Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
HIV-1 and hepatitis B: In patients receiving tenofovir disoproxil, rare events of renal impairment, renal failure and uncommon events of proximal renal tubulopathy (including Fanconi syndrome) sometimes leading to bone abnormalities (infrequently contributing to fractures) have been reported.
Monitoring of renal function is recommended for patients receiving Viread (see section 4.4).

HIV-1: Approximately one third of patients can be expected to experience adverse reactions following treatment with tenofovir disoproxil in combination with other antiretroviral agents. These reactions are usually mild to moderate gastrointestinal events. Approximately 1% of tenofovir disoproxil-treated adult patients discontinued treatment due to the gastrointestinal events.

Hepatitis B: Approximately one quarter of patients can be expected to experience adverse reactions following treatment with tenofovir disoproxil, most of which are mild. In clinical trials of HBV infected patients, the most frequently occurring adverse reaction to tenofovir disoproxil was nausea (5.4%).

Acute exacerbation of hepatitis has been reported in patients on treatment as well as in patients who have discontinued hepatitis B therapy (see section 4.4).

Tabulated summary of adverse reactions
Assessment of adverse reactions for tenofovir disoproxil is based on safety data from clinical studies and post-marketing experience. All adverse reactions are presented in Table 2.

HIV-1 clinical studies: Assessment of adverse reactions from HIV-1 clinical study data is based on experience in two studies in 653 treatment-experienced patients receiving treatment with tenofovir disoproxil (n = 443) or placebo (n = 210) in combination with other antiretroviral medicinal products for 24 weeks and also in a double-blind comparative controlled study in which 600 treatment-naïve patients received treatment with tenofovir disoproxil 245 mg (n = 299) or stavudine (n = 301) in combination with lamivudine and efavirenz for 144 weeks.

Hepatitis B clinical studies: Assessment of adverse reactions from HBV clinical study data is primarily based on experience in two double-blind comparative controlled studies in which 641 adult patients with chronic hepatitis B and compensated liver disease received treatment with tenofovir disoproxil 245 mg daily (n = 426) or adefovir dipivoxil 10 mg daily (n = 215) for 48 weeks. The adverse reactions observed with continued treatment for 384 weeks were consistent with the safety 
profile of tenofovir disoproxil. After an initial decline of approximately -4.9 ml/min (using Cockcroft-Gault equation) or -3.9 ml/min/1.73 m2 (using modification of diet in renal disease [MDRD] equation) after the first 4 weeks of treatment, the rate of annual decline post baseline of renal function reported in tenofovir disoproxil treated patients was -1.41 ml/min per year (using Cockcroft-Gault equation) and -0.74 ml/min/1.73 m2 per year (using MDRD equation).

Patients with decompensated liver disease: The safety profile of tenofovir disoproxil in patients with decompensated liver disease was assessed in a double-blind active controlled study (GS-US-174-0108) in which adult patients received treatment with tenofovir disoproxil (n = 45) or emtricitabine plus tenofovir disoproxil (n = 45) or entecavir (n = 22) for 48 weeks.

In the tenofovir disoproxil treatment arm, 7% of patients discontinued treatment due to an adverse event; 9% of patients experienced a confirmed increase in serum creatinine of ≥ 0.5 mg/dl or confirmed serum phosphate of < 2 mg/dl through week 48; there were no statistically significant differences between the combined tenofovir-containing arms and the entecavir arm. After 168 weeks, 16% (7/45) of the tenofovir disoproxil group, 4% (2/45) of the emtricitabine plus tenofovir disoproxil group, and 14% (3/22) of the entecavir group experienced tolerability failure. Thirteen percent (6/45) of the tenofovir disoproxil group, 13% (6/45) of the emtricitabine plus tenofovir disoproxil group, and 9% (2/22) of the entecavir group had a confirmed increase in serum creatinine ≥ 0.5 mg/dl or confirmed serum phosphate of < 2 mg/dl.

At week 168, in this population of patients with decompensated liver disease, the rate of death was of 13% (6/45) in the tenofovir disoproxil group, 11% (5/45) in the emtricitabine plus tenofovir disoproxil group and 14% (3/22) in the entecavir group. The rate of hepatocellular carcinoma was 18% (8/45) in the tenofovir disoproxil group, 7% (3/45) in the emtricitabine plus tenofovir disoproxil group and 9% (2/22) in the entecavir group.

Subjects with a high baseline CPT score were at higher risk of developing serious adverse events (see section 4.4).

Patients with lamivudine-resistant chronic hepatitis B: No new adverse reactions to tenofovir disoproxil were identified from a randomised, double-blind study (GS-US-174-0121) in which 280 lamivudine-resistant patients received treatment with tenofovir disoproxil (n = 141) or emtricitabine/tenofovir disoproxil (n = 139) for 240 weeks.

The adverse reactions with suspected (at least possible) relationship to treatment 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) or rare (≥ 1/10,000 to < 1/1,000).

Table 2: Tabulated summary of adverse reactions associated with tenofovir disoproxil based on clinical study and post-marketing experience

Frequency            Tenofovir disoproxil
Metabolism and nutrition disorders:
Very common:         hypophosphataemia1
Uncommon:            hypokalaemia1
Rare:                lactic acidosis
Nervous system disorders:
Very common:         Dizziness
Common:              Headache
Gastrointestinal disorders:
Very common:         diarrhoea, vomiting, nausea
Common:              abdominal pain, abdominal distension, flatulence Uncommon:            Pancreatitis


Hepatobiliary disorders:
Common:             increased transaminases
Rare:               hepatic steatosis, hepatitis
Skin and subcutaneous tissue disorders:
Very common:        Rash
Rare:               Angioedema
Musculoskeletal and connective tissue disorders:
Uncommon:           rