRUG INTERACTIONS).
Gemfibrozil: The combined use of lovastatin with gemfibrozil should be avoided.
Other lipid-lowering drugs (other fibrates or ≥ 1 g/day of niacin): Caution should be used when prescribing other fibrates or lipid-lowering doses ( ≥ 1 g/day) of niacin with lovastatin, as these agents can cause myopathy when given alone. The benefit of further alterations in lipid levels by the combined use of lovastatin with other fibrates or niacin should be carefully weighed against the potential risks of these combinations.
Cyclosporine: The use of lovastatin with cyclosporine should be avoided.
Danazol, diltiazem, dronedarone or verapamil with higher doses of lovastatin: The dose of lovastatin should not exceed 20 mg daily in patients receiving concomitant medication with danazol, diltiazem, dronedarone, or verapamil. The benefits of the use of lovastatin in patients receiving danazol, diltiazem, dronedarone, or verapamil should be carefully weighed against the risks of these combinations.
Amiodarone: The dose of lovastatin should not exceed 40 mg daily in patients receiving concomitant medication with amiodarone. The combined use of lovastatin at doses higher than 40 mg daily with amiodarone should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy. The risk of myopathy/rhabdomyolysis is increased when amiodarone is used concomitantly with higher doses of a closely related member of the HMG-CoA reductase inhibitor class.
Colchicine: Cases of myopathy, including rhabdomyolysis, have been reported with lovastatin coadministered with colchicine, and caution should be exercised when prescribing lovastatin with colchicine (see PRECAUTIONS: DRUG INTERACTIONS).
Ranolazine: The risk of myopathy, including rhabdomyolysis, may be increased by concomitant administration of ranolazine. Dose adjustment of lovastatin may be considered during coadministration with ranolazine.
Prescribing recommendations for interacting agents are summarized in Table VII (see also CLINICAL PHARMACOLOGY, Pharmacokinetics; PRECAUTIONS: DRUG INTERACTIONS; DOSAGE AND ADMINISTRATION).
Table VII: Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis
Interacting Agents | Prescribing Recommendations |
Strong CYP3A4 inhibitors, e.g.: Ketoconazole Itraconazole Posaconazole Voriconazole Erythromycin Clarithromycin Telithromycin HIV protease inhibitors Boceprevir Telaprevir Nefazodone | Contraindicated with lovastatin |
Gemfibrozil Cyclosporine | Avoid with lovastatin |
Danazol Diltiazem Dronedarone Verapamil | Do not exceed 20 mg lovastatin daily |
Amiodarone | Do not exceed 40 mg lovastatin daily |
Grapefruit juice | Avoid grapefruit juice |
Liver Dysfunction
Persistent increases (to more than 3 times the upper limit of normal) in serum transaminases occurred in 1.9% of adult patients who received lovastatin for at least one year in early clinical trials (see ADVERSE REACTIONS). When the drug was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pretreatment levels. The increases usually appeared 3 to 12 months after the start of therapy with lovastatin, and were not associated with jaundice or other clinical signs or symptoms. There was no evidence of hypersensitivity. In the EXCEL study (see CLINICAL PHARMACOLOGY, Clinical Studies), the incidence of persistent increases in serum transaminases over 48 weeks was 0.1% for placebo, 0.1% at 20 mg/day, 0.9% at 40 mg/day, and 1.5% at 80 mg/day in patients on lovastatin. However, in post-marketing experience with Мевакор, symptomatic liver disease has been reported rarely at all dosages (see ADVERSE REACTIONS).
In AFCAPS/TexCAPS, the number of participants with consecutive elevations of either alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ( > 3 times the upper limit of normal), over a median of 5.1 years of follow-up, was not significantly different between the Мевакор and placebo groups (18 [0.6%] vs. 11 [0.3%]). The starting dose of Мевакор was 20 mg/day; 50% of the Мевакор treated participants were titrated to 40 mg/day at Week 18. Of the 18 participants on Мевакор with consecutive elevations of either ALT or AST, 11 (0.7%) elevations occurred in participants taking 20 mg/day, while 7 (0.4%) elevations occurred in participants titrated to 40 mg/day. Elevated transaminases resulted in discontinuation of 6 (0.2%) participants from therapy in the Мевакор group (n=3,304) and 4 (0.1%) in the placebo group (n=3,301).
It is recommended that liver enzyme tests be obtained prior to initiating therapy with Мевакор and repeated as clinically indicated.
There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including lovastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with Мевакор, promptly interrupt therapy. If an alternate etiology is not found do not restart Мевакор.
The drug should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver disease or unexplained transaminase elevations are contraindications to the use of lovastatin.
As with other lipid-lowering agents, moderate (less than three times the upper limit of normal) elevations of serum transaminases have been reported following therapy with Мевакор (see ADVERSE REACTIONS). These changes appeared soon after initiation of therapy with Мевакор, were often transient, were not accompanied by any symptoms and interruption of treatment was not required.
PRECAUTIONS
General
Lovastatin may elevate creatine phosphokinase and transaminase levels (see WARNINGS and ADVERSE REACTIONS). This should be considered in the differential diagnosis of chest pain in a patient on therapy with lovastatin.
