Atorvastatin Viatris 10 mg, 20 mg, 40 mg & 80 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 10 mg atorvastatin (as atorvastatin calcium trihydrate).
Each film-coated tablet contains 20 mg atorvastatin (as atorvastatin calcium trihydrate).
Each film-coated tablet contains 40 mg atorvastatin (as atorvastatin calcium trihydrate).
Each film-coated tablet contains 80 mg atorvastatin (as atorvastatin calcium trihydrate).

Excipient with known effect:
Each tablet contains 42.5 mg lactose (as anhydrous lactose).
Each tablet contains 85 mg lactose (as anhydrous lactose).
Each tablet contains 170 mg lactose (as anhydrous lactose).
Each tablet contains 340 mg lactose (as anhydrous lactose).

4.2 Posology and method of administration

Posology
The patient should be placed on a standard cholesterol-lowering diet before receiving atorvastatin and should continue on this diet during treatment with Atorvastatin Mylan.

The dose should be individualised according to baseline LDL-C levels, the goal of therapy, and patient response.

The usual starting dose is 10 mg once a day. Adjustment of dose should be made at intervals of 4 weeks or more. The maximum dose is 80 mg once a day.

Primary hypercholesterolaemia and combined (mixed) hyperlipidaemia
The majority of patients are controlled with Atorvastatin Mylan 10 mg once a day. A therapeutic response is evident within 2 weeks, and the maximum therapeutic response is usually achieved within 4 weeks. The response is maintained during chronic therapy.

Heterozygous familial hypercholesterolaemia
Patients should be started with Atorvastatin Mylan 10 mg daily. Doses should be individualised and adjusted every 4 weeks to 40 mg daily. Thereafter, either the dose may be increased to a maximum of 80 mg daily or a bile acid sequestrant may be combined with 40 mg atorvastatin once daily.

Homozygous familial hypercholesterolaemia
Only limited data are available (see section 5.1)
The dose of atorvastatin in patients with homozygous familial hypercholesterolemia hypercholesterolaemia is 10 to 80 mg daily (see section 5.1). Atorvastatin should be used as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) in these patients or if such treatments are unavailable.

Hypercholesterolaemia
Paediatric use should only be carried out by physicians experienced in the treatment of paediatric hyperlipidaemia and patients should be re-evaluated on a regular basis to assess progress.

For patients with Heterozygous Familial Hypercholesterolemia aged 10 years and above, the recommended starting dose of atorvastatin is 10 mg per day (see section 5.1). The dose may be increased to 80 mg daily, according to the response and tolerability. with titration up to 20 mg per day.
Doses should be individualised according to the recommended goal of therapy. Adjustments should be made at intervals of 4 weeks or more. The dose titration to 80 mg daily is supported by study data in adults and by limited clinical data from studies in children with Heterozygous Familial Hypercholesterolemia (see sections 4.8 and 5.1).Titration should be conducted according to the individual response and tolerability in paediatric patients. Safety information for paediatric patients treated with doses above 20 mg, corresponding to about 0.5 mg/kg is limited.

There is are limited safety and efficacy data available experience in children with Heterozygous Familial Hypercholesterolemia between 6-10 years of age derived from open-label studies(see section 5.1). Atorvastatin is not indicated in the treatment of patients below the age of 10 years.
Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation on a posology can be made.

Paediatric population

No clinically significant effect on growth and sexual maturation was observed in a 3year study based on the assessment of overall maturation and development, assessment of Tanner Stage, and measurement of height and weight (see section 4.8). Developmental safety in the paediatric population has not been established (see section 4.8).

4.5 Interaction with other medicinal products and other forms of interaction

Effect of co-administered medicinal products on atorvastatin

Atorvastatin is metabolised metabolized by cytochrome P450 3A4 (CYP3A4) and is a substrate to transport proteins e.g. the hepatic uptake transporter OATP1B1. Concomitant administration of medicinal products that are inhibitors of CYP3A4 or transport proteins may lead to increased plasma concentrations of atorvastatin and an increased risk of myopathy. The risk might also be increased at concomitant administration of atorvastatin with other medicinal products that have a potential to induce myopathy, such as fibric acid derivatives and ezetimibe (see section 4.4).

Ezetimibe
The use of ezetimibe alone is associated with muscle related events including rhabdomyolysis. The risk of these events may therefore be increased with concomitant use of ezetimibe and atorvastatin. Appropriate clinical monitoring of the these patients is recommended.

