Primobolan enanthate steroid is a selective, competitive inhibitor of HMG-CoA reductase inhibitors are the enzymes that determines the speed limit cholesterol biosynthesis responsible for the conversion of 3-hydroxy-3-methyl glyutaril-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. In the liver, triglycerides and cholesterol are included in the very low density lipoproteins (VLDL), enter in the blood plasma and transported to peripheral tissues. Low density lipoproteins (LDL) are formed from VLDL, which are catabolized primarily through interaction with high-affinity receptors of LDL. primobolan steroid reduces cholesterol levels th plasma lipoproteins by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the amount of ” liver “of LDL receptors on the cell surface, increasing the capture and catabolism of LDL. primobolan steroid reduces LDL production and the number of LDL particles. primobolan steroid causes marked and persistent increase in the activity of LDL receptors in combination with favorable changes in the quality of circulating LDL particles. Dozozawisimo reduces the level of LDL in patients with homozygous hereditary hypercholesterolemia resistant to therapy other gipolipidemicheskimy means. Research dose / effect relationships showed that primobolan steroid reduces total cholesterol (by 30-46%), LDL cholesterol (by 41-61%), apolipoprotein B (34-50 at%) (at 14-33%) and triglycerides while causing a greater or lesser extent, an increase in HDL cholesterol levels and apolipoprotein A. These results were similar in patients with heterozygous familial hypercholesterolemia, non-family forms of hypercholesterolemia, and mixed hyperlipidemia, including patients with non-insulin dependent diabetes mellitus. In connection with the reduction of total cholesterol, LDL cholesterol and apolipoprotein B decreases the risk of cardiovascular diseases and accordingly, it decreases the risk of death. Studies of the effect of primobolan steroid on cardiovascular morbidity and mortality has not yet been completed. When using the drug in elderly patients differences in safety, efficacy or achieve lipid-lowering therapy purposes in comparison with the general population were observed. Pharmacokinetics Absorption After oral administration, primobolan steroid is rapidly absorbed into the bloodstream. The maximum concentration (C max ) is reached within 1-2 hours, the plasma C max women above 20%, the area under “concentration-time” curve (AUC) – below 10%; C max in patients with alcoholic liver cirrhosis, increases by 16 times, AUC – and in time. Ingestion somewhat reduces the rate and duration of absorption of the drug (25% and 9% respectively) but cholesterol reduction is similar to that when receiving primobolan steroid without food. The absolute bioavailability of primobolan steroid is approximately 12%, sistemnaya- bioavailability determines inhibitory activity against HMG-CoA reductase – 30%. The low systemic bioavailability due to first pass metabolism in the mucosa of the gastrointestinal tract and “first pass” through the liver. The distribution mean volume of distribution of primobolan steroid is about 381 liters.Communication with the plasma proteins -98%. Metabolism primobolan steroid is metabolized primarily in the liver with the participation isozymes CYP3A4, CYP3A5 and CYP3A7 of cytochrome P450 with the formation of pharmacologically active metabolites (ortho and paragidroksilirovannyh derivatives, beta-oxidation products). In vitro metabolites paragidroksilirovannye ortho- and have an inhibitory effect on HMG-CoA reductase, comparable with that of primobolan steroid. . The inhibitory effect of the drug with respect to the HMG-CoA reductase inhibitor of approximately 70% is determined by the activity of circulating metabolites Excretion primobolan steroid is excreted mainly in the bile following hepatic and / or extrahepatic metabolism (not exposed to pronounced enterohepatic recirculation). The half-life – 14 hours. The inhibitory activity against HMG-CoA reductase remains about 20-30 hours due to the presence of active metabolites. Less than 2% of an oral dose is determined in urine. Not output during hemodialysis.
- in patients with primary hypercholesterolemia, heterozygous familial and non-familial hypercholesterolaemia and combined (mixed) hyperlipidemia (Type Pa and lib on Fredryksonu) in conjunction with diet to reduce elevated total cholesterol, LDL cholesterol, apolipoprotein B, and triglycerides and increase HDL cholesterol
- for the treatment of patients with elevated serum levels of triglycerides (type IV according Fredryksonu) and patients with disbetalipoproteinemiey (type III according Fredryksonu), whose diet therapy does not provide adequate effect
- in patients with homozygous familial hypercholesterolemia to reduce total cholesterol and LDL cholesterol when diet therapy and other non-pharmacological treatments are not sufficiently effective;
- Hypersensitivity to the drug;
- active liver disease or increased activity of “liver” enzymes of unknown origin (more than 3 times the upper limit of normal);
- hepatic failure (severity classification Child-Pugh A and B);
- age of 18 years (effectiveness and safety have been established)
Precautions: alcohol abuse, history of liver disease, severe electrolyte imbalance, endocrine and metabolic disorders, arterial hypotension, severe acute infection (sepsis), uncontrolled epilepsy, extensive surgery, trauma, skeletal muscle disease.