Homozygous Familial Hypercholesterolemia
Мевакор is less effective in patients with the rare homozygous familial hypercholesterolemia, possibly because these patients have no functional LDL receptors. Мевакор appears to be more likely to raise serum transaminases (see ADVERSE REACTIONS) in these homozygous patients.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 21-month carcinogenic study in mice, there was a statistically significant increase in the incidence of hepatocellular carcinomas and adenomas in both males and females at 500 mg/kg/day. This dose produced a total plasma drug exposure 3 to 4 times that of humans given the highest recommended dose of lovastatin (drug exposure was measured as total HMG-CoA reductase inhibitory activity in extracted plasma). Tumor increases were not seen at 20 and 100 mg/kg/day, doses that produced drug exposures of 0.3 to 2 times that of humans at the 80 mg/day dose. A statistically significant increase in pulmonary adenomas was seen in female mice at approximately 4 times the human drug exposure. (Although mice were given 300 times the human dose [HD] on a mg/kg body weight basis, plasma levels of total inhibitory activity were only 4 times higher in mice than in humans given 80 mg of Мевакор.)
There was an increase in incidence of papilloma in the non-glandular mucosa of the stomach of mice beginning at exposures of 1 to 2 times that of humans. The glandular mucosa was not affected. The human stomach contains only glandular mucosa.
In a 24-month carcinogenicity study in rats, there was a positive dose response relationship for hepatocellular carcinogenicity in males at drug exposures between 2-7 times that of human exposure at 80 mg/day (doses in rats were 5, 30 and 180 mg/kg/day).
An increased incidence of thyroid neoplasms in rats appears to be a response that has been seen with other HMG-CoA reductase inhibitors.
A chemically similar drug in this class was administered to mice for 72 weeks at 25, 100, and 400 mg/kg body weight, which resulted in mean serum drug levels approximately 3, 15, and 33 times higher than the mean human serum drug concentration (as total inhibitory activity) after a 40 mg oral dose. Liver carcinomas were significantly increased in high dose females and mid- and high dose males, with a maximum incidence of 90 percent in males. The incidence of adenomas of the liver was significantly increased in mid- and high dose females. Drug treatment also significantly increased the incidence of lung adenomas in mid- and high dose males and females. Adenomas of the Harderian gland (a gland of the eye of rodents) were significantly higher in high dose mice than in controls.
No evidence of mutagenicity was observed in a microbial mutagen test using mutant strains of Salmonella typhimurium with or without rat or mouse liver metabolic activation. In addition, no evidence of damage to genetic material was noted in an in vitro alkaline elution assay using rat or mouse hepatocytes, a V-79 mammalian cell forward mutation study, an in vitro chromosome aberration study in CHO cells, or an in vivo chromosomal aberration assay in mouse bone marrow.
Drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation were seen in dogs starting at 20 mg/kg/day. Similar findings were seen with another drug in this class. No drug-related effects on fertility were found in studies with lovastatin in rats. However, in studies with a similar drug in this class, there was decreased fertility in male rats treated for 34 weeks at 25 mg/kg body weight, although this effect was not observed in a subsequent fertility study when this same dose was administered for 11 weeks (the entire cycle of spermatogenesis, including epididymal maturation). In rats treated with this same reductase inhibitor at 180 mg/kg/day, seminiferous tubule degeneration (necrosis and loss of spermatogenic epithelium) was observed. No microscopic changes were observed in the testes from rats of either study. The clinical significance of these findings is unclear.
Pregnancy
Pregnancy Category X
See CONTRAINDICATIONS.
Safety in pregnant women has not been established.
Lovastatin has been shown to produce skeletal malformations in offspring of pregnant mice and rats dosed during gestation at 80 mg/kg/day (affected mouse fetuses/total: 8/307 compared to 4/289 in the control group; affected rat fetuses/total: 6/324 compared to 2/308 in the control group). Female rats dosed before mating through gestation at 80 mg/kg/day also had fetuses with skeletal malformations (affected fetuses/total: 1/152 compared to 0/171 in the control group). The 80 mg/kg/day dose in mice is 7 times the human dose based on body surface area and in rats results in 5 times the human exposure
based on AUC. In pregnant rats given doses of 2, 20, or 200 mg/kg/day and treated through lactation, the following effects were observed: neonatal mortality (4.1%, 3.5%, and 46%, respectively, compared to 0.6% in the control group), decreased pup body weights throughout lactation (up to 5%, 8%, and 38%, respectively, below control), supernumerary ribs in dead pups (affected fetuses/total: 0/7, 1/17, and 11/79, respectively, compared to 0/5 in the control group), delays in ossification in dead pups (affected fetuses/total: 0/7, 0/17, and 1/79, respectively, compared to 0/5 in the control group) and delays in pup development (delays in the appearance of an auditory startle response at 200 mg/kg/day and free-fall righting reflexes at 20 and 200 mg/kg/day).
Direct dosing of neonatal rats by subcutaneous injection with 10 mg/kg/day of the open hydroxyacid form of lovastatin resulted in delayed passive avoidance learning in female rats (mean of 8.3 trials to criterion, compared to 7.3 and 6.4 in untreated and vehicle-treated controls; no effects on retention 1 week later) at exposures 4 times the human systemic exposure at 80 mg/day based on AUC. No effect was seen in male rats. No evidence of malformations was observed when pregnant rabbits were given 5 mg/kg/day (doses equivalent to a human dose of 80 mg/day based on body surface area) or a maternally toxic dose of 15 mg/kg/day (3 times the human dose of 80 mg/day based on body surface area).
Rare clinical reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been received. However, in an analysis3 of greater than 200 prospectively followed pregnancies exposed during the first trimester to Мевакор or another closely related HMG-CoA reductase inhibitor, the incidence of congenital anomalies was comparable to that seen in the general population. This number of pregnancies was sufficient to exclude a 3-fold or greater increase in congenital anomalies over the background incidence.