Colestipol
Plasma concentrations of atorvastatin and its active metabolite metabolites were lower (ratio of atorvastatin concentration: 0.74 by approx 25 %) when colestipol was co-administered with atorvastatin. However, lipid effects were greater when Atorvastatin Mylan atorvastatin and colestipol were co-administered than when either medicinal product was given alone.

Oral Contraceptives
Co-administration of Atorvastatin Mylan atorvastatin with an oral contraceptive produced increases in plasma concentrations of norethindrone and ethinyl oestradiol.

& Represents ratio of treatments (co-administered drug plus atorvastatin versus atorvastatin alone). Data given as x-fold change represent a simple ratio between co-administration and atorvastatin alone (i.e., 1-fold = no change). Data given as % change represent % difference relative to atorvastatin alone (i.e., 0% = no change).
# See sections 4.4 and 4.5 for clinical significance.
* Contains one or more components that inhibit CYP3A4 and can increase plasma concentrations of medicinal products metabolised metabolized by CYP3A4. Intake of one 240 ml glass of grapefruit juice also resulted in a decreased AUC of 20.4% for the active orthohydroxy metabolite. Large quantities of grapefruit juice (over 1.2 l daily for 5 days) increased AUC of atorvastatin 2.5 fold and AUC of active (atorvastatin and metabolites). HMG-CoA reductase inhibitors 1.3 fold.
** Ratio based on a single sample taken 8-16 h post dose.
^ Total atorvastatin equivalent activity
Increase is indicated as “↑”, decrease as “↓”
OD = once daily; SD = single dose; BID = twice daily; TID = three times daily; QID = four times daily

& Represents ratio of treatments (co-administered drug plus atorvastatin versus atorvastatin alone). Data given as % change represent % difference relative to atorvastatin alone (i.e., 0% = no change)
* Co-administration of multiple doses of atorvastatin and phenazone showed little or no detectable effect in the clearance of phenazone.
Increase is indicated as “↑”, decrease as “↓”
OD = once daily; SD = single dose; BID = twice daily

4.6 Fertility, pregnancy and lactation

Pregnancy
Atorvastatin Mylan is contra-indicated contraindicated during pregnancy (see section 4.3). Safety in pregnant women has not been established. No controlled clinical trials with atorvastatin have been conducted in pregnant women. Rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been received. Animal studies Studies in animals have shown toxicity to reproduction (see section 5.3).

Maternal treatment with atorvastatin may reduce the foetal levels of mevalonate which is a precursor of cholesterol biosynthesis. Atherosclerosis is a chronic process, and ordinarily discontinuation of lipid-lowering medicinal products during pregnancy should have little impact on the long-term risk associated with primary hypercholesterolaemia.

For these reasons, Atorvastatin Mylan should not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with Atorvastatin Mylan should be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant (see section 4.3).

Breast feeding Breastfeeding
It is not known whether atorvastatin or its metabolites are excreted in human milk. In rats, plasma concentrations of atorvastatin and its active metabolites are similar to those in milk (see section 5.3). Because of the potential for serious adverse reactions, women taking Atorvastatin Mylan should not breast-feed their infants (see section 4.3). Atorvastatin is contraindicated during breastfeeding (see section 4.3).

4.8 Undesirable effects

In the atorvastatin placebo-controlled clinical trial database of 16,066 (8755 atorvastatin vs. 7311 placebo) patients treated for a mean period of 53 weeks, 5.2% of patients on atorvastatin discontinued due to adverse reactions compared to 4.0% of the patients on placebo.

Based on data from clinical studies and extensive post-marketing experience, the following table presents the adverse reaction profile for Atorvastatin Mylan atorvastatin.

Estimated frequencies of reactions are ranked according to the following convention: Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1,000 to < 1/100); Rare (≥ 1/10,000 to < 1/1,000); Very rare (< 1/10,000), Not known (cannot be estimated from the 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
Common: hyperglycaemia.
Uncommon: hypoglycaemia, weight gain, anorexia

Psychiatric disorders
Uncommon: nightmare, insomnia.

Nervous system disorders
Common: headache.
Uncommon: dizziness, paraesthesia, hypoesthesia, dysgeusia, amnesia.
Rare: peripheral neuropathy.

Eye disorders
Uncommon: vision blurred.
Rare: visual disturbance.

Ear and labyrinth disorders
Uncommon: tinnitus
Very rare: hearing loss.

Respiratory, thoracic and mediastinal disorders
Common: pharyngolaryngeal pain, epistaxis.

