Adverse reactions : תופעות לוואי

7 ADVERSE REACTIONS

The following important adverse reactions are described below and elsewhere in the labeling: Myopathy and Rhabdomyolysis [see Warnings and Precautions (6.1)]
Immune-Mediated Necrotizing Myopathy [see Warnings and Precautions (6.2)] Hepatic Dysfunction [see Warnings and Precautions (6.3)]
Increases in HbA1c and Fasting Serum Glucose Levels [see Warnings and Precautions (6.4)] 
7.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In the LIPITOR placebo-controlled clinical trial database of 16,066 patients (8755 LIPITOR vs. 7311 placebo; age range 10-93 years, 39% women, 91% White, 3% Black, 2% Asian, 4% other) with a median treatment duration of 53 weeks, the most common adverse reactions in patients treated with LIPITOR that led to treatment discontinuation and occurred at a rate greater than placebo were: myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), alanine aminotransferase increase (0.4%), and hepatic enzyme increase (0.4%).


Table 2 summarizes adverse reactions reported in ≥ 2% and at a rate greater than placebo in patients treated with LIPITOR (n=8755), from seventeen placebo-controlled trials.


Table 2. Adverse Reactions Occurring in ≥ 2% in Patients LIPITOR-Treated with any Dose and Greater than Placebo

% Any
% Placebo      % 10 mg      % 20 mg      % 40 mg      % 80 mg
Adverse Reaction                                                                           dose N=7311         N=3908       N=188        N=604        N=4055
N=8755
Nasopharyngitis         8.2            12.9         5.3          7.0          4.2          8.3 Arthralgia              6.5            8.9          11.7         10.6         4.3          6.9 Diarrhea                6.3            7.3          6.4          14.1         5.2          6.8 Pain in extremity       5.9            8.5          3.7          9.3          3.1          6.0 Urinary tract                                                                              5.7 5.6            6.9          6.4          8.0          4.1 infection
Dyspepsia               4.3            5.9          3.2          6.0          3.3          4.7 Nausea                  3.5            3.7          3.7          7.1          3.8          4.0 Musculoskeletal                                                                            3.8 3.6            5.2          3.2          5.1          2.3 pain
Muscle Spasms           3.0            4.6          4.8          5.1          2.4          3.6 Myalgia                 3.1            3.6          5.9          8.4          2.7          3.5 Insomnia                2.9            2.8          1.1          5.3          2.8          3.0 Pharyngolaryngeal                                                                          2.3 2.1            3.9          1.6          2.8          0.7 pain


Other adverse reactions reported in placebo-controlled trials include: Body as a whole: malaise, pyrexia
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Digestive system: abdominal discomfort, eructation, flatulence, hepatitis, cholestasis; Musculoskeletal system: musculoskeletal pain, muscle fatigue, neck pain, joint swelling, lupus like syndrom
Metabolic and nutritional system: transaminases increase, liver function test abnormal, blood alkaline phosphatase increase, creatine phosphokinase increase, hyperglycemia;
Nervous system: nightmare
Respiratory system: epistaxis;
Skin and appendages: urticaria;
Special senses: vision blurred, tinnitus,;
Urogenital system: white blood cells urine positive.

Elevations in Liver Enzyme Tests
Persistent elevations in serum transaminases, defined as more than 3 times the ULN and occurring on 2 or more occasions, occurred in 0.7% of patients who received LIPITOR in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for 10, 20, 40, and 80 mg, respectively.

One patient in clinical trials developed jaundice. Increases in liver enzyme tests in other patients were not associated with jaundice or other clinical signs or symptoms. Upon dose reduction, drug interruption, or discontinuation, transaminase levels returned to or near pretreatment levels without sequelae. Eighteen of 30 patients with persistent liver enzyme elevations continued treatment with a reduced dose of LIPITOR.