Maternal treatment with Мевакор may reduce the fetal levels of mevalonate, which is a precursor of cholesterol biosynthesis. Atherosclerosis is a chronic process, and ordinarily discontinuation of lipidlowering drugs during pregnancy should have little impact on the long-term risk associated with primary hypercholesterolemia. For these reasons, Мевакор should not be used in women who are pregnant, or can become pregnant (see CONTRAINDICATIONS). Мевакор should be administered to women of child-bearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards. Treatment should be immediately discontinued as soon as pregnancy is recognized.
Nursing Mothers
It is not known whether lovastatin is excreted in human milk. Because a small amount of another drug in this class is excreted in human breast milk and because of the potential for serious adverse reactions in nursing infants, women taking Мевакор should not nurse their infants (see CONTRAINDICATIONS).
Pediatric Use
Safety and effectiveness in patients 10-17 years of age with heFH have been evaluated in controlled clinical trials of 48 weeks duration in adolescent boys and controlled clinical trials of 24 weeks duration in girls who were at least 1 year post-menarche. Patients treated with lovastatin 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 these limited controlled studies, there was no detectable effect on growth or sexual maturation in the adolescent boys or on menstrual cycle length in girls. See CLINICAL PHARMACOLOGY, Clinical Studies in Adolescent Patients; ADVERSE REACTIONS, Adolescent Patients; and DOSAGE AND ADMINISTRATION, Adolescent Patients (10-17 years of age) with Heterozygous Familial Hypercholesterolemia. Adolescent females should be counseled on appropriate contraceptive methods while on lovastatin therapy (see CONTRAINDICATIONS and PRECAUTIONS, Pregnancy). Lovastatin has not been studied in pre-pubertal patients or patients younger than 10 years of age.
Geriatric Use
A pharmacokinetic study with lovastatin showed the mean plasma level of HMG-CoA reductase inhibitory activity to be approximately 45% higher in elderly patients between 70-78 years of age compared with patients between 18-30 years of age; however, clinical study experience in the elderly indicates that dosage adjustment based on this age-related pharmacokinetic difference is not needed. In the two large clinical studies conducted with lovastatin (EXCEL and AFCAPS/TexCAPS), 21% (3094/14850) of patients were ≥ 65 years of age. Lipid-lowering efficacy with lovastatin was at least as great in elderly patients compared with younger patients, and there were no overall differences in safety over the 20 to 80 mg/day dosage range (see CLINICAL PHARMACOLOGY).
Мевакор is generally well tolerated; adverse reactions usually have been mild and transient.
Phase III Clinical Studies
In Phase III controlled clinical studies involving 613 patients treated with Мевакор, the adverse experience profile was similar to that shown below for the 8,245-patient EXCEL study (see Expanded Clinical Evaluation of Lovastatin [EXCEL] Study).
Persistent increases of serum transaminases have been noted (see WARNINGS, Liver Dysfunction). About 11% of patients had elevations of CK levels of at least twice the normal value on one or more occasions. The corresponding values for the control agent cholestyramine was 9 percent. This was attributable to the noncardiac fraction of CK. Large increases in CK have sometimes been reported (see WARNINGS, Myopathy/Rhabdomyolysis).
Expanded Clinical Evaluation of Lovastatin (EXCEL) Study
Мевакор was compared to placebo in 8,245 patients with hypercholesterolemia (total-C 240-300 mg/dL [6.2-7.8 mmol/L]) in the randomized, double-blind, parallel, 48-week EXCEL study. Clinical adverse experiences reported as possibly, probably or definitely drug-related in ≥ 1% in any treatment group are shown in the table below. For no event was the incidence on drug and placebo statistically different.
Placebo (N = 1663) % | Мевакор 20 mg q.p.m. (N = 1642) % | Мевакор 40 mg q.p.m. (N = 1645) % | Мевакор 20 mg b.i.d. (N = 1646) % | Мевакор 40 mg b.i.d. (N = 1649) % | |
Body As a Whole | |||||
Asthenia | 1.4 | 1.7 | 1.4 | 1.5 | 1.2 |
Gastrointestinal | |||||
Abdominal pain | 1.6 | 2.0 | 2.0 | 2.2 | 2.5 |
Constipation | 1.9 | 2.0 | 3.2 | 3.2 | 3.5 |
Diarrhea | 2.3 | 2.6 | 2.4 | 2.2 | 2.6 |
Dyspepsia | 1.9 | 1.3 | 1.3 | 1.0 | 1.6 |
Flatulence | 4.2 | 3.7 | 4.3 | 3.9 | 4.5 |
Nausea | 2.5 | 1.9 | 2.5 | 2.2 | 2.2 |
Musculoskeletal | |||||
Muscle cramps | 0.5 | 0.6 | 0.8 | 1.1 | 1.0 |
Myalgia | 1.7 | 2.6 | 1.8 | 2.2 | 3.0 |
Nervous System/ Psychiatric | |||||
Dizziness | 0.7 | 0.7 | 1.2 | 0.5 | 0.5 |
Headache | 2.7 | 2.6 | 2.8 | 2.1 | 3.2 |
Skin | |||||
Rash | 0.7 | 0.8 | 1.0 | 1.2 | 1.3 |
Special Senses | |||||
Blurred vision | 0.8 | 1.1 | 0.9 | 0.9 | 1.2 |
Other clinical adverse experiences reported as possibly, probably or definitely drug-related in 0.5 to 1.0 percent of patients in any drug-treated group are listed below. In all these cases the incidence on drug and placebo was not statistically different. Body as a Whole: chest pain; Gastrointestinal: acid regurgitation, dry mouth, vomiting; Musculoskeletal: leg pain, shoulder pain, arthralgia; Nervous System/Psychiatric: insomnia, paresthesia; Skin: alopecia, pruritus; Special Senses: eye irritation.
