tahor drug Uses, Dosage, Side Effects, Precautions &Warnings  

tahor drug >> Generic drug of the therapeutic class: Cardiology and angiology
active principles: Atorvastatin

tahor drug uses and indication

TAHOR Dosage

Dosage

• Before starting treatment with TAHOR, the patient should follow a standard cholesterol-lowering diet. This diet will then continue for the duration of treatment with TAHOR.
• The dosage should be adjusted individually based on the initial levels of LDL-cholesterol, the therapeutic goal and the response to the patient’s treatment.
• The usual starting dose is 10 mg once a day. Dosage adjustment should be performed within a minimum interval of 4 weeks. The maximum dosage is 80 mg once a day.

Primary hypercholesterolemia and combined (mixed) hyperlipidemia

• Atorvastatin 10 mg once is sufficient in most patients. A therapeutic effect is observed after two weeks of treatment, the maximum effect being reached after 4 weeks of treatment. The effect is maintained in case of prolonged treatment.

Heterozygous familial hypercholesterolemia

• Treatment with TAHOR should start at a dose of 10 mg daily. The dose will then be individually adjusted every four weeks to 40 mg daily. Thereafter, the dosage can be increased up to 80 mg per day maximum. A bile acid chelator may also be prescribed in combination with atorvastatin 40 mg daily.

Homozygous familial hypercholesterolemia

• The available data are limited (see section on Pharmacodynamic properties ).
• In patients with homozygous familial hypercholesterolemia, the dose of atorvastatin ranges from 10 to 80 mg per day (see section 5.1 ). In these patients, atorvastatin should be administered in addition to other lipid-lowering drugs (including LDL-cholesterol apheresis) or when such treatments are not available.

Prevention of cardiovascular diseases

• In primary prevention studies, the dosage used was 10 mg / day. A higher dosage may be required to achieve the LDL-cholesterol (LDL) targets set by current guidelines.

Renal failure

No dose adjustment is required (see Warnings and Precautions ).

Hepatic insufficiency

• TAHOR should be used with caution in patients with hepatic impairment (see Warnings and Precautions and Pharmacokinetic Properties sections ). TAHOR is contraindicated in patients with active liver disease .

The elderly

• In patients over 70 years of age treated at the recommended doses, the efficacy and safety of use are similar to those seen in the general population.

Pediatric population

hypercholesterolemia

• Pediatric use should only be performed by physicians experienced in the treatment of pediatric hyperlipidemia and patients should be monitored regularly to assess progress.
• For patients with heterozygous familial hypercholesterolemia aged 10 years and older, the recommended initial dose of atorvastatin is 10 mg daily (see section 5.1 ). The dose can be increased up to 80 mg per day, depending on response and tolerance. Doses should be individualized according to the recommended therapeutic purpose. Adjustments should be made at least 4 weeks apart. The dose increase of up to 80 mg daily is supported by data from studies in adults and limited clinical data from studies in children with).
• The safety and efficacy data available in children with heterozygous familial hypercholesterolemia aged 6 to 10 years are limited and are from open label studies. Atorvastatin is not indicated for the treatment of patients under 10 years of age. Currently available data are described under Adverse Reactions , Pharmacodynamic Propertiesand Pharmacokinetic Properties, but no dosage recommendation can be made.
• Other dosage forms / dosages may be more appropriate for this population.

Administration mode

• TAHOR is for the oral route. Atorvastatin will be taken as a single daily dose regardless of the time of day, during or after meals.

Contraindications

TAHOR is contraindicated in patients:

• – hypersensitive to the active substance or to any of the excipients of this medication mentioned in the Composition section .
• – have active liver disease or have persistent and unexplained elevations in serum transaminases greater than three times the upper limit of normal

In women who are pregnant, breastfeeding or of childbearing potential and not using a reliable contraceptive method (see section Pregnancy and breast-feeding ).

How it works TAHOR?

Pharmacotherapeutic group: Lipid-lowering agents, HMG-CoA reductase inhibitors, ATC code: C10AA05.

• Atorvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the enzyme responsible for controlling the rate of biotransformation of 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a sterol precursor, and especially cholesterol .
• Hepatic triglycerides and cholesterol are incorporated into very low density lipoproteins (VLDL) and released into the plasma to reach peripheral tissues. Low density lipoproteins (LDL) are formed from VLDLs and are essentially catabolised at the high affinity receptors for LDL (LDL receptors).
• Atorvastatin decreases plasma cholesterol levels and serum lipoprotein concentrations by inhibiting HMG-CoA reductase and, as a result, hepatic cholesterol biosynthesis. Atorvastatin also increases the number of LDL receptors on the surface of hepatocytes, thereby enhancing uptake and catabolism of LDL.
• Atorvastatin decreases LDL synthesis and the number of LDL particles. It leads to a significant and prolonged increase in LDL receptor activity as well as a qualitative improvement of circulating LDL particles. Atorvastatin effectively reduces LDL-C in patients with homozygous familial hypercholesterolemia, a population usually resistant to other lipid-lowering drugs.
• A dose-response study has shown that atorvastatin reduces total cholesterol (30% to 46%), LDL-C (41% to 61%), apolipoprotein B (34% to 50%) and triglycerides (14% to 33%) and increased those of HDL-C and apolipoprotein A1. These results are also observed in patients with heterozygous familial hypercholesterolemia, non-familial hypercholesterolemia or mixed hyperlipidemia, as well as in patients with non-insulin-dependent diabetes mellitus.
• Decreases in total cholesterol, LDL-C, and apolipoprotein B have been shown to reduce the risk of cardiovascular events and cardiovascular deaths.

