What happens if I overdose Belvas?
Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.
Proper storage of Belvas extended-release tablets:
Store Belvas extended-release tablets at room temperature, between 68 and 77 degrees F (20 and 25 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Belvas extended-release tablets out of the reach of children and away from pets.
Overdose of Belvas in details
After oral administration of Belvas immediate-release to mice the median lethal dose observed was > 15 g/m.
Five healthy human volunteers have received up to 200 mg of Belvas as a single dose without clinically significant adverse experiences. A few cases of accidental overdosage with Belvas immediate-release have been reported; no patients had any specific symptoms, and all patients recovered without sequelae. The maximum dose taken was 5 g - 6 g.
Until further experience is obtained, no specific treatment of overdosage with Belvas™ can be recommended.
The dialyzability of Belvas and its metabolites in man is not known at present.
What should I avoid while taking Belvas?
Avoid eating foods that are high in fat or cholesterol. Belvas will not be as effective in lowering your cholesterol if you do not follow a cholesterol-lowering diet plan.
Avoid drinking alcohol while taking Belvas. Alcohol can raise triglyceride levels, and may also damage your liver while you are taking Belvas.
Grapefruit and grapefruit juice may interact with Belvas and lead to potentially dangerous effects. Discuss the use of grapefruit products with your doctor. Do not increase or decrease the amount of grapefruit products in your diet without first talking to your doctor.
Belvas warnings
Myopathy/Rhabdomyolysis
Belvas, 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 Belvas 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 Belvas, or whose dose of Belvas 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 Belvas. Belvas 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 Belvas 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 Belvas have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus. Such patients merit closer monitoring. Belvas therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Belvas 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 Belvas with the following:
Strong inhibitors of CYP3A4: Belvas, 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 Belvas 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 Belvas is contraindicated. If short-term treatment with strong CYP3A4 inhibitors is unavoidable, therapy with Belvas should be suspended during the course of treatment.
Gemfibrozil: The combined use of Belvas 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 Belvas, as these agents can cause myopathy when given alone. The benefit of further alterations in lipid levels by the combined use of Belvas with other fibrates or niacin should be carefully weighed against the potential risks of these combinations.
Cyclosporine: The use of Belvas with cyclosporine should be avoided.
Danazol, diltiazem, dronedarone or verapamil with higher doses of Belvas: The dose of Belvas should not exceed 20 mg daily in patients receiving concomitant medication with danazol, diltiazem, dronedarone, or verapamil. The benefits of the use of Belvas in patients receiving danazol, diltiazem, dronedarone, or verapamil should be carefully weighed against the risks of these combinations.
Amiodarone: The dose of Belvas should not exceed 40 mg daily in patients receiving concomitant medication with amiodarone. The combined use of Belvas 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 Belvas coadministered with colchicine, and caution should be exercised when prescribing Belvas with colchicine.
Ranolazine: The risk of myopathy, including rhabdomyolysis, may be increased by concomitant administration of ranolazine. Dose adjustment of Belvas may be considered during coadministration with ranolazine.
Prescribing recommendations for interacting agents are summarized in Table VII.
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 Belvas |
| Gemfibrozil Cyclosporine | Avoid with Belvas |
| Danazol Diltiazem Dronedarone Verapamil | Do not exceed 20 mg Belvas daily |
| Amiodarone | Do not exceed 40 mg Belvas 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 Belvas for at least one year in early clinical trials. 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 Belvas, and were not associated with jaundice or other clinical signs or symptoms. There was no evidence of hypersensitivity. In the EXCEL study, 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 Belvas. However, in post-marketing experience with Belvas, symptomatic liver disease has been reported rarely at all dosages.
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 Belvas and placebo groups (18 [0.6%] vs. 11 [0.3%]). The starting dose of Belvas was 20 mg/day; 50% of the Belvas treated participants were titrated to 40 mg/day at Week 18. Of the 18 participants on Belvas 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 Belvas 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 Belvas and repeated as clinically indicated.
There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including Belvas. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with Belvas, promptly interrupt therapy. If an alternate etiology is not found do not restart Belvas.
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 Belvas.