In the EXCEL study (see CLINICAL PHARMACOLOGY, Clinical Studies), 4.6% of the patients treated up to 48 weeks were discontinued due to clinical or laboratory adverse experiences which were rated by the investigator as possibly, probably or definitely related to therapy with Мевакор. The value for the placebo group was 2.5%.
Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)
In AFCAPS/TexCAPS (see CLINICAL PHARMACOLOGY, Clinical Studies) involving 6,605 participants treated with 20-40 mg/day of Мевакор (n=3,304) or placebo (n=3,301), the safety and tolerability profile of the group treated with Мевакор was comparable to that of the group treated with placebo during a median of 5.1 years of follow-up. The adverse experiences reported in AFCAPS/TexCAPS were similar to those reported in EXCEL (see ADVERSE REACTIONS, Expanded Clinical Evaluation of Lovastatin (EXCEL) Study).
Concomitant Therapy
In controlled clinical studies in which lovastatin was administered concomitantly with cholestyramine, no adverse reactions peculiar to this concomitant treatment were observed. The adverse reactions that occurred were limited to those reported previously with lovastatin or cholestyramine. Other lipid-lowering agents were not administered concomitantly with lovastatin during controlled clinical studies. Preliminary data suggests that the addition of gemfibrozil to therapy with lovastatin is not associated with greater reduction in LDL-C than that achieved with lovastatin alone. In uncontrolled clinical studies, most of the patients who have developed myopathy were receiving concomitant therapy with cyclosporine, gemfibrozil or niacin (nicotinic acid). The combined use of lovastatin with cyclosporine or gemfibrozil should be avoided. Caution should be used when prescribing other fibrates or lipid-lowering doses ( ≥ 1 g/day) of niacin with lovastatin (see WARNINGS, Myopathy/Rhabdomyolysis).
The following effects have been reported with drugs in this class. Not all the effects listed below have necessarily been associated with lovastatin therapy.
Skeletal: muscle cramps, myalgia, myopathy, rhabdomyolysis, arthralgias.
There have been rare reports of immune-mediated necrotizing myopathy associated with statin use (see WARNINGS, Myopathy/Rhabdomyolysis).
Neurological: dysfunction of certain cranial nerves (including alteration of taste, impairment of extraocular movement, facial paresis), tremor, dizziness, vertigo, paresthesia, peripheral neuropathy, peripheral nerve palsy, psychic disturbances, anxiety, insomnia, depression.
There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).
Hypersensitivity Reactions: An apparent hypersensitivity syndrome has been reported rarely which has included one or more of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome.
Gastrointestinal: pancreatitis, hepatitis, including chronic active hepatitis, cholestatic jaundice, fatty change in liver; and rarely, cirrhosis, fulminant hepatic necrosis, and hepatoma; anorexia, vomiting, fatal and non-fatal hepatic failure.
Skin: alopecia, pruritus. A variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails) have been reported.
Reproductive: gynecomastia, loss of libido, erectile dysfunction.
Eye: progression of cataracts (lens opacities), ophthalmoplegia.
Laboratory Abnormalities
elevated transaminases, alkaline phosphatase, γ-glutamyl transpeptidase, and bilirubin; thyroid function abnormalities.
Adolescent Patients (ages 10-17 years)
In a 48-week controlled study in adolescent boys with heFH (n=132) and a 24-week controlled study in girls who were at least 1 year post-menarche with heFH (n=54), the safety and tolerability profile of the groups treated with Мевакор (10 to 40 mg daily) was generally similar to that of the groups treated with placebo (see CLINICAL PHARMACOLOGY, Clinical Studies in Adolescent Patients and PRECAUTIONS, Pediatric Use).
After oral administration of Мевакор to mice, the median lethal dose observed was > 15 g/m².
Five healthy human volunteers have received up to 200 mg of lovastatin as a single dose without clinically significant adverse experiences. A few cases of accidental overdosage have been reported; no patients had any specific symptoms, and all patients recovered without sequelae. The maximum dose taken was 5-6 g.
Until further experience is obtained, no specific treatment of overdosage with Мевакор can be recommended.
The dialyzability of lovastatin and its metabolites in man is not known at present.
Dosage in Patients taking Amiodarone
In patients taking amiodarone concomitantly with Мевакор, the dose should not exceed 40 mg/day (see WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS: DRUG INTERACTIONS, Other Drug Interactions).
Adolescent Patients (10-17 years of age) with Heterozygous Familial Hypercholesterolemia
The recommended dosing range of lovastatin is 10-40 mg/day; the maximum recommended dose is 40 mg/day. Doses should be individualized according to the recommended goal of therapy (see NCEP Pediatric Panel Guidelines4, CLINICAL PHARMACOLOGY, and INDICATIONS AND USAGE). Patients requiring reductions in LDL-C of 20% or more to achieve their goal should be started on 20 mg/day of Мевакор. A starting dose of 10 mg of lovastatin may be considered for patients requiring smaller reductions. Adjustments should be made at intervals of 4 weeks or more.
