Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
In phase 3 clinical trials with doravirine plus 2 nucleoside analogue reverse transcriptase inhibitors (NRTIs), the most frequently reported adverse reactions were nausea (4 %) and headache (3 %).

Tabulated summary of adverse reactions
The adverse reactions with doravirine plus 2 NRTIs from Phase 3 clinical trials (DRIVE FORWARD, DRIVE SHIFT and DRIVE AHEAD) are listed below by body system organ class and frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), or very rare (< 1/10,000).

Table 2: Tabulated summary of adverse reactions associated with doravirine/lamivudine/tenofovir disoproxil

Frequency                                          Adverse reactions
Infections and infestations
Rare                                               rash pustular
Blood and lymphatic systems disorders
Uncommon                                           neutropenia*, anaemia*, thrombocytopenia* Very rare                                          pure red cell aplasia* Metabolism and nutrition disorders
Uncommon                                           hypophosphataemia, hypokalaemia* Rare                                               hypomagnesaemia, lactic acidosis* Psychiatric disorders
Common                                             abnormal dreams, insomnia1, Uncommon                                           nightmare, depression2, anxiety3, irritability, confusional state, suicidal ideation
Rare                                               aggression, hallucination, adjustment disorder, mood altered, somnambulism
Nervous system disorders
Common                                             headache, dizziness, somnolence Uncommon                                           disturbance in attention, memory impairment, paraesthesia, hypertonia, poor quality sleep
Very rare                                          peripheral neuropathy (or paraesthesia)* 
Frequency                                     Adverse reactions
Vascular disorders
Uncommon                                       hypertension
Respiratory, thoracic and mediastinal disorders
Common                                        cough*, nasal symptoms* Rare                                          dyspnoea, tonsillar hypertrophy Gastrointestinal disorders
Common                                        nausea, diarrhoea, abdominal pain4, vomiting, flatulence
Uncommon                                      constipation, abdominal discomfort5, abdominal distension, dyspepsia, faeces soft6,
gastrointestinal motility disorder7, pancreatitis*
Rare                                          rectal tenesmus
Hepatobiliary disorders
Rare                                          hepatic steatosis*, hepatitis* Skin and subcutaneous tissue disorders
Common                                        alopecia*, rash8
Uncommon                                      pruritus
Rare                                          dermatitis allergic, rosacea, angioedema* Musculoskeletal and connective tissue disorders
Common                                        muscle disorders*
Uncommon                                      myalgia, arthralgia, rhabdomyolysis*†, muscular weakness*†
Rare                                          musculoskeletal pain, osteomalacia (manifested as bone pain and infrequently contributing to fractures)*, myopathy*
Renal and urinary disorders
Uncommon                                      increased creatinine*, proximal renal tubulopathy (including Fanconi syndrome)*
Rare                                          acute kidney injury, renal disorder, calculus urinary, nephrolithiasis, acute renal failure*,
renal failure*, acute tubular necrosis*, nephritis
(including acute interstitial)*, nephrogenic diabetes insipidus*
General disorders and administration site conditions
Common                                        fatigue, fever*
Uncommon                                      asthenia, malaise
Rare                                          chest pain, chills, pain, thirst 


Frequency                                                    Adverse reactions Investigations
Common                                                       alanine aminotransferase increased9 

Uncommon                                                     aspartate aminotransferase increased, lipase increased, amylase increased, haemoglobin decreased

Rare                                                         blood creatine phosphokinase increased 


*This adverse reaction was not identified as an adverse reaction associated with doravirine from the Phase 3 clinical studies (DRIVE-FORWARD, DRIVE-AHEAD, DRIVE-SHIFT), but is included in this table as an adverse reaction based on the Summary of Product Characteristics of 3TC and/or TDF. The highest frequency category reported in the 3TC or TDF Summary of Product Characteristics is used.
†
This adverse reaction may occur as a consequence of proximal renal tubulopathy. It is not considered to be causally associated with tenofovir disoproxil in the absence of this condition.
1 insomnia includes: insomnia, initial insomnia and sleep disorder.
2 depression includes: depression, depressed mood, major depression, and persistent depressive disorder.
3 anxiety includes: anxiety and generalised anxiety disorder.
4 abdominal pain includes: abdominal pain, and abdominal pain upper.
5 abdominal discomfort includes: abdominal discomfort, and epigastric discomfort.
6 faeces soft includes: faeces soft and abnormal faeces.
7 gastrointestinal motility disorder includes: gastrointestinal motility disorder, and frequent bowel movements.
8 rash includes: rash, rash macular, rash erythematous, rash generalised, rash maculo-papular, rash papular, and urticarial.
9 alanine aminotransferase increased includes: alanine aminotransferase increased and hepatocellular injury.


Immune reactivation syndrome
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 these events can occur many months after initiation of treatment (see section 4.4).

Lactic acidosis
Cases of lactic acidosis have been reported with tenofovir disoproxil alone or in combination with other antiretrovirals. Patients with predisposing factors such as patients with decompensated liver disease, or patients receiving concomitant medicinal products known to induce lactic acidosis are at increased risk of experiencing severe lactic acidosis during tenofovir disoproxil treatment, including fatal outcomes.

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