Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
Ritonavir dosed as a pharmacokinetic enhancer

Adverse reactions associated with the use of ritonavir as a pharmacokinetic enhancer are dependent on the specific co-administered PI. For information on adverse reactions refer to the prescribing information of the specific co-administered PI.

Ritonavir dosed as an antiretroviral agent

Adverse reactions from clinical trials and post-marketing experience in adult patients 
The most frequently reported adverse drug reactions among patients receiving ritonavir alone or in combination with other antiretroviral drugs were gastrointestinal (including diarrhea, nausea, vomiting, abdominal pain (upper and lower)), neurological disturbances (including paresthesia and oral paresthesia) and fatigue/asthenia.

Tabulated list of adverse reactions

The following adverse reactions of moderate to severe intensity with possible or probable relationship to ritonavir have been reported. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); not known (cannot be estimated from the available data).

Events noted as having frequency not known were identified via post-marketing surveillance.
Adverse reactions in clinical studies and post-marketing in adult patients System Order Class                     Frequency       Adverse reaction 
Blood and lymphatic system             Common          Decreased white blood cells, decreased disorders                                              haemoglobin, decreased neutrophils, increased eosinophils, thrombocytopenia
Uncommon        Increased neutrophils
Immune system disorders                Common          Hypersensitivity including urticaria and face oedema Rare            Anaphylaxis
Metabolism and nutrition disorders     Common          Hypercholesterolaemia, hypertriglyceridaemia, gout, oedema and peripheral oedema, dehydration (usually associated with gastrointestinal symptoms)
Uncommon        Diabetes mellitus
Rare            Hyperglycaemia


Nervous system disorders              Very common Dysgeusia, oral and peripheral paraesthesia, headache, dizziness, peripheral neuropathy
Common         Insomnia, anxiety, confusion, disturbance in attention, syncope, seizure
Eye disorders                         Common         Blurred vision
Cardiac disorders                     Uncommon       Myocardial infarction Vascular disorders                    Common         Hypertension, hypotension including orthostatic hypotension, peripheral coldness
Respiratory, thoracic and             Very common Pharyngitis, oropharyngeal pain, cough mediastinal disorders
Gastrointestinal disorders            Very common Abdominal pain (upper and lower), nausea, diarrhoea (including severe with electrolyte imbalance),
vomiting, dyspepsia
Common         Anorexia, flatulence, mouth ulcer, gastrointestinal haemorrhage, gastroesophageal reflux disease,
pancreatitis
Hepatobiliary disorders               Common         Hepatitis (including increased AST, ALT, GGT), blood bilirubin increased (including jaundice)
Skin and subcutaneous tissue          Very common Pruritus, rash (including erythematous and disorders                                         maculopapular)
Common         Acne
Rare           Stevens Johnson syndrome, toxic epidermal necrolysis (TEN)
Musculosketal and connective tissue Very common Arthralgia and back pain disorders
Common      Myositis, rhabdomyolysis, myalgia, myopathy/CPK increased
Renal and urinary disorders           Common         Increased urination, renal impairment (e.g. oliguria, elevated creatinine)
Uncommon       Acute renal failure
Not known      Nephrolithiasis
Reproductive system and breast        Common         Menorrhagia disorders
General disorders and administration Very common Fatigue including asthenia, flushing, feeling hot site conditions
Common      Fever, weight loss
Investigations                        Common         Increased amylase, decreased free and total thyroxin Uncommon       Increased glucose, increased magnesium, increased alkaline phosphatase

Description of selected adverse reactions

Hepatic transaminase elevations exceeding five times the upper limit or normal, clinical hepatitis, and jaundice have occurred in patients receiving ritonavir alone or in combination with other antiretrovirals.

Metabolic parameters

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4).
In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and can occur many months after initiation of treatment (see section 4.4).

Pancreatitis has been observed in patients receiving ritonavir therapy, including those who developed hypertriglyceridemia. In some cases fatalities have been observed. Patients with advanced HIV disease may be at risk of elevated triglycerides and pancreatitis (see section 4.4).

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown (see section 4.4).

Paediatric populations
The safety profile of Norvir in children 2 years of age and older is similar to that seen in adults.

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