Concomitant Lipid-Lowering Therapy
Мевакор is effective alone or when used concomitantly with bile-acid sequestrants (see WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS: DRUG INTERACTIONS).
Dosage in Patients with Renal Insufficiency
In patients with severe renal insufficiency (creatinine clearance < 30 mL/min), dosage increases above 20 mg/day should be carefully considered and, if deemed necessary, implemented cautiously (see CLINICAL PHARMACOLOGY and WARNINGS, Myopathy/Rhabdomyolysis).
HOW SUPPLIED
No. 8123 — Tablets Мевакор 20 mg are blue, octagonal tablets, coded MSD 731 on one side and plain on the other. They are supplied as follows:
NDC 0006-0731-61 unit of use bottles of 60.
No. 8124 — Tablets Мевакор 40 mg are green, octagonal tablets, coded MSD 732 on one side and plain on the other. They are supplied as follows:
NDC 0006-0732-61 unit of use bottles of 60.
Storage
Store at 20-25°C (68-77°F). Tablets Мевакор must be protected from light and stored in a well-closed, light-resistant container.
REFERENCES
2 Classification of Hyperlipoproteinemias
4 National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics. 89(3):495-501. 1992.
By: Mylan Pharmaceuticals Inc. Morgantown, WV 26505, USA OR Mylan Pharmaceuticals ULC, Etobicoke, Ontario, Canada M8Z 2S6. Revised: 10/2012
Side Effects & Drug InteractionsSIDE EFFECTS
Мевакор is generally well tolerated; adverse reactions usually have been mild and transient.
Phase III Clinical Studies
In Phase III controlled clinical studies involving 613 patients treated with Мевакор, the adverse experience profile was similar to that shown below for the 8,245-patient EXCEL study (see Expanded Clinical Evaluation of Lovastatin [EXCEL] Study).
Persistent increases of serum transaminases have been noted (see WARNINGS, Liver Dysfunction). About 11% of patients had elevations of CK levels of at least twice the normal value on one or more occasions. The corresponding values for the control agent cholestyramine was 9 percent. This was attributable to the noncardiac fraction of CK. Large increases in CK have sometimes been reported (see WARNINGS, Myopathy/Rhabdomyolysis).
Expanded Clinical Evaluation of Lovastatin (EXCEL) Study
Мевакор was compared to placebo in 8,245 patients with hypercholesterolemia (total-C 240-300 mg/dL [6.2-7.8 mmol/L]) in the randomized, double-blind, parallel, 48-week EXCEL study. Clinical adverse experiences reported as possibly, probably or definitely drug-related in ≥ 1% in any treatment group are shown in the table below. For no event was the incidence on drug and placebo statistically different.
Placebo (N = 1663) % | Мевакор 20 mg q.p.m. (N = 1642) % | Мевакор 40 mg q.p.m. (N = 1645) % | Мевакор 20 mg b.i.d. (N = 1646) % | Мевакор 40 mg b.i.d. (N = 1649) % | |
Body As a Whole | |||||
Asthenia | 1.4 | 1.7 | 1.4 | 1.5 | 1.2 |
Gastrointestinal | |||||
Abdominal pain | 1.6 | 2.0 | 2.0 | 2.2 | 2.5 |
Constipation | 1.9 | 2.0 | 3.2 | 3.2 | 3.5 |
Diarrhea | 2.3 | 2.6 | 2.4 | 2.2 | 2.6 |
Dyspepsia | 1.9 | 1.3 | 1.3 | 1.0 | 1.6 |
Flatulence | 4.2 | 3.7 | 4.3 | 3.9 | 4.5 |
Nausea | 2.5 | 1.9 | 2.5 | 2.2 | 2.2 |
Musculoskeletal | |||||
Muscle cramps | 0.5 | 0.6 | 0.8 | 1.1 | 1.0 |
Myalgia | 1.7 | 2.6 | 1.8 | 2.2 | 3.0 |
Nervous System/ Psychiatric | |||||
Dizziness | 0.7 | 0.7 | 1.2 | 0.5 | 0.5 |
Headache | 2.7 | 2.6 | 2.8 | 2.1 | 3.2 |
Skin | |||||
Rash | 0.7 | 0.8 | 1.0 | 1.2 | 1.3 |
Special Senses | |||||
Blurred vision | 0.8 | 1.1 | 0.9 | 0.9 | 1.2 |
Other clinical adverse experiences reported as possibly, probably or definitely drug-related in 0.5 to 1.0 percent of patients in any drug-treated group are listed below. In all these cases the incidence on drug and placebo was not statistically different. Body as a Whole: chest pain; Gastrointestinal: acid regurgitation, dry mouth, vomiting; Musculoskeletal: leg pain, shoulder pain, arthralgia; Nervous System/Psychiatric: insomnia, paresthesia; Skin: alopecia, pruritus; Special Senses: eye irritation.
In the EXCEL study (see CLINICAL PHARMACOLOGY, Clinical Studies), 4.6% of the patients treated up to 48 weeks were discontinued due to clinical or laboratory adverse experiences which were rated by the investigator as possibly, probably or definitely related to therapy with Мевакор. The value for the placebo group was 2.5%.
Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)
In AFCAPS/TexCAPS (see CLINICAL PHARMACOLOGY, Clinical Studies) involving 6,605 participants treated with 20-40 mg/day of Мевакор (n=3,304) or placebo (n=3,301), the safety and tolerability profile of the group treated with Мевакор was comparable to that of the group treated with placebo during a median of 5.1 years of follow-up. The adverse experiences reported in AFCAPS/TexCAPS were similar to those reported in EXCEL (see ADVERSE REACTIONS, Expanded Clinical Evaluation of Lovastatin (EXCEL) Study).