Gastrointestinal disorders
Common: constipation, flatulence, dyspepsia, nausea, diarrhoea.
Uncommon: vomiting, abdominal pain upper and lower, eructation, pancreatitis.

Hepatobiliary disorders
Uncommon: hepatitis.
Rare: cholestasis.
Very rare: hepatic failure.

Skin and subcutaneous tissue disorders
Uncommon: urticaria, skin rash, pruritus, alopecia.
Rare: angioneurotic oedema, dermatitis bullous including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders
Common: myalgia, arthralgia, pain in extremity, muscle spasms, joint swelling, back pain.
Uncommon: neck pain, muscle fatigue.
Rare: myopathy, myositis, rhabdomyolysis with or without acute renal failure, tendonopathy, sometimes complicated by rupture.
Not known: immune-mediated necrotising myopathy (see section 4.4).

Reproductive system and breast disorders
Very rare: gynecomastia.

General disorders and administration site conditions
Uncommon: malaise, asthenia, chest pain, peripheral oedema, fatigue, pyrexia.

Investigations
Common: liver function test abnormal, blood creatine kinase increased.
Uncommon: white blood cells urine positive.

As with other HMG-CoA reductase inhibitors elevated serum transaminases have been reported in patients receiving Atorvastatin Mylan atorvastatin. These changes were usually mild, and transient and did not require interruption of treatment. Clinically important (> 3 times upper normal limit) elevations in serum transaminases occurred in 0.8% of the patients on Atorvastatin Mylan atorvastatin. These elevations were dose related and were reversible in all patients.

Elevated creatine kinase (CK) levels greater than 3 times upper limit of normal occurred in 2.5% of the patients on Atorvastatin Mylanatorvastatin, similar to other HMG-CoA reductase inhibitors in clinical trials. Levels above 10 times the normal upper range occurred in 0.4% Atorvastatin Mylan atorvastatin-treated patients (see section 4.4.).

Paediatric population

Paediatric patients aged from 10 to 17 years of age treated with atorvastatin had an adverse experience profile generally similar to that of patients treated with placebo, the most common adverse experiences observed in both groups, regardless of causality assessment, were infections. No clinically significant effect on growth and sexual maturation was observed in a 3 year study based on the assessment of overall maturation and development, assessment of Tanner Stage, and measurement of height and weight. The safety and tolerability profile in paediatric patients was similar to the known safety profile of atorvastatin in adult patients.

The clinical safety database includes safety data for 249 520 paediatric patients who received atorvastatin, among which 7 patients were < 6 years old, 14 121 patients were in the age range of 6 to 9, and 228 392 patients were in the age range of 10 to 17. Based on the data available, the frequency, type and severity of adverse reactions in children is similar to adults.

Nervous system disorders
Common: Headache

Gastrointestinal disorders
Common: Abdominal pain

Investigations
Common: Alanine aminotransferase increased, blood creatine phosphokinase increased

Based on the data available, frequency, type and severity of adverse reactions in children are expected to be the same as in adults. There is currently limited experience with respect to long term safety in the paediatric population.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; e-mail: medsafety@hpra.ie.

4.9 Overdose

Specific treatment is not available for Atorvastatin Mylan atorvastatin overdose. Should an overdose occur, the patient should be treated symptomatically and supportive measures instituted, as required. Liver function tests should be performed and serum CK levels should be monitored. Due to extensive atorvastatin binding to plasma proteins, haemodialysis is not expected to significantly enhance atorvastatin clearance.

5.1 Pharmacodynamic properties

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

Mechanism of action
Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme responsible for the conversion of 3-hydroxy-3-methyl-glutarylcoenzyme A to mevalonate, a precursor of sterols, including cholesterol. Triglycerides and cholesterol in the liver are incorporated into very low-density lipoproteins (VLDL) and released into the plasma for delivery to peripheral tissues. Low-density lipoprotein (LDL) is formed from VLDL and is catabolised catabolized primarily through the receptor with high affinity to LDL (LDL receptor).

Paediatric population

Heterozygous Familial Hypercholesterolaemia in Paediatric Patients aged 6-17 years old

An 8-week, open-label study to evaluate pharmacokinetics, pharmacodynamics, and safety and tolerability of atorvastatin was conducted in children and adolescents with genetically confirmed heterozygous familial hypercholesterolaemia and baseline LDL-C ≥4 mmol/L. A total of 39 children and adolescents, 6 to 17 years of age, were enrolled. Cohort A included 15 children, 6 to 12 years of age and at Tanner Stage 1. Cohort B included 24 children, 10 to 17 years of age and at Tanner Stage ≥ 2.