Homozygous familial hypercholesterolemia

• A multicenter, open-label, eight-week compassionate use trial with an optional extension phase of varying duration was performed in 335 patients, 89 of whom had homozygous familial hypercholesterolemia. In these 89 patients, the mean percentage decrease in LDL-C was approximately 20%. Atorvastatin has been administered at doses up to 80 mg / day.

atherosclerosis

• REVERSAL (Reversing Atherosclerosis with Aggressive Lipid-Lowering Study) investigated the effect on coronary atherosclerosis of intensive lipid-lowering therapy with atorvastatin 80 mg compared to standard lipid-lowering therapy with 40 mg pravastatin evaluated by intravascular ultrasound (IVUS) performed during angiography in patients with coronary artery disease. In this multicenter, double-blind, randomized, controlled trial, an IVUS was performed at inclusion and 18 months later in 502 patients. No progression of atherosclerosis was observed in the atorvastatin group (n = 253).
• The change in total atheromatous volume in percent (median) versus baseline (primary endpoint of the study) was -0.4% (p = 0.98) in the atorvastatin group and +2.7 % (p = 0.001) in the pravastatin group (n = 249). The effect obtained in the atorvastatin group compared to that obtained in the pravastatin group is significant (p = 0.02). The purpose of this study was not to investigate the effect of intensive lipid-lowering therapy on the occurrence of cardiovascular events (such as revascularization, the occurrence of non-fatal myocardial infarction, or death from coronary).
• In the atorvastatin group, the mean LDL-C level was reduced to 2.04 ± 0.8 mmol / l (78.9 ± 30 mg / dl) compared to the baseline value of 3.89 ± 0.7 mmol / l (150 ± 28 mg / dl). In the pravastatin group, the mean LDL-C level was reduced to 2.85 ± 0.7 mmol / l (110 ± 26 mg / dl) compared to the basal value of 3.89 ± 0.7 mmol / 1 (150 ± 26 mg / dl) (p <0.0001).
• Atorvastatin also significantly reduced the mean total cholesterol level by 34.1% (pravastatin group: -18.4%, p <0.0001), mean triglyceride levels by 20% (pravastatin group: -6, 8%, p <0.0009) and mean apolipoprotein B levels of 39.1% (pravastatin group: -22.0%, p <0.0001).
• Atorvastatin increased the mean HDL-C level by 2.9% (pravastatin group: + 5.6%, p = NS). An average reduction of 36.4% of the PCR rate was observed in the atorvastatin group, compared to a reduction of 5.2% in the pravastatin group (p <0.0001).
• The results of the study were obtained with the 80 mg assay and therefore can not be extrapolated to lower dosages.
• The safety and tolerability profiles were similar between the two treatment groups.
• This study was not intended to evaluate the effect of intensive lipid-lowering therapy on the occurrence of major cardiovascular events. The relationship between the imaging results obtained in this study and the clinical efficacy in terms of primary and secondary prevention of cardiovascular events is not established.

Acute Coronary Syndrome

• In the MIRACL study, 80 mg of atorvastatin was evaluated in 3086 patients (1538 patients in the atorvastatin group, 1548 patients in the placebo group) with acute coronary syndrome (non-Q wave myocardial infarction or unstable angina). Treatment was initiated during the acute phase after hospitalization and continued for 16 weeks. Treatment with atorvastatin 80 mg / day increased the time to occurrence of the primary composite endpoint, which included the occurrence of all-cause death, non-fatal myocardial infarction, resuscitated cardiac arrest, or angina with signs of ischemia. myocardium requiring hospitalization. The risk reduction was 16% (p = 0.048). This was mainly due to a 26% reduction in readmissions for angina with signs of myocardial ischemia (p = 0.018). The differences observed for the secondary endpoints were not statistically significant (placebo: 22.2%, atorvastatin: 22.4%).
• The safety profile of atorvastatin in the MIRACL study was consistent with that described in the Adverse Reactions section .

Prevention of cardiovascular disease

• The effect of atorvastatin on fatal and non-fatal coronary events was evaluated in a randomized, double-blind controlled versusplacebo, “The Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm” (ASCOT-LLA), in hypertensive patients aged 40 to 79 years, with no history of myocardial infarction or treated angina, and had CT ≤ 6.5 mmol / l (251 mg / dl). All patients had at least 3 of the following predefined cardiovascular risk factors: male sex, age (≥ 55 years), smoking, diabetes, history of coronary artery disease in a first degree relative, CT / HDL-C> 6, peripheral arterial disease, left ventricular hypertrophy, history of cerebrovascular accident, specific electrocardiographic abnormality, proteinuria / albuminuria. All included patients were not considered to be at high risk of first cardiovascular event.
• Patients received antihypertensive therapy with amlodipine or atenolol combined with either atorvastatin 10 mg / day (n = 5168) or placebo (n = 5137).

The effect of atorvastatin on relative and absolute risk reduction was:

Event	Relative risk reduction (%)	Nb. of events (atorvastatin vs. placebo)	Absolute risk reduction 1 (%)	P value
Coronary death and non-fatal myocardial infarction Total cardiovascular events and revascularization procedures Total coronary events	36%   20%   29%	100 vs 154 389 vs 483   178 vs 247	1.1%   1.9%   1.4%	0.0005   0.0008   0.0006

• ¹ Based on the difference in event rates after an average follow-up of 3.3 years.
• The decrease in total and cardiovascular mortality was not significant (185 versus 212 events, p = 0.17 and 74 versus 82 events, p = 0.51). Subgroup analyzes by sex (81% male, 19% female) showed atorvastatin benefit in men but not in women; this can be explained by the low number of events in the women’s group. The total and cardiovascular mortality was numerically higher in the group of women (38 versus 30 and 17 versus 12), but without reaching statistical significance. A significant interaction as a function of initial antihypertensive treatment was observed.
• Atorvastatin decreases the number of “coronary deaths and non-fatal MIs” (primary endpoint) in patients treated with amlodipine (HR 0.47 (0.32-0.69), p = 0.00008), unlike those treated with atenolol (HR 0.83 (0.59-1.17), p = 0.287).
• The effect of atorvastatin was also evaluated on the fatal and non-fatal cardiovascular events in the Collaborative Atorvastatin Diabetes Study (CARDS) study. This is a randomized, double-blind, multicenter, controlled versusplacebo conducted in patients with type 2 diabetes, aged 40 to 75 years with no history of cardiovascular disease, with an LDL-C levels ≤ 4.14 mmol / l (160 mg / dl) and a TG level ≤ 6.78 mmol / l (600 mg / dl).
• All patients had at least 1 of the following cardiovascular risk factors: hypertension, smoking, retinopathy, microalbuminuria or macroalbuminuria.
• Patients received either atorvastatin 10 mg daily (n = 1428) or placebo (n = 1410) for an average of 3.9 years.