Concomitant Therapy
In controlled clinical studies in which lovastatin was administered concomitantly with cholestyramine, no adverse reactions peculiar to this concomitant treatment were observed. The adverse reactions that occurred were limited to those reported previously with lovastatin or cholestyramine. Other lipid-lowering agents were not administered concomitantly with lovastatin during controlled clinical studies. Preliminary data suggests that the addition of gemfibrozil to therapy with lovastatin is not associated with greater reduction in LDL-C than that achieved with lovastatin alone. In uncontrolled clinical studies, most of the patients who have developed myopathy were receiving concomitant therapy with cyclosporine, gemfibrozil or niacin (nicotinic acid). The combined use of lovastatin with cyclosporine or gemfibrozil should be avoided. Caution should be used when prescribing other fibrates or lipid-lowering doses ( ≥ 1 g/day) of niacin with lovastatin (see WARNINGS, Myopathy/Rhabdomyolysis).
The following effects have been reported with drugs in this class. Not all the effects listed below have necessarily been associated with lovastatin therapy.
Skeletal: muscle cramps, myalgia, myopathy, rhabdomyolysis, arthralgias.
There have been rare reports of immune-mediated necrotizing myopathy associated with statin use (see WARNINGS, Myopathy/Rhabdomyolysis).
Neurological: dysfunction of certain cranial nerves (including alteration of taste, impairment of extraocular movement, facial paresis), tremor, dizziness, vertigo, paresthesia, peripheral neuropathy, peripheral nerve palsy, psychic disturbances, anxiety, insomnia, depression.
There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).
Hypersensitivity Reactions: An apparent hypersensitivity syndrome has been reported rarely which has included one or more of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome.
Gastrointestinal: pancreatitis, hepatitis, including chronic active hepatitis, cholestatic jaundice, fatty change in liver; and rarely, cirrhosis, fulminant hepatic necrosis, and hepatoma; anorexia, vomiting, fatal and non-fatal hepatic failure.
Skin: alopecia, pruritus. A variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails) have been reported.
Reproductive: gynecomastia, loss of libido, erectile dysfunction.
Eye: progression of cataracts (lens opacities), ophthalmoplegia.
Laboratory Abnormalities
elevated transaminases, alkaline phosphatase, γ-glutamyl transpeptidase, and bilirubin; thyroid function abnormalities.
Adolescent Patients (ages 10-17 years)
In a 48-week controlled study in adolescent boys with heFH (n=132) and a 24-week controlled study in girls who were at least 1 year post-menarche with heFH (n=54), the safety and tolerability profile of the groups treated with Мевакор (10 to 40 mg daily) was generally similar to that of the groups treated with placebo (see CLINICAL PHARMACOLOGY, Clinical Studies in Adolescent Patients and PRECAUTIONS, Pediatric Use).
DRUG INTERACTIONS
CYP3A4 Interactions
Lovastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A4. Strong inhibitors of CYP3A4 (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, and erythromycin), and grapefruit juice increase the risk of myopathy by reducing the elimination of lovastatin. (See CONTRAINDICATIONS, WARNINGS, Myopathy/Rhabdomyolysis, and CLINICAL PHARMACOLOGY, Pharmacokinetics.)
Interactions With Lipid-Lowering Drugs That Can Cause Myopathy When Given Alone
The risk of myopathy is also increased by the following lipid-lowering drugs that are not strong CYP3A4 inhibitors, but which can cause myopathy when given alone.
See WARNINGS, Myopathy/Rhabdomyolysis.
Gemfibrozil
Other fibrates
Niacin (nicotinic acid) ( ≥ 1 g/day)
Other Drug Interactions
Cyclosporine: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of cyclosporine (see WARNINGS, Myopathy/Rhabdomyolysis).
Danazol, Diltiazem, Dronedarone or Verapamil: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of danazol, diltiazem, dronedarone or verapamil particularly with higher doses of lovastatin (see WARNINGS, Myopathy/Rhabdomyolysis; CLINICAL PHARMACOLOGY, Pharmacokinetics).
Amiodarone: The risk of myopathy/rhabdomyolysis is increased when amiodarone is used concomitantly with a closely related member of the HMG-CoA reductase inhibitor class (see WARNINGS, Myopathy/Rhabdomyolysis).
Coumarin Anticoagulants: In a small clinical trial in which lovastatin was administered to warfarin treated patients, no effect on prothrombin time was detected. However, another HMG-CoA reductase inhibitor has been found to produce a less than two-second increase in prothrombin time in healthy volunteers receiving low doses of warfarin. Also, bleeding and/or increased prothrombin time have been reported in a few patients taking coumarin anticoagulants concomitantly with lovastatin. It is recommended that in patients taking anticoagulants, prothrombin time be determined before starting lovastatin and frequently enough during early therapy to insure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of lovastatin is changed, the same procedure should be repeated. Lovastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.
Colchicine: Cases of myopathy, including rhabdomyolysis, have been reported with lovastatin coadministered with colchicine. See WARNINGS, Myopathy/Rhabdomyolysis.
Ranolazine: The risk of myopathy, including rhabdomyolysis, may be increased by concomitant administration of ranolazine. See WARNINGS, Myopathy/Rhabdomyolysis.
Propranolol: In normal volunteers, there was no clinically significant pharmacokinetic or pharmacodynamic interaction with concomitant administration of single doses of lovastatin and propranolol.