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 Belvas. These changes appeared soon after initiation of therapy with Belvas, were often transient, were not accompanied by any symptoms and interruption of treatment was not required.
What should I discuss with my healthcare provider before taking Belvas?
You should not take Belvas if you are allergic to it, if you are pregnant or breast-feeding, or if you have active liver disease.
The following drugs can increase your risk of serious muscle problems if you take them together with Belvas. These drugs should not be used while you are taking Belvas:
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nefazodone;
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an antibiotic--clarithromycin, erythromycin, telithromycin;
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antifungal medication--itraconazole, ketoconazole, posaconazole, voriconazole;
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hepatitis C medications--boceprevir, telaprevir; or
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HIV/AIDS medication--atazanavir, cobicistat (Stribild, Tybost), darunavir, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir, tipranavir.
Before you start taking Belvas, tell your doctor if you are already using any of these other medicines:
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cyclosporine;
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danazol;
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gemfibrozil; or
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heart medication--amiodarone, diltiazem, dronedarone, ranolazine, verapamil.
To make sure Belvas is safe for you, tell your doctor if you have:
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history of liver or kidney disease;
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diabetes;
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a thyroid disorder; or
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if you drink more than 2 alcoholic beverages daily.
Belvas can cause a condition that results in the breakdown of skeletal muscle tissue, leading to kidney failure. This condition may be more likely to occur in older adults and in people who have kidney disease or poorly controlled hypothyroidism (underactive thyroid).
FDA pregnancy category X. This medicine can harm an unborn baby or cause birth defects. Do not take Belvas if you are pregnant. Stop taking this medication and tell your doctor right away if you become pregnant. Use effective birth control to avoid pregnancy while you are taking Belvas.
Belvas may pass into breast milk and could harm a nursing baby. Do not breast-feed while you are taking Belvas.
Belvas precautions
Hepatic Effects: Before treatment with Belvas begins, it is recommended that transaminase tests are performed and the tests be repeated periodically during treatment particularly in patients who have abnormal liver function tests and/or consume substantial quantities of alcohol. If serum transaminase levels increase no more than 3 times the upper limit of normal, the potential risk of continuing Belvas therapy should be carefully studied against the anticipated benefits. Transaminase measurements should be repeated promptly and if these elevations are persistent or progressive, therapy with Belvas should be discontinued.
Moderate elevation of serum transaminases have been reported soon after initiation of therapy with Belvas but these were transient and not accompanied by any symptoms. In such cases, discontinuation of therapy is not required.
Belvas should be cautiously used in patients with a previous history of liver disease.
Muscle Effects: Mild elevations of creatine phosphokinase levels are frequently observed in patients treated with Belvas but these are transient having no clinical significance. Myalgia has also been associated with Belvas therapy.
More rarely, myopathy has occurred and this should be taken into account for any patient with diffuse myalgias, muscle tenderness or weakness and/or marked elevation of creatine phosphokinase in which case, Belvas therapy should be discontinued.
Ophthalmic Evaluations: There are no indications that Belvas has an adverse effect on the human lens.
Homozygous Familial Hypercholesterolemia: In patients with the rare homozygous familial hypercholesterolemia, Belvas was less effective; possible because these patients have no functional LDL receptors.
Belvas appears to be more likely to raise serum transaminases.
Hypertriglyceridemia: Belvas is not indicated where hypertriglyceridemia is the abnormality of most concern (ie, hyperlipidemia types I, IV and V).
Use in children: Safety and effectiveness in children have not been established.
Use in the
Elderly: No apparent increase in the adverse effects in elderly patients has been observed.
What happens if I miss a dose of Belvas?
Take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take only the next regularly scheduled dose. Do not take extra medicine to make up the missed dose.
References
- DailyMed. "LOVASTATIN: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
- DrugBank. "lovastatin". http://www.drugbank.ca/drugs/DB00227 (accessed September 17, 2018).
- MeSH. "Hydroxymethylglutaryl-CoA Reductase Inhibitors". https://www.ncbi.nlm.nih.gov/mesh/68... (accessed September 17, 2018).
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Information checked by Dr. Sachin Kumar, MD Pharmacology