The effect of atorvastatin on relative and absolute risk reduction was:

Event	Relative risk reduction (%)	Nb. of events (atorvastatin vs. placebo)	Absolute risk reduction 1(%)	P value
Major cardiovascular events (acute and non-fatal acute MI, asymptomatic MI, acute coronary death, unstable angina, CAP, PTCA, revascularization, stroke) IDM (acute, fatal, non-fatal, asymptomatic) Stroke (fatal and nonfatal acute)	37%           42%   48%	83 vs 127   38 vs 64   21 vs 39	3,2%           1.9%   1.3%	0.0010           0.0070   0.0163

¹ Based on the difference in event rates after an average of 3.9 years. MI: myocardial infarction; PAC:

• coronary artery bypass grafting; PTCA: percutaneous transluminal coronary angioplasty; Stroke: stroke.
• No difference in treatment effect was observed based on patient sex, age, or LDL-C at baseline. A favorable trend was observed in mortality (82 deaths in the placebo group versus 61 in the atorvastatin group, p = 0.0592).

Recurrence of strokes

• In SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels), the effect of atorvastatin 80 mg or placebo on stroke recurrence was evaluated in 4731 patients with stroke or transient ischemic attack (AIT) in the previous 6 months and no history of coronary heart disease. 60% of patients were men, aged 21 to 92 years (mean age: 63 years) with baseline LDL cholesterol levels of 133 mg / dl (3.4 mmol / l). The mean LDL-C level was 73 mg / dL (1.9 mmol / L) atorvastatin and 129 mg / dL (3.3 mmol / L) placebo. The average duration of follow-up was 4.9 years.
• In comparison to placebo, atorvastatin 80 mg decreased the risk of fatal or non-fatal stroke by 15% (primary endpoint), a relative risk of 0.85 (95% confidence interval: 0, 72-1.00, p = 0.05) or 0.84 (95% CI: 0.71-0.99, p = 0.03) after adjusting for baseline values. The all-cause mortality rate was 9.1% (216/2365) in patients treated with atorvastatin versus 8.9% (211/2366) in placebo-treated patients.
• A performed analysis a posteriori demonstrated that 80 mg of atorvastatin reduced the incidence of ischemic attacks of 9.2% (218/2365) versus 11.6% (274/2366) on placebo (p = 0.01), and increased the frequency of hemorrhagic stroke by 2.3% (55/2365) versus 1.4% (33/2366) on placebo (p = 0.02).
• The risk of haemorrhagic stroke was higher in the included patients with a history of haemorrhagic stroke (7/45 atorvastatin versus 2/48 at placebo), a relative risk of 4.06 (95% Confidence Interval) or 95% CI: 0.84-19.57).
• The risk of ischemic stroke was similar in both groups (3/45 atorvastatin versus 2/48 at placebo), a relative risk of 1.64 (95% CI: 0.27-9.82).
• The risk of haemorrhagic stroke was higher in the included patients with a history of lacunar infarction (20/708 with atorvastatin versus 4/701 with placebo), a relative risk of 4.99 (95% CI: 1, 71 to 14.61). The risk of ischemic stroke was lower in these patients (79/708 with atorvastatin versus 102/701 with placebo); a relative risk of 0.76 (95% CI: 0.57-1.02).
• The absolute risk of stroke may be higher in patients treated with 80 mg atorvastatin daily with a history of lacunar infarction.
• The all-cause mortality rate was 15.6% (7/45) atorvastatin versus 10.4% (5/48) in the subgroup of patients with a history of hemorrhagic stroke; this rate was 10.9% (77/708) on atorvastatin versus 9.1% (64/701) on placebo in the subgroup of patients with a history of lacunar infarction.

Pediatric population

Familial hypercholesterolemia heterozygous in pediatric patients aged 6 to 17 years

• An 8-week open-label study to evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of atorvastatin was conducted in children and adolescents with genetically-confirmed heterozygous familial hypercholesterolaemia and an initial LDL- C ≥ 4 mmol / L. A total of 39 children and adolescents aged 6 to 17 years were included. Cohort A included 15 children, ages 6 to 12, and being in Tanner stage 1. Cohort B included 24 children, aged 10 to 17, with a Tanner stage ≥ 2.
• The initial dose of atorvastatin was 5 mg daily as a chewable tablet in Cohort A and 10 mg daily as a tablet in Cohort B. The dose of atorvastatin could be doubled if the subject did not reach target LDL-C <3.35 mmol / L at Week 4 and if atorvastatin was well tolerated.
• Mean values ​​of LDL-C, Chol-T, VLDL-C and Apo B were decreased at Week 2 in all subjects. For subjects in whom the dose was doubled, an additional decrease was observed as early as 2 weeks, during the first measurement following the dose increase. Mean percent decreases in lipid parameters were similar in both cohorts, whether subjects remained at their initial dose or had their initial dose doubled. At Week 8, on average, percent change from baseline LDL-C and Chol-T levels were approximately 40% and 30%, respectively, regardless of dose.
• In a second open-label, non-comparative study, 271 boys and girls with heterozygous familial hypercholesterolemia aged 6 to 15 years were included and treated with atorvastatin for up to three years. Inclusion in this study required confirmed heterozygous familial hypercholesterolemia and an initial LDL-C level ≥ 4 mmol / L (approximately 152 mg / dL). The study included 139 children at stage I of Tanner’s development (usually between 6 and 10 years old). The dose of atorvastatin (once daily) started at 5 mg (chewable tablet) in children under 10 years of age. Children 10 years and older started on atorvastatin 10 mg (once daily). All children could benefit from increased doses to target LDL-C <3.35 mmol / L.
• The initial mean value (+/- standard deviation) of LDL-C was 6.12 (1.26) mmol / L, which corresponds to approximately 233 (48) mg / dL. See Table 3 below for the final results.
• The data were consistent with the lack of effect of the drug on all growth and development parameters (such as height, weight, BMI, Tanner stage, maturation investigator ratio, and overall development) in subjects pediatrics and adolescents with heterozygous familial hypercholesterolemia receiving atorvastatin treatment during the 3-year study. No effect of the drug was reported in the investigator’s report during visits as to height, weight, BMI by age or gender.