Digoxin: In patients with hypercholesterolemia, concomitant administration of lovastatin and digoxin resulted in no effect on digoxin plasma concentrations.
Oral Hypoglycemic Agents: In pharmacokinetic studies of Мевакор in hypercholesterolemic noninsulin dependent diabetic patients, there was no drug interaction with glipizide or with chlorpropamide (see CLINICAL PHARMACOLOGY, Clinical Studies).
Endocrine Function
Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including Мевакор.
HMG-CoA reductase inhibitors interfere with cholesterol synthesis and as such might theoretically blunt adrenal and/or gonadal steroid production. Results of clinical trials with drugs in this class have been inconsistent with regard to drug effects on basal and reserve steroid levels. However, clinical studies have shown that lovastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve, and does not reduce basal plasma testosterone concentration. Another HMG-CoA reductase inhibitor has been shown to reduce the plasma testosterone response to HCG. In the same study, the mean testosterone response to HCG was slightly but not significantly reduced after treatment with lovastatin 40 mg daily for 16 weeks in 21 men. The effects of HMG-CoA reductase inhibitors on male fertility have not been studied in adequate numbers of male patients. The effects, if any, on the pituitarygonadal axis in pre-menopausal women are unknown. Patients treated with lovastatin who develop clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should also be exercised if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is administered to patients also receiving other drugs (e.g., spironolactone, cimetidine) that may decrease the levels or activity of endogenous steroid hormones.
CNS Toxicity
Lovastatin produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose (as measured by total enzyme inhibitory activity). Vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis were also seen in dogs treated for 14 weeks at 180 mg/kg/day, a dose which resulted in a mean plasma drug level (Cmax) similar to that seen with the 60 mg/kg/day dose.
CNS vascular lesions, characterized by perivascular hemorrhage and edema, mononuclear cell infiltration of perivascular spaces, perivascular fibrin deposits and necrosis of small vessels, were seen in dogs treated with lovastatin at a dose of 180 mg/kg/day, a dose which produced plasma drug levels (Cmax) which were about 30 times higher than the mean values in humans taking 80 mg/day.
Similar optic nerve and CNS vascular lesions have been observed with other drugs of this class.
Cataracts were seen in dogs treated for 11 and 28 weeks at 180 mg/kg/day and 1 year at 60 mg/kg/day.
Warnings & PrecautionsWARNINGS
Myopathy/Rhabdomyolysis
Lovastatin, 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 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 study (EXCEL) in which patients were carefully monitored and some interacting drugs were excluded, there was one case of myopathy among 4933 patients randomized to lovastatin 20- 40 mg daily for 48 weeks, and 4 among 1649 patients randomized to 80 mg daily.
There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.
All patients starting therapy with Мевакор, or whose dose of Мевакор is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing Мевакор. Мевакор therapy should be discontinued immediately if myopathy is diagnosed or suspected. In most cases, muscle symptoms and CK increases resolved when treatment was promptly discontinued. Periodic CK determinations may be considered in patients starting therapy with Мевакор or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy.
Many of the patients who have developed rhabdomyolysis on therapy with lovastatin have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus. Such patients merit closer monitoring. Мевакор therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Мевакор therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.
The risk of myopathy/rhabdomyolysis is increased by concomitant use of lovastatin with the following:
Strong inhibitors of CYP3A4: Lovastatin, like several other inhibitors of HMG-CoA reductase, is a substrate of cytochrome P450 3A4 (CYP3A4). Certain drugs which inhibit this metabolic pathway can raise the plasma levels of lovastatin and may increase the risk of myopathy. These include itraconazole, ketoconazole, posaconazole, voriconazole, the macrolide antibiotics erythromycin and clarithromycin, the ketolide antibiotic telithromycin, HIV protease inhibitors, boceprevir, telaprevir, or the antidepressant nefazodone. Combination of these drugs with lovastatin is contraindicated. If short-term treatment with strong CYP3A4 inhibitors is unavoidable, therapy with lovastatin should be suspended during the course of treatment (see CONTRAINDICATIONS; PRECAUTIONS: DRUG INTERACTIONS).
Gemfibrozil: The combined use of lovastatin with gemfibrozil should be avoided.
Other lipid-lowering drugs (other fibrates or ≥ 1 g/day of niacin): Caution should be used when prescribing other fibrates or lipid-lowering doses ( ≥ 1 g/day) of niacin with lovastatin, as these agents can cause myopathy when given alone. The benefit of further alterations in lipid levels by the combined use of lovastatin with other fibrates or niacin should be carefully weighed against the potential risks of these combinations.
Cyclosporine: The use of lovastatin with cyclosporine should be avoided.
Danazol, diltiazem, dronedarone or verapamil with higher doses of lovastatin:
Amiodarone: The dose of lovastatin should not exceed 40 mg daily in patients receiving concomitant medication with amiodarone. The combined use of lovastatin at doses higher than 40 mg daily with amiodarone should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy. The risk of myopathy/rhabdomyolysis is increased when amiodarone is used concomitantly with higher doses of a closely related member of the HMG-CoA reductase inhibitor class.
Colchicine: Cases of myopathy, including rhabdomyolysis, have been reported with lovastatin coadministered with colchicine, and caution should be exercised when prescribing lovastatin with colchicine (see PRECAUTIONS: DRUG INTERACTIONS).
Ranolazine: The risk of myopathy, including rhabdomyolysis, may be increased by concomitant administration of ranolazine. Dose adjustment of lovastatin may be considered during coadministration with ranolazine.