Pregnancy and lactation
primobolan steroid is contraindicated during pregnancy and breast-feeding.
It is not known whether primobolan steroid is excreted in breast milk. Given the potential for adverse effects in infants, if necessary, use during lactation should decide the issue of termination of breastfeeding.
Women of reproductive age during treatment should use adequate contraception. primobolan steroid can be administered to women of childbearing age only when the probability of pregnancy are very low, and the patient is informed about the possible risk of treatment to the fetus.
Dosing and Administration
Typically, the initial dose is 10 mg 1 time per day. The dose varies from 10 to 80 mg / day. The drug can be taken at any time of the day, once a day regardless of the meal. Dosages should be adjusted individually depending on the starting LDL cholesterol level, the goals of therapy and the patient’s response to treatment. At the beginning and / or during dose escalation Atorvatatina -Teva every 2-4 weeks is necessary to control the levels of lipids in blood plasma and accordingly to correct dose.
To carry out dose correction should be at intervals of not less than 4 weeks. The maximum daily dose is 80 mg.
For patients with established coronary heart disease (CHD) and other patients at high risk of cardiovascular complications, we recommend setting the following goals lipid levels of correction: LDL cholesterol less than 3.0 mmol / L (115 or less mg / dl) and total cholesterol less than 5.0 mmol / l (or less than 190 mg / dL). Primary hypercholesterolaemia and combined (mixed) hyperlipidaemia The majority of patients required control lipid levels provided by receiving 10 mg of primobolan steroid -Teva once a day. Significant therapeutic effect is usually observed after 4 weeks. With long-term treatment of this effect is maintained. Heterozygous familial hypercholesterolemia. Treatment of patients should begin with the appointment of 10 mg of primobolan steroid per day -Teva. By individual correction dose every 4 weeks, you should bring it up to 40 mg / day. You can then increase the dose to a maximum level of 80 mg / day, or use a combination of 40 mg primobolan steroid appointment -Teva and bile acid sequestrant. Homozygous familial hypercholesterolemia prescribed in a dose of 80 mg 1 time per day. . In patients with renal insufficiency, renal disease does not affect the concentration of primobolan steroid in the blood or plasma lipid-lowering degree when it is used; therefore, any dose adjustment for patients with renal disease is not required. In patients with hepatic failure. In liver failure may require dose reduction or withdrawal of the drug (cm. “special instructions” section).
Side effects The most commonly (1% or more): insomnia, headache, asthenic syndrome; nausea, diarrhea, abdominal pain, dyspepsia, flatulence, constipation; myalgia. Less commonly (less than 1%):Nervous system: malaise, dizziness, amnesia, paresthesia, peripheral neuropathy, hypoesthesia. From the digestive system: vomiting, anorexia, hepatitis, pancreatitis, holestatitcheskaya jaundice. From the musculoskeletal system: pain back pain, muscle cramps, myositis, myopathy, myalgia, arthralgia, rhabdomyolysis. Allergic reactions: urticaria, pruritus, rash, anaphylaxis, bullous eruption, polymorphic erythema (including Stevens-Johnson syndrome), Lyell’s syndrome, angioedema swelling. From the side of hematopoiesis: thrombocytopenia. metabolism: hypo- or hyperglycemia, elevated serum creatine phosphokinase (CPK). Other: impotence, peripheral edema, weight gain, pain in the chest, secondary renal failure, alopecia, noise tinnitus, fatigue. Most often develop adverse effects from the gastrointestinal tract: constipation, flatulence, dyspepsia, abdominal pain; These phenomena are usually subside with continued treatment. During clinical trials removal of the drug due to adverse events was required in less than 2% of patients.
No specific antidote. In case of overdose necessary symptomatic and supportive therapy should be carried out. It requires monitoring of liver function and CK levels in blood serum. Hemodialysis is ineffective.
The interaction with other drugs and other forms of interaction
risk of myopathy in the treatment of HMG-CoA reductase is increased when used in combination with cyclosporin, fibrate, macrolide antibiotics (including erythromycin), azole antifungal agents or nicotinic acid.