Table 3: Effects of atorvastatin on lipid lowering in adolescents with heterozygous familial hypercholesterolemia (mmol / L)

Steps	NOT	TC (standard deviation)	LDL-C (standard deviation)	HDL-C (standard deviation)	TG (standard deviation)	Apo B (standard deviation ) #
D0	271	7.86 (1.30)	6.12 (1.26)	1,314 (0.2663)	0.93 (0.47)	1.42 (0.28) **
Month 30	206	4.95 (0.77) *	3.25 (0.67)	1,327 (0.2796)	0.79 (0.38) *	0.90 (0.17) *
Month 36 / stop premature treatment	240	5.12 (0.86)	3.45 (0.81)	1.308 (0.2739)	0.78 (0.41)	0.93 (0.20) ***
TC = total cholesterol; LDL-C = low density C-lipoproteins; HDL-C = high density C-lipoproteins; TG = triglycerides; Apo B = apolipoprotein B; “Month 36 / Discontinuation of Premature Treatment” includes data from the final visit for patients whose participation ended before the 36-month period and complete data at 36 months for patients whose participation reached 36 months “*” = Month 30, the N for this parameter was 207; “**” = J0, the N for this parameter was 270; “***” = Month 36 / stop premature treatment, the N for this parameter was 243; “#” = G / L for Apo B.

Heterozygous Familial Hypercholesterolemia in Pediatric Patients Aged 10-17 Years

• In a double-blind, placebo-controlled study followed by an open-label phase, 187 postmenarche boys and girls aged 10 to 17 years (mean age 14.1 years) with heterozygous familial hypercholesterolemia (HF) or hypercholesterolemia were randomized and received atorvastatin (n = 140) or placebo (n = 47) for 26 weeks and all received atorvastatin for 26 weeks. The dose of atorvastatin (once daily) was 10 mg for the first 4 weeks and then increased to 20 mg if the LDL-C level was> 3.36 mmol / l. Atorvastatin significantly reduced plasma levels of Chol-T, LDL-C, triglycerides, and apolipoprotein B during the 26-week double-blind phase. The mean value of LDL-C reached was 3.38 mmol / l (range:
• An additional pediatric study evaluating atorvastatin versus colestipol in patients aged 10 to 18 years with hypercholesterolemia demonstrated that atorvastatin (N = 25) significantly reduced LDL-C at week 26 (p < 0.05) relative to colestipol (N = 31).
• A compassionate use study in patients with severe hypercholesterolemia (including homozygous hypercholesterolemia) included 46 pediatric patients treated with atorvastatin, the dose was tailored to the response (some subjects received 80 mg atorvastatin daily). The study lasted 3 years: LDL-cholesterol was decreased by 36%.
• The long-term effectiveness of atorvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.
• The European Medicines Agency has waived the obligation to submit the results of studies with atorvastatin in children aged 0 to less than 6 years in the treatment of heterozygous hypercholesterolemia and in children aged 0 to below 18 years in the treatment of homozygous familial hypercholesterolemia, mixed hypercholesterolemia, primary hypercholesterolemia and prevention of cardiovascular events (see Dosage and administration for information about the pediatric use).

What are the most common side effects of TAHOR?

In controlled clinical studies comparing the effect of atorvastatin with placebo in 16,066 patients (8755 TAHOR-treated patients, 7311 placebo-treated patients) treated for an average of 53 weeks, 5.2% of patients treated by atorvastatin discontinued treatment due to adverse events, compared to 4.0% of patients receiving placebo.

The following adverse reactions observed with atorvastatin are from clinical studies and significant experience gained since product marketing.

The estimated frequencies of adverse reactions are classified according to the following convention: common (≥ 1/100, <1/10); uncommon (≥ 1/1000, <1/100); rare (≥ 1/10000, <1/1000); very rare (<1/10000); indeterminate frequency (can not be estimated based on available data).

Infections and infestations

• Common: nasopharyngitis
• Blood and lymphatic system disorders
• Rare: thrombocytopenia.

Immune system disorders

• Common: allergic reactions
• Very rare: anaphylaxis.

Metabolism and nutrition disorders

• Frequent: hyperglycemia.
• Uncommon: hypoglycemia, weight gain, anorexia.

Psychiatric disorders

• Uncommon: nightmares, insomnia.

Nervous system disorders

• Frequent: headache.
• Uncommon: dizziness, paresthesia, hypoesthesia, dysgeusia, amnesia.
• Rare: peripheral neuropathy.

Eye disorders

• Uncommon: blurred vision.
• Rare: visual disturbances.

Affections of the ear and labyrinth

• Uncommon: tinnitus.
• Very rare: hearing loss.

Respiratory, thoracic and mediastinal disorders

• Common: pharyngolaryngeal pain, epistaxis.

Gastrointestinal disorders

• Common: constipation, flatulence, dyspepsia, nausea, diarrhea
• Uncommon: vomiting, upper and lower abdominal pain, belching, pancreatitis.

Hepatobiliary disorders

• Uncommon: Hepatitis
• Rare: cholestasis.
• Very rare: liver failure.

Skin and subcutaneous tissue disorders

• Uncommon: urticaria, rash, pruritus, alopecia.
• Rare: angioneurotic edema, bullous dermatosis including erythema multiforme, Stevens-Johnson syndrome and Lyell syndrome.

Musculoskeletal and connective tissue disorders

• Common: myalgia, arthralgia, extremity pain, muscle spasm, joint swelling, back pain.
• Uncommon: cervical pain, muscle fatigue.
• Rare: myopathy, myositis, rhabdomyolysis, tendinopathy, sometimes complicated by rupture.

Not known: necrotizing myopathy with autoimmune mediation (see Warnings and Precautions for Use section ).

Disorders of reproductive organs and breast

• Very rare: gynecomastia.

General disorders and administration site conditions

• Uncommon: malaise, asthenia, chest pain, peripheral edema, fatigue, pyrexia.

investigations

• Frequent: abnormal liver function tests, increased blood levels of creatine phosphokinase.
• Uncommon: leukocyturia.

As with other HMG-CoA reductase inhibitors, increases in serum transaminase levels have been reported in patients receiving TAHOR. These changes were usually mild and transient and did not necessitate discontinuation of treatment. Clinically significant increases (> 3 times the upper limit of normal) in serum transaminase levels were observed in 0.8% of patients treated with TAHOR. These increases were dose-dependent and reversible in all patients.

An increase in serum creatine phosphokinase (CPK) by more than three times the upper limit of normal was observed in 2.5% of patients on TAHOR, a proportion similar to that seen with other HMG-2 inhibitors. CoA reductase in clinical studies. Serum levels greater than 10 times the upper limit of normal were found in 0.4% of patients treated with TAHOR (see Warnings and Precautions ).

Pediatric population

• Atorvastatin-treated children 10 to 17 years of age have a generally similar adverse event profile to placebo-treated patients; the most common adverse events observed in both groups were infections, regardless of the causality assessment. No clinically significant effects on growth and sexual maturation were observed in a 3-year study based on the assessment of overall maturation and development, Tanner’s assessment and size and weight. The safety and safety profile in pediatric patients was similar to the known safety profile of atorvastatin in adult patients.
• The clinical pharmacovigilance database includes safety data for 520 pediatric patients who received atorvastatin, of which 7 patients were under 6 years of age, 121 patients were in the 6 to 9 year age group, and 392 patients were in an age range of 10 to 17 years. On the basis of available data, the frequency, type and severity of adverse reactions are similar in children and adults.

The following adverse events have been reported with some statins:

1. Sexual disorders.
2. Depression.
3. Exceptional cases of interstitial lung disease, especially during long-term treatment (see Warnings and Precautions section ).
4. Diabetes: The frequency depends on the presence or absence of risk factors (fasting blood glucose ≥ 5.6 mmol / l, BMI> 30 kg / m², increased triglyceride levels, history of hypertension).

TAHOR Interactions

Effect of certain medicinal products on the plasma concentration of atorvastatin

Atorvastatin is metabolized by cytochrome P450 3A4, and is also a substrate for protein transporters such as the OATP1B1 hepatocyte transporter.

Concomitant administration of CYP3A4 inhibitors or protein carriers may increase plasma concentrations of atorvastatin and lead to an increased risk of myopathy. The risk may also be increased when concomitant administration of atorvastatin with other drugs that may induce myopathies, such as fibrates and ezetimibe (see Warnings and Precautions ).

CYP3A4 inhibitors

• Atorvastatin plasma concentrations are significantly increased when combined with potent CYP3A4 inhibitors (see Table 1 and specific information below). The combination of potent CYP3A4 inhibitors (such as ciclosporin, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, etc.) should be avoided as far as possible. In cases where the combination of these drugs is needed, a lower initial dose and a lower maximum dose should be considered and careful clinical monitoring of the patient is recommended (see Table 1).
• Moderate inhibitors of CYP3A4 (such as erythromycin, diltiazem, verapamil, and fluconazole) may increase plasma concentrations of atorvastatin (see Table 1). An increased risk of myopathy has been observed when concomitant administration of erythromycin and statins.
• No interaction studies assessing the effects of amiodarone or verapamil on atorvastatin have been performed. Since amiodarone and verapamil are both known to inhibit CYP3A4 activity, their association with atorvastatin may result in increased exposure to atorvastatin.
• Therefore, a lower initial dose of atorvastatin should be prescribed and adequate clinical monitoring of the patient should be performed. Appropriate clinical monitoring is recommended after initiation of treatment or after dose adjustment of the CYP 3A4 inhibitor.

CYP3A4 inducers

• Concomitant administration of atorvastatin with a cytochrome P450 3A inducer (such as efavirenz, rifampicin, or St. John’s wort) may result in variable decreases in the plasma concentration of atorvastatin.
• Due to the dual mechanism of interaction of rifampicin (induction of cytochrome P450 3A and inhibition of the hepatocyte transporter OATP1B1), simultaneous administration of atorvastatin and rifampicin is advisable, as a separate administration of atorvastatin that of rifampicin has been associated with a significant decrease in plasma concentrations of atorvastatin.
• The effect of rifampicin on hepatocyte concentrations of atorvastatin is, however, unknown. If the combination is needed, the effectiveness of the treatment should be particularly monitored.

Inhibitors of carriers

• Transporters inhibitors (such as ciclosporin) may increase systemic exposure to atorvastatin (see Table 1). The effect of hepatocyte transporter inhibition on hepatocyte atorvastatin concentrations is unknown. If the combination is needed, the dose should be decreased and the efficacy of the treatment should be monitored (see Table 1).

Gemfibrozil / fibric acid derivatives

1. Treatment with fibrates alone is sometimes associated with muscle events, such as rhabdomyolysis. The risk of occurrence of these events may be increased when concomitant use of a derivative of fibric acid and atorvastatin. If combination therapy is needed, a lower dose of atorvastatin to achieve the therapeutic goal should be used and the patient should be followed up appropriately (see Warnings and Precautions section ).

ezetimibe

1. Ezetimibe alone is associated with muscle events, such as rhabdomyolysis. The risk of occurrence of these events can be increased if concomitant treatment with ezetimibe and atorvastatin. Adequate clinical monitoring of these patients is recommended.

colestipol

1. The combination of TAHOR and colestipol results in decreased plasma concentrations of atorvastatin and its active metabolites (ratio of atorvastatin concentration: 0.74). The lipid-lowering effects are, however, greater when TAHOR and colestipol are administered simultaneously compared to a separate administration.

Fusidic acid

1. The risk of myopathy, including rhabdomyolysis, may be increased by co-administration of systemic fusidic acid and statin. The mechanism of this interaction (whether pharmacodynamic, pharmacokinetic, or both) is still unknown. Cases of rhabdomyolysis (some fatal) have been reported in patients receiving this combination.
2. If treatment with systemic fusidic acid is required, treatment with atorvastatin should be discontinued for the duration of treatment with fusidic acid (see Warnings and Precautions ).

colchicine

1. Although no interaction studies between atorvastatin and colchicine have been performed, cases of myopathy have been reported in association with atorvastatin and colchicine. Care should be taken when prescribing atorvastatin with colchicine.

Effect of atorvastatin on combination drugs

digoxin

• At steady-state plasma concentrations of digoxin are slightly increased when concomitant administration of repeated doses of digoxin and atorvastatin 10 mg is used. Patients treated with digoxin should be adequately monitored.

Oral contraceptives

• Concomitant administration of TAHOR with an oral contraceptive resulted in increased plasma concentrations of norethindrone and ethinyl estradiol.

warfarin

• In a clinical study in patients receiving chronic warfarin therapy, concomitant atorvastatin 80 mg daily with warfarin induced a slight decrease in prothrombin time of approximately 1.7 the first 4 days of treatment, this time normalizing in the first 15 days of treatment with atorvastatin.
• Although only very rare cases of clinically significant anticoagulant interactions have been reported, prothrombin time should be determined prior to initiation of atorvastatin therapy in patients receiving coumarin-derived anticoagulants, and then at the beginning of treatment at one frequency. sufficient to ensure that no significant change in prothrombin time occurs. As soon as the stability of prothrombin time is reached, the prothrombin time can be followed at the frequency usually performed in patients treated with anticoagulants derived from coumarin. If the dose of atorvastatin is changed or treatment discontinued, the same procedure should be repeated. Treatment with atorvastatin

Pediatric population

• Drug interaction studies have only been performed in adults. The importance of interactions in the pediatric population is not known. The above mentioned interactions in adults and the precautions for use in the Warnings and Precautions for Use section should be taken into account for the pediatric population.

Drugs interactions

Table 1: Effect of drugs in combination with atorvastatin on pharmacokinetic parameters of atorvastatin

Drug administered in association and dosage	atorvastatin
	Dose (mg)	Ratio of the SSC &	Clinical recommendations #
Tipranavir 500 mg 2x / day / Ritonavir 200 mg 2x / day, 8 days (days 14 to 21)	40 mg on the 1st day, 10 mg on the 20th day	9.4	In the case where the combination of atorvastatin is necessary, do not exceed 10 mg / day of atorvastatin. Adequate clinical follow-up of these patients is recommended.
Telaprevir 750 mg every 8h, 10 days	20 mg DU	7.9
Ciclosporin 5.2 mg / kg / day, stable dose	10 mg 1x / day for 28 days	8.7
Lopinavir 400 mg 2x / day / Ritonavir 100 mg 2x / day, 14 days	20 mg 1x / day for 4 days	5.9	In cases where atorvastatin combination is required, a reduction in the maintenance dose of atorvastatin is recommended. At doses of atorvastatin> 20 mg, clinical monitoring of patients is recommended.
Clarithromycin 500 mg 2x / day, 9 days	80 mg 1x / day for 8 days	4.5
Saquinavir 400 mg 2x / day / Ritonavir (300 mg 2x / day from 5-7 days, increased to 400 mg 2x / day on day 8), days 4-18, 30 min after taking atorvastatin	40 mg 1x / day for 4 days	3.9	In cases where atorvastatin combination is required, a reduction in the maintenance dose of atorvastatin is recommended. At doses of atorvastatin> 40 mg, clinical monitoring of patients is recommended .
Darunavir 300 mg 2x / day / Ritonavir 100 mg 2x / day, 9 days	10 mg 1x / day for 4 days	3.4
Itraconazole 200 mg 1x / day, 4 days	40 mg DU	3.3
Fosamprenavir 700 mg 2x / day / Ritonavir 100 mg 2x / day, 14 days	10 mg 1x / day for 4 days	2.5
Fosamprenavir 1400 mg 2x / day, 14 days	10 mg 1x / day for 4 days	2.3
Nelfinavir 1 250 mg 2x / day, 14 days	10 mg 1x / day for 28 days	1.74	No specific recommendation.
Grapefruit juice, 240 ml 1x / day *	40 mg, DU	1.37	Consumption of large amounts of grapefruit juice is not recommended during treatment with atorvastatin.
Diltiazem 240 mg 1x / day, 28 days	40 mg, DU	1.51	Appropriate clinical monitoring of patients is recommended following initiation of treatment or dose adjustment of diltiazem.
Erythromycin 500 mg 4x / day, 7 days	10 mg, DU	1.33	A lower maximum dose and clinical monitoring of these patients is recommended.
Amlodipine 10 mg single dose	80 mg DU	1.18	No specific recommendation.
Cimetidine 300 mg 4x / day, 2 weeks	10 mg 1x / day for 2 weeks	1.00	No specific recommendation.
Colestipol 10 g 2x / day, 28 weeks	40 mg 1x / day for 28 weeks	0.74 **	No specific recommendation.
Antacid suspension of magnesium and aluminum hydroxides, 30 ml 4x / day, 17 days	10 mg 1x / day for 15 days	0.66	No specific recommendation.
Efavirenz 600 mg 1x / day, 14 days	10 mg for 3 days	0.59	No specific recommendation.
Rifampicin 600 mg 1x / day, 7 days (taken simultaneously)	40 mg DU	1.12	If combination therapy is necessary, concurrent administration of atorvastatin and rifampicin is recommended, with clinical follow-up.
Rifampicin 600 mg 1x / day, 5 days (divided doses)	40 mg DU	0.20
Gemfibrozil 600 mg 2x / day, 7 days	40 mg DU	1.35	A lower initial dose and clinical follow-up of patients are recommended.
Fenofibrate 160 mg 1x / day, 7 days	40 mg DU	1.03	A lower initial dose and clinical follow-up of patients are recommended.
Boceprevir 800 mg 3x / day, 7 days	40 mg DU	2.3	A lower initial dose and clinical follow-up of patients are recommended. The dose of atorvastatin should not exceed 20 mg daily during concomitant administration of boceprevir.

^& Represents the treatment ratio (co-administered drug plus atorvastatin versus atorvastatin alone).

^# See sections Warnings and precautions for use and Interactions with other medicinal products and other forms of interaction for clinical relevance.

* Contains one or more components that inhibit CYP3A4 and may increase plasma concentrations of drugs metabolized by CYP3A4. Taking a 240 ml glass of grapefruit juice also resulted in a 20.4% decrease in SSC of the active orthohydroxy metabolite. Large amounts of grapefruit juice (more than 1.2 liters per day for five days) increased by 2.5 times the atorvastatin AUC and that of the active substances (atorvastatin and metabolites) and by 1.3 times that inhibitors of HMG-CoA reductase.

** Ratio based on a single sample taken between 8 and 16 hours after taking the dose.

1x / day = once a day; DU = single dose; 2x / day = twice a day; 3x / day = three times a day; 4x / day = four times a day.

Table 2: Effect of Atorvastatin on the Pharmacokinetic Parameters of Co-Administered Drugs

Dosage of atorvastatin	Drug co-administered
	Dosage of the drug (mg)	Ratio of the SSC &	Clinical recommendations
80 mg 1x / day for 10 days	Digoxin 0.25 mg 1x / day, 20 days	1.15	Patients treated with digoxin should be adequately monitored.
40 mg 1x / day for 22 days	Oral contraceptive 1x / day, 2 months – norethindrone 1 mg – 35mg ethinylestradiol	1.28 1.19	No specific recommendation.
80 mg 1x / day for 15 days	* Phenazone, 600 mg DU	1.03	No specific recommendation.
10 mg, DU	Tipranavir 500 mg 2x / day / Ritonavir 200 mg 2x / day, 7 days	1.08	No specific recommendation.
10 mg, 1x / day for 4 days	Fosamprenavir 1400 mg 2x / day, 14 days	0.73	No specific recommendation.
10 mg 1x / day for 4 days	Fosamprenavir 700 mg 2x / day / Ritonavir 100 mg 2x / day, 14 days	0.99	No specific recommendation.

^& Represents the treatment ratio (co-administered drug plus atorvastatin versus atorvastatin alone). ^* Co-administration of repeated doses of atorvastatin and phenazone has exercised little or no detectable effect on the clearance of phenazone.

1x / day = once a day; DU = single dose; 2x / day = twice a day.

Warnings and Precautions

Liver effects

• Hepatic functional tests should be performed before the start of treatment and regularly after the start of treatment. Liver function tests should be performed in patients with signs or symptoms suggestive of hepatic impairment.
• Patients with elevated serum transaminases should be monitored until normalized.
• If persistent transaminase elevations above three times the upper limit of normal (ULN), the dose should be reduced or TAHOR should be stopped (see section Undesirable effects ).
• TAHOR should be used with caution in patients who consume significant amounts of alcohol and / or have a history of liver disease.

Prevention of Stroke by Aggressive Decrease in Cholesterol Levels (SPARCL Study)

• In a post hoc analysis performed in subgroups of patients with recent stroke or transient ischemic attack (TIA) but no coronary insufficiency, a higher frequency of hemorrhagic stroke was observed in treated patients. 80 mg of atorvastatin compared to placebo patients.
• This high risk is particularly observed in patients who have already had a haemorrhagic stroke or a lacunar infarction at the inclusion of the study.
• In patients with a history of haemorrhagic stroke or lacunar infarction, the benefit / risk balance of atorvastatin 80 mg is uncertain. As a result, the potential risk of haemorrhagic stroke should be carefully assessed before initiation of treatment.

Effects on skeletal muscles

• Atorvastatin, like other HMG-CoA reductase inhibitors, may, in rare cases, affect skeletal muscle and lead to myalgia, myositis and myopathies that may progress to potentially fatal rhabdomyolysis with high levels of creatine phosphokinase (CPK) (> 10 times ULN), myoglobinemia and myoglobinuria may cause renal failure.
• Very rare cases of autoimmune necrotizing myopathies (IMNM) have been reported during or after treatment with some statins. IMNM is clinically characterized by persistent proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin therapy.

Before initiation of treatment

Atorvastatin should be prescribed with caution in patients with predisposing factors for rhabdomyolysis. Before starting statin therapy, the CPK rate should be measured in the following situations:

• Renal insufficiency;
• Hypothyroidism;
• Personal or family history of hereditary muscular diseases;
• History of muscle toxicity during treatment with a statin or fibrate;
• History of liver disease and / or excessive alcohol consumption;
• In elderly patients (> 70 years of age), the need for these measures should be assessed, depending on the presence of other factors predisposing to rhabdomyolysis;
• Situations where increased plasma concentrations may occur as a result of interactions, and use in special populations including genetic polymorphisms.

In these situations, a regular reassessment of the benefit / risk of treatment, as well as regular clinical monitoring, is recommended.

If the basal CPK level is significantly elevated (> 5 times the ULN) treatment should not start.

Measurement of creatine phosphokinase

• Measurement of creatine phosphokinase (CPK) should not be performed after significant physical exercise or in the presence of factors that may increase the rate, the interpretation of results being difficult in these cases. If there is a significant elevation of CPK (> 5 ULN) before treatment, a check will be performed 5 to 7 days later to confirm the results.

During treatment

• Patients should be prompted to promptly report any unexplained muscular pain, cramps, or muscle weakness, particularly if accompanied by discomfort or fever.
• If these symptoms occur during treatment with atorvastatin, a CPK assay should be performed. If CPK is significantly elevated (> 5 ULN), treatment should be discontinued.
• If these symptoms are severe and cause daily discomfort, discontinuation of treatment should be considered, even if the CPK level is equal to or less than 5 times the ULN.
• If symptoms subside and CPK levels are normalized, restarting atorvastatin or other statin therapy may be considered at the lowest dose under close supervision.
• Atorvastatin therapy should be discontinued if there is a clinically significant increase in CPK (> 10 times the ULN) or if rhabdomyolysis is diagnosed or suspected.

Association with other drugs

• The risk of rhabdomyolysis is increased when atorvastatin is administered in combination with certain drugs that may increase the plasma concentration of atorvastatin, such as potent CYP3A4 inhibitors or protein transporters (ciclosporin, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, etc.). The risk of myopathy may also be increased in combination with gemfibrozil and other fibrates, boceprevir, erythromycin, niacin, ezetimibe, telaprevir, or the tipranavir / ritonavir combination.
• In the case where the combination of these drugs is necessary, the benefit / risk of concomitant treatments should be carefully evaluated. A lower maximum dose is recommended in patients receiving drugs that may increase plasma concentrations of atorvastatin. Similarly, when combined with strong CYP3A4 inhibitors, a lower starting dose of atorvastatin should be used and close clinical monitoring is recommended .
• Atorvastatin should not be administered concomitantly with fusidic acid in systemic form and for up to 7 days following discontinuation of fusidic acid therapy. In patients where the use of systemic fusidic acid is considered essential, statin therapy should be discontinued throughout treatment with fusidic acid. Cases of rhabdomyolysis (some fatal) have been reported in patients receiving fusidic acid and a statin in combination . Patients should be informed of the need for immediate medical attention if they experience symptoms of muscle weakness,
• Statin therapy may be reintroduced seven days after the last dose of fusidic acid.
• In exceptional circumstances, when prolonged treatment with systemic fusidic acid is necessary, for example for the treatment of severe infections, the need for co-administration of TAHOR and fusidic acid should be considered only in case by case and under close medical supervision.

Pediatric population

• No clinically significant effects on growth and sexual maturation were observed in a 3-year study based on the assessment of overall maturation and development, the Tanner classification assessment and the size and weight (see section on side effects ).

Interstitial lung disease

• Exceptional cases of interstitial lung disease have been reported with certain statins, particularly in the case of long-term treatment (see section 4.8 ). Symptoms include dyspnea, nonproductive cough, and general impairment of health (fatigue, weight loss, and fever). If there is suspicion of interstitial lung disease in a patient, statin therapy should be discontinued.

Diabetes

• Some data suggest that statins as a pharmacological class, would increase blood sugar. In some patients at high risk of developing diabetes, statins may cause hyperglycaemia requiring the initiation of antidiabetic therapy. This risk is nevertheless offset by the reduction of the vascular risk under statins and consequently it must not be a reason for stopping statins. Patients at risk (fasting plasma glucose between 5.6 and 6.9 mmol / l, BMI> 30 kg / m², increased triglyceride levels, high blood pressure) should be clinically and biologically national recommendations.

excipients

• TAHOR contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency and glucose-galactose malabsorption should not take this medicine.

TAHOR and PREGNANCY / BREAST FEEDING / FERTILITY

Pregnancy 

• Tahor is contraindicated during pregnancy ( see Contraindications ). The safety of atorvastatin has not been established in pregnant women. No controlled clinical trials have been conducted in pregnant women treated with atorvastatin. Following intrauterine exposure to HMG-CoA reductase inhibitors, congenital anomalies have been reported rarely. Studies in animals have shown reproductive toxicity ( see Preclinical Safety ).
• Treatment of the mother with atorvastatin may reduce the fetal level of mevalonate, a precursor to cholesterol biosynthesis. Atherosclerosis is a chronic process, and discontinuing a lipid-lowering drug during pregnancy should generally have little effect on the long-term risk associated with primary hypercholesterolemia.
• For these reasons, Tahor should not be used during pregnancy, or in a woman planning a pregnancy or in which a pregnancy is suspected. Treatment with Tahor must be suspended during pregnancy or until it has been determined that the woman is not pregnant ( see Contraindications ).

Breastfeeding

• It is not known if atorvastatin or its metabolites are excreted in breast milk. In rats, plasma concentrations of atorvastatin and its active metabolites are similar to those found in milk ( see Preclinical safety ).
• Due to the possibility of serious side effects, women treated with Tahor should not breast-feed their infants ( see Contraindications ). Atorvastatin is contraindicated during breastfeeding ( see Contraindications ).

Fertility

• No effect of atorvastatin on fertility has been demonstrated in studies conducted in either male or female animals ( see Preclinical Safety ).

What happens if I overdose from TAHOR ?

• There is no specific treatment for overdosage with atorvastatin. In case of overdose, treatment should be symptomatic and appropriate accompanying measures should be implemented as needed.
• Liver function and CPK levels should be monitored. Because of the importance of atorvastatin binding to plasma proteins, hemodialysis is not expected to significantly increase the clearance of atorvastatin.

What is  Forms and Composition?

• 10 mg film-coated tablet (white, round, 5.6 mm diameter, engraved “10” on one side and “ATV” on the other side), 20 mg (white, round, 7.1 mm diameter, engraved “20” on one side and “ATV” on the other side), 40 mg (white, round, 9.5 mm in diameter, engraved “40” on one side and “ATV” on the other side), and 80 mg (white, round, 11.9 mm in diameter, engraved “80” on one side and “ATV” on the other side):   Boxes of 28, under blister packs of 7; boxes of 90, blister packs of 10.
• Hospital models: Boxes of 50, blister packs of 10.
  10 mg chewable tablet (white to off-white, with pink to purple spots, round, engraved with “10” on one side and “LCT” on the other side, measuring 7.1 mm in diameter) and 20 mg (white to off-white, with pink to purple spots, round, engraved with “20” on one side and “LCT” on the other side, 8.7 mm in diameter):  Boxes of 30, under blister packs .

NOT’s

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general information:

• Includes a general description of the drug, its use, brand names, FAQs, and relevant news and articles

Additional information:

• General explanation about dealing with the medicine: how to take the medicine, the doses and times of it, the start and duration of its effectiveness, the recommended diet during the period of taking the medicine, the method of storage and storage, recommendations in cases for forgetting the dose and instructions to stop taking the drug and take additional doses.

Special warnings:

• For pregnant and breastfeeding women, the elderly, boys and drivers, and use before surgery.

Side effects:

• It treats possible side effects and drug interactions that require attention and its effect on continuous use.
• The information contained in this medicine is based on medical literature, but it is not a substitute for consulting a doctor.