Prescribing recommendations for interacting agents are summarized in Table VII (see also CLINICAL PHARMACOLOGY, Pharmacokinetics; PRECAUTIONS: DRUG INTERACTIONS; DOSAGE AND ADMINISTRATION).
Table VII: Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis
Interacting Agents | Prescribing Recommendations |
Strong CYP3A4 inhibitors, e.g.: Ketoconazole Itraconazole Posaconazole Voriconazole Erythromycin Clarithromycin Telithromycin HIV protease inhibitors Boceprevir Telaprevir Nefazodone | Contraindicated with lovastatin |
Gemfibrozil Cyclosporine | Avoid with lovastatin |
Danazol Diltiazem Dronedarone Verapamil | Do not exceed 20 mg lovastatin daily |
Amiodarone | Do not exceed 40 mg lovastatin daily |
Grapefruit juice | Avoid grapefruit juice |
Liver Dysfunction
Persistent increases (to more than 3 times the upper limit of normal) in serum transaminases occurred in 1.9% of adult patients who received lovastatin for at least one year in early clinical trials (see ADVERSE REACTIONS). When the drug was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pretreatment levels. The increases usually appeared 3 to 12 months after the start of therapy with lovastatin, and were not associated with jaundice or other clinical signs or symptoms. There was no evidence of hypersensitivity. In the EXCEL study (see CLINICAL PHARMACOLOGY, Clinical Studies), the incidence of persistent increases in serum transaminases over 48 weeks was 0.1% for placebo, 0.1% at 20 mg/day, 0.9% at 40 mg/day, and 1.5% at 80 mg/day in patients on lovastatin. However, in post-marketing experience with Мевакор, symptomatic liver disease has been reported rarely at all dosages (see ADVERSE REACTIONS).
In AFCAPS/TexCAPS, the number of participants with consecutive elevations of either alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ( > 3 times the upper limit of normal), over a median of 5.1 years of follow-up, was not significantly different between the Мевакор and placebo groups (18 [0.6%] vs. 11 [0.3%]). The starting dose of Мевакор was 20 mg/day; 50% of the Мевакор treated participants were titrated to 40 mg/day at Week 18. Of the 18 participants on Мевакор with consecutive elevations of either ALT or AST, 11 (0.7%) elevations occurred in participants taking 20 mg/day, while 7 (0.4%) elevations occurred in participants titrated to 40 mg/day. Elevated transaminases resulted in discontinuation of 6 (0.2%) participants from therapy in the Мевакор group (n=3,304) and 4 (0.1%) in the placebo group (n=3,301).
It is recommended that liver enzyme tests be obtained prior to initiating therapy with Мевакор and repeated as clinically indicated.
There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including lovastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with Мевакор, promptly interrupt therapy. If an alternate etiology is not found do not restart Мевакор.
The drug should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver disease or unexplained transaminase elevations are contraindications to the use of lovastatin.
As with other lipid-lowering agents, moderate (less than three times the upper limit of normal) elevations of serum transaminases have been reported following therapy with Мевакор (see ADVERSE REACTIONS). These changes appeared soon after initiation of therapy with Мевакор, were often transient, were not accompanied by any symptoms and interruption of treatment was not required.
PRECAUTIONS
General
Lovastatin may elevate creatine phosphokinase and transaminase levels (see WARNINGS and ADVERSE REACTIONS). This should be considered in the differential diagnosis of chest pain in a patient on therapy with lovastatin.
Homozygous Familial Hypercholesterolemia
Мевакор is less effective in patients with the rare homozygous familial hypercholesterolemia, possibly because these patients have no functional LDL receptors. Мевакор appears to be more likely to raise serum transaminases (see ADVERSE REACTIONS) in these homozygous patients.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 21-month carcinogenic study in mice, there was a statistically significant increase in the incidence of hepatocellular carcinomas and adenomas in both males and females at 500 mg/kg/day. This dose produced a total plasma drug exposure 3 to 4 times that of humans given the highest recommended dose of lovastatin (drug exposure was measured as total HMG-CoA reductase inhibitory activity in extracted plasma). Tumor increases were not seen at 20 and 100 mg/kg/day, doses that produced drug exposures of 0.3 to 2 times that of humans at the 80 mg/day dose. A statistically significant increase in pulmonary adenomas was seen in female mice at approximately 4 times the human drug exposure. (Although mice were given 300 times the human dose [HD] on a mg/kg body weight basis, plasma levels of total inhibitory activity were only 4 times higher in mice than in humans given 80 mg of Мевакор.)
There was an increase in incidence of papilloma in the non-glandular mucosa of the stomach of mice beginning at exposures of 1 to 2 times that of humans. The glandular mucosa was not affected. The human stomach contains only glandular mucosa.
In a 24-month carcinogenicity study in rats, there was a positive dose response relationship for hepatocellular carcinogenicity in males at drug exposures between 2-7 times that of human exposure at 80 mg/day (doses in rats were 5, 30 and 180 mg/kg/day).
An increased incidence of thyroid neoplasms in rats appears to be a response that has been seen with other HMG-CoA reductase inhibitors.
A chemically similar drug in this class was administered to mice for 72 weeks at 25, 100, and 400 mg/kg body weight, which resulted in mean serum drug levels approximately 3, 15, and 33 times higher than the mean human serum drug concentration (as total inhibitory activity) after a 40 mg oral dose. Liver carcinomas were significantly increased in high dose females and mid- and high dose
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