In some rare cases, these combinations cause rhabdomyolysis, accompanied by renal failure due to myoglobinuria. Therefore, careful evaluation of the risk-benefit ratio of the combined treatment (see. Section “Special instructions”). Inhibitors of CYP P450 isoenzyme pitohroma ZA4 metabolism of primobolan steroid is carried out with the participation of cytochrome P450 isoenzyme CYP 3A4. When using primobolan steroid in combination with inhibitors of cytochrome P450 CYP isoenzyme ZA4 (eg, cyclosporine, macrolide antibiotics such as erythromycin and clarithromycin, nefazodone, azole antifungals, such as itraconazole and HIV protease inhibitors), drug interactions can occur. With the combined use of drugs may experience increased plasma concentrations of primobolan steroid. In this connection, it should be very careful when using primobolan steroid in combination with the above drugs (see. The “Special instructions”). The simultaneous use of drugs that reduce the concentration of endogenous steroid hormones (including cimetidine, ketoconazole, spironolactone) increases reduce the risk of endogenous steroid goromonov (be careful). inhibitors of P-glycoprotein primobolan steroid and its metabolites are substrates for P-glycoprotein. Inhibitors of P-glycoprotein (e.g., cyclosporin) can increase the bioavailability of primobolan steroid. Erythromycin, clarithromycin With simultaneous use of primobolan steroid and erythromycin (500 mg four times / day.) And clarithromycin (500 mg, 2 times / day.) That inhibit cytochrome P450 ZA4, observed increase in primobolan steroid plasma concentrations. With the simultaneous use of primobolan steroid / 10 mg once / day.) and azithromycin (500p 1 time / day.) primobolan steroid plasma concentrations did not change. itraconazole The combined use of primobolan steroid 40 mg and itraconazole dose of 200 mg once a day showed an increase in AUC up to a level above normal three times. protease inhibitors Concomitant use of primobolan steroid with protease inhibitors, known as inhibitors of cytochrome P450 ZA4, accompanied by an increase in plasma concentrations of primobolan steroid. Grapefruit juice Grapefruit juice does not contain at least one ingredient is an inhibitor of CYP3A4, and may cause an increase in plasma concentrations of the drugs which are metabolized by CYP3A4. Daily consumption of 240 ml of grapefruit juice increased the AUC of primobolan steroid by 37% and decreased the AUC of the active metabolite ortogidroksi 20.4%.Consuming large amounts of grapefruit juice (1.2 liters per day for 5 days) primobolan steroid AUC increased 2.5 times, a AUC of active HMG-CoA reductase inhibitors (primobolan steroid metabolites +) – 1.3-fold.Therefore the consumption of large amounts of grapefruit juice during treatment with primobolan steroid is not recommended. Inducers of cytochrome P450. Exposure to drugs that induce CYP isoenzyme cytochrome P450 ZA4. (eg, rifampicin and phenazone) is unknown to primobolan steroid. The interactions with primobolan steroid and other substrates of this isoenzyme are not known; however, the ability of these interactions should be considered when using drugs with a low therapeutic index -. In particular, class III antiarrhythmics, such as amiodarone Gemfibrozil / Fibrates risk of myopathy caused primobolan steroid may increase with concomitant use of fibrates. In vitro studies indicate that gemfibrozil may also interact with primobolan steroid by inhibiting eiro glyukuronirovaniya that can cause increased plasma concentrations of primobolan steroid (sm. section “Special instructions”). Digoxin Repeated reception of digoxin and primobolan steroid 10 mg of the equilibrium concentrations digoxin in the blood plasma did not change. However, digoxin when applied in combination with primobolan steroid 80 mg / day. digoxin concentrations increased by approximately 20%. Patients receiving digoxin in combination with primobolan steroid should be observed. Oral contraceptives primobolan steroid in combination with an oral contraceptive containing ethinyl estradiol and norethisterone, norethisterone concentrations caused an increase in plasma and ethinylestradiol. These increasing concentrations should be considered when selecting oral contraceptive doses. With simultaneous use of primobolan steroid and oral contraceptives containing norethisterone and ethinyl estradiol, there was a significant increase in AUC of norethisterone and ethinyl estradiol by approximately 30% and 20%, respectively. This effect should be considered when selecting an oral contraceptive to women receiving primobolan steroid. Colestipol When administered colestipol in combination with primobolan steroid primobolan steroid was decreased plasma concentrations of approximately 25%. However, the combined use of primobolan steroid and colestipol effects on lipids was greater than when using each of these drugs alone. Antacids With simultaneous ingestion of primobolan steroid and a suspension containing magnesium and aluminum gidrokisid, primobolan steroid plasma concentration lowered by approximately 35%; however, the