Treating to New Targets Study (TNT)In TNT [see Clinical Studies (14.1)] 10,001 patients (age range 29-78 years, 19% women; 94 % White, 3% Black,1%, Asian 2% other) with clinically evident CHD were treated with LIPITOR 10 mg daily (n=5006) or LIPITOR 80 mg daily (n=4995 ). In the high- dose LIPITOR group, there were more patients with serious adverse reactions (1.8%) and discontinuations due to adverse reactions i9.9%) as compared to the low-dose group (1.4%; 8.1%, respectively) during a median follow-up of 4.9 years. Persistent transaminase elevations (≥3 x ULN twice within 4-10 days) occurred in 1.3 individuals with Lipitor 80 mg and in (0.2% of individuals with Lipitor 10 mg. Elevations of CK (≥ 10 x ULN) were higher in the high-dose Lipitor group (0.3%) compared to the low-dose Lipitor group (0.1%).


Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) In SPARCL,4731 patients (age range 21–92 years, 40% women; 93% White, 3% Black, 1% Asian, 3% other) without clinically evident CHD but with a stroke or transient ischemic attack (TIA) within the previous 6 months were treated with LIPITOR 80 mg (n=2365) or placebo (n=2366) for a median follow-up of 4.9 years.,There was a higher incidence of persistent hepatic transaminase elevations (≥ 3 x ULN twice within 4-10 days) in the Lipitor group (0.9%) compared to placebo (0.1%). Elevations of CK (>10 x ULN) were rare, but were higher in the Lipitor group (0.1%) compared to placebo (0.0%). Diabetes was reported as an adverse reaction in 6.1% of subjects in the Lipitor group and 3.8% of subjects in the placebo.

In a post-hoc analysis, LIPITOR 80 mg reduced the incidence of ischemic stroke (9.2% vs. 11.6%) and increased the incidence of hemorrhagic stroke ( 2.3% vs. 1.4%) compared to placebo. The incidence of fatal hemorrhagic stroke was similar between groups (17 LIPITOR vs. 18 placebo).
The incidence of non-fatal hemorrhagic strokes was significantly greater in the Lipitor group (38 non- fatal hemorrhagic strokes) as compared to the placebo group (16 non-fatal hemorrhagic strokes). Patients who entered the trial with a hemorrhagic stroke appeared to be at increased risk for hemorrhagic stroke (16% LIPITOR vs. 4% placebo)..


Adverse Reactions from Clinical Studies of LIPITOR in Pediatric Patients with HeFH In a 26-week controlled study in pediatric patients with HeFH (ages 10 years to 17 years) (n=140, 31% female; 92% White, 1.6% Blacks, 1.6% Asians, 4.8% other), the safety and tolerability profile of LIPITOR 10 to 20 mg daily, as an adjunct to diet to reduce total cholesterol, LDL-C, and apo B levels, was generally similar to that of placebo [see Use in Specific Populations (9.4) and Clinical Studies (14.6)].

7.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of LIPITOR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.


Gastrointestinal disorders: pancreatitis
General disorders: fatigue


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Hepatobiliary Disorders: fatal and non-fatal hepatic failure
Immune system disorders: anaphylaxis
Injury: tendon rupture
Musculoskeletal and connective tissue disorders: rhabdomyolysis, myositis.
There have been rare reports of immune-mediated necrotizing myopathy associated with statin use Eye disorders: ocular myasthenia
Nervous System Disorders: dizziness, peripheral neuropathy, myasthenia gravis There have been rare reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with the use. of all statins. Cognitive impairment was generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).
There have been rare reports of new onset or exacerbation of myasthenia gravis, including ocular myasthenia, and reports of recurrence when the same or a different statin was administered
Psychiatric disorders: depression
Respiratory disorders: interstitial lung disease
Skin and subcutaneous tissue disorders: angioneurotic edema, bullous rashes (including erythema multiforme, Stevens- Johnson syndrome, and toxic epidermal necrolysis)


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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/