The initial dose of atorvastatin was 5 mg daily of a chewable tablet in Cohort A and 10 mg daily of a tablet formulation in Cohort B. The atorvastatin dose was permitted to be doubled if a subject had not attained target LDL-C of <3.35 mmol/L at Week 4 and if atorvastatin was well tolerated.

Mean values for LDL-C, TC, VLDL-C, and Apo B decreased by Week 2 among all subjects.
For subjects whose dose was doubled, additional decreases were observed as early as 2 weeks, at the first assessment, after dose escalation. The mean percent decreases in lipid parameters were similar for both cohorts, regardless of whether subjects remained at their initial dose or doubled their initial dose. At Week 8, on average, the percent change from baseline in LDL-C and TC was approximately 40% and 30%, respectively, over the range of exposures.

In a second open label, single arm study, 271 male and female HeFH children 6-15 years of age were enrolled and treated with atorvastatin for up to three years. Inclusion in the study required confirmed HeFH and a baseline LDL-C level ≥ 4 mmol/L (approximately 152 mg/dL). The study included 139 children at Tanner 1 developmental stage (generally ranging from 6-10 years of age). The dosage of atorvastatin (once daily) was initiated at 5 mg (chewable tablet) in children less than 10 years of age. Children age 10 and above were initiated at 10 mg atorvastatin (once daily). All children could titrate to higher doses to achieve a target of < 3.35 mmol/L LDL-C. The mean weighted dose for children aged 6 to 9 years was 19.6 mg and the mean weighted dose for children aged 10 years and above was 23.9 mg.
The mean (± SD) baseline LDL-C value was 6.12 (1.26) mmol/L which was approximately 233 (48) mg/dL. See table 3 below for final results.
The data were consistent with no drug effect on any of the parameters of growth and development (i.e., height, weight, BMI, Tanner stage, Investigator assessment of Overall Maturation and Development) in paediatric and adolescent subjects with HeFH receiving atorvastatin treatment over the 3 year study. There was no Investigator assessed drug effect noted in height, weight, BMI by age or by gender by visit.

6.1 List of excipients

Tablet Core
Silica, colloidal anhydrous
Sodium carbonate anhydrous
Microcrystalline cellulose
L-Arginine
Lactose anhydrous
Croscarmellose sodium
Hydroxypropyl cellulose
Magnesium stearate

6.5 Nature and contents of container

Opaque HDPE tablet container and PP closure containing 10, 14, 28, 30, 50, 56, 60, 90, 100, 200, 250 and 500 tablets.

PVC/Aclar (Aclar/PVC/Al) or (OPA/Al/PVC/Al) opaque blisters containing 10, 14, 28, 30, 50, 56, 60, 84, 90, 98 and 100 tablets, or calendar packs of 28 tablets or multipacks containing 98 (2 packs of 49) tablets.

Not all pack sizes may be marketed

3. PHARMACEUTICAL FORM

 

Film-coated tablet

 

White, oval, biconvex, film coated tablet, approximately 9.2mm × 4.7mm, plain on one side and debossed ‘10’ on the other side.
White, oval, biconvex, film coated tablet, approximately 11.2mm × 6.2mm, with

 

a score line on one side and debossed ‘20’ on the other side.
White, oval, biconvex, film coated tablet, approximately 14.2mm × 7.2mm, with a score line on one side and debossed ‘40’ on the other side.
White, oval, biconvex, film coated tablet, approximately 18.2mm × 8.7mm, with a score line on one side and debossed ‘80’ on the other side.

 

 

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

 

4.4 Special warnings and precautions for use

 

 Skeletal muscle effects

Atorvastatin, like other HMG-CoA reductase inhibitors, may in rare occasions affect the skeletal muscle and cause myalgia, myositis, and myopathy that may rarely progress to rhabdomyolysis, a potentially life-threatening condition characterised by markedly elevated creatine kinase (CK) levels (> 10 times ULN), myoglobinaemia and myoglobinuria which may lead to renal failure.

 

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

 

Whilst on treatment

 

In cases where co-administration of these medicinal products with atorvastatin is necessary, the benefit and the risk of concurrent treatment should be carefully considered. When patients are receiving medicinal products that increase the plasma concentration of atorvastatin, a lower maximum dose of atorvastatin is recommended. In addition, in the case of potent CYP3A4 inhibitors, a lower starting dose of atorvastatin should be considered and appropriate clinical monitoring of these patients is recommended (see section 4.5).