degree of reduction in LDL level is not changed. Warfarin When receiving primobolan steroid in combination with warfarin indicated a small decrease in prothrombin time during the first days of primobolan steroid; however, in the next 15 days ratio of prothrombin time returned to normal. Dark, however, in the case of joint use of primobolan steroid and warfarin, patients should be carefully monitored. Phenazone With simultaneous use of primobolan steroid does not affect the pharmacokinetics of phenazone, so interaction with other drugs metabolized by the same cytochrome isozymes are not expected. Cimetidine study combined administration of cimetidine and primobolan steroid revealed no significant interaction between these drugs. amlodipineIf concomitant administration of primobolan steroid 80 mg and 10 mg amlodipine changes pharmacokinetic parameters of primobolan steroid at steady state has been identified. Other There was no clinically significant adverse interaction of primobolan steroid and antihypertensive agents. Interaction studies with all specific drugs have not been conducted. primobolan steroid is not clinically significant effect on the concentration of terfenadine in the blood plasma, which is metabolized primarily by cytochrome P450 ZA4; therefore it seems unlikely that primobolan steroid can significantly affect the pharmacokinetic parameters of other P450 substrates ZA4.
Before starting therapy with primobolan steroid -Teva patient must assign a standard gipoholestesterinovuyu diet, which he must comply during the entire treatment period.
The use of inhibitors of HMG-CoA reductase inhibitors to reduce the level of lipids in the blood can lead to changes in biochemical parameters, refuses liver function, function liver should be monitored before treatment and after 6 weeks, 12 weeks after the start of primobolan steroid and improve after each dose, and periodically, for example every 6 months. The increased activity of “liver” enzymes in the blood serum may occur during therapy with primobolan steroid. Patients with marked increase in enzyme levels should be controlled to the level of enzymes return to normal. In the case of a persistent increase of ALT values (ALT) or aspartate aminotransferase (ACT) to a level exceeding by more than 3 times the upper allowable limit, it is recommended to reduce the dose of primobolan steroid -Teva or discontinue treatment.
primobolan steroid -Teva should be used with caution in patients who abuse alcohol and / or have liver disease. Active liver disease or persistent elevation of transaminases of unknown origin are contraindications to the appointment of primobolan steroid -Teva.
primobolan steroid treatment, like other inhibitors of HMG-CoA reductase inhibitors may cause myopathy. The diagnosis of myopathy (pain and weakness in the muscles, combined with increased activity of creatine phosphokinase (CPK) more than 10 times compared to the upper limit of normal) should be discussed in patients with widespread myalgia or muscle weakness and / or marked increase in activity of CK. Patients should be warned that they should immediately inform your doctor about poyavtenii unexplained pain or weakness in muscles, if accompanied by malaise or fever. primobolan steroid therapy should be discontinued in the event expressed increasing CPK or in the presence of confirmed or suspected myopathy. The risk of myopathy during treatment with other drugs in this class increased, while the use of cyclosporine, fibrates, erythromycin, niacin or azole antifungal agents. Many of these drugs inhibit the metabolism by cytochrome P450 mediated ZA4, and / or transport of drugs. primobolan steroid is biotransformed by the action of CYP ZA4.
By assigning primobolan steroid in combination with fibrates, erythromycin, immunosuppressive agents, azole antifungal agents or with nicotinic acid in a lipid-lowering doses must carefully evaluate the risks and potential benefits of the treatment and regularly monitor patients in order to detect pain or weakness in the muscles, especially during the first months of treatment and periods of increased dose of any drug.In such situations, we can recommend periodic determination of CPK activity, although such control does not prevent the development of severe myopathy.
In the application of primobolan steroid, as well as other tools in this class have been described cases of rhabdomyolysis with acute renal failure due to myoglobinuria.
primobolan steroid therapy should be suspended or completely cancel when the signs of myopathy or possible risk factors of renal insufficiency on the background of rhabdomyolysis (eg, severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures).
you must try before starting therapy with primobolan steroid -Teva achieve adequate control of hypercholesterolemia by diet therapy, physical activity, weight loss in obese patients, and the treatment of other conditions.
Effects on driving ability and work with the mechanisms of adverse effects of primobolan steroid on the ability to drive and work with the mechanisms have not been reported.