 

 

The concurrent use of atorvastatin and fusidic acid is not recommended, therefore, temporary suspension of atorvastatin may be considered during fusidic acid therapy (see section 4.5). 

 

 

 

 

 

Atorvastatin must not be co-administered with systemic formulations of fusidic acid or within 7 days of stopping fusidic acid treatment. In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment.

There have been reports of rhabdomyolysis (including some fatalities) in patients receiving fusidic acid and statins in combination (see section 4.5). The patient should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness.

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

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

 

 

 

 

 

4.5 Interaction with other medicinal products and other forms of interaction

 

Fusidic acid 

 

  

 

 

The risk of myopathy including rhabdomyolysis may be increased by the concomitant administration of systemic fusidic acid with statins. The mechanism of this interaction (whether it is pharmacodynamic or pharmacokinetic, or both) is yet unknown. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination.

If treatment with systemic fusidic acid is necessary, atorvastatin treatment should be discontinued throughout the duration of the fusidic acid treatment (see section 4.4)

 

 

Atorvastatin must not be co-administered with fusidic acid. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination. In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. The patient should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness.
Statin therapy may be re-introduced seven days after the last dose of fusidic acid. In exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g., for the treatment of severe infections, the need for co-administration of atorvastatin and fusidic acid should only be considered on a case by case basis and under close medical supervision. Interaction studies with atorvastatin and fusidic acid have not been conductedas with other statins, muscle related events, including rhabdomyolysis have been reported in post-marketing experience with atorvastatin and fusidic acid given concurrently. The mechanism of this interaction is not known. Patients should be closely monitored and temporary suspension of atorvastatin treatment may be appropriate.

 

 

 

 

 

4.8 Undesirable effects

 

 

In the atorvastatin placebo-controlled clinical trial database of 16,066 (8755 atorvastatin vs. 7311 placebo) patients treated for a mean period of 53 weeks, 5.2% of patients on atorvastatin discontinued due to adverse reactions compared to 4.0% of the patients on placebo.

Based on data from clinical studies and extensive post-marketing experience, the following table presents the adverse reaction profile for Atorvastatin Mylan.

Estimated frequencies of reactions are ranked according to the following convention: Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1,000 to < 1/100); Rare (≥ 1/10,000 to < 1/1,000); Very rare (≤ 1/10,000)

 

, Not known (cannot be estimated from the available data).

 

 

Musculoskeletal and connective tissue disorders

Common: myalgia, arthralgia, pain in extremity, muscle spasms, joint swelling, back pain.
Uncommon: neck pain, muscle fatigue.
Rare: myopathy, myositis, rhabdomyolysis with or without acute renal failure, tendonopathy, sometimes complicated by rupture.

 

Not known: immune-mediated necrotising myopathy (see section 4.4). 

 

 

6.4 Special precautions for storage

 

 

OPA/Al/PVC/Al blisters and tablet container: Store in the original 

 

container package in order to protect from light and moisture.
PVC/Aclar blisters: Store in the original packagecontainer in order to protect from moisture, keep the blister in the outer carton in order to protect from light.

 

 

 

 

 

Extensive updates in line with the reference product and QRD template during the renewal application.

6.3 Shelf life
OPA/Al/PVC/Al blisters and bottles:18 months 2 years
PVC/Aclar blisters and bottles: 18 months
Bottles: Use within 3 months after the first opening of the bottle.

6.4 Special precautions for storage
OPA/Al/PVC/Al: Store in the original container to protect from light and moisture.
Bottles and opaque blisters: Do not store above 25ºC. Store in the original container to protect from
light and moisture.
PVC/Aclar blisters: Store in the original container in order to protect from moisture, keep the blister in
the outer carton in order to protect from light.

6.5 Nature and contents of container
Opaque HDPE bottle (with stabilox) and PP closure containing 10, 14, 28, 30, 50, 56, 60, 90, 100, 200, 250 and 500 tablets.
PVC/Aclar (Aclar/PVC/Al) or (OPA/Al/PVC/Al) opaque blisters containing 10, 14, 28, 30, 50, 56, 60, 84, 90, 98 and 100 tablets or calendar packs of 28 tablets.
Not all pack sizes may be marketed.

In section 4.4, paragraph added - PhVWP recommendation on new risk for onset diabetes.
In section 4.8, paragraph added - PhVWP recommendation on new risk for onset diabetes.
In section 6.1, excipients amended in line with Ph Eur.
In section 6.4, storage conditions for PVC/Aclar blisters added.
In section 6.5, addition of PVC/Aclar Aluminium blisters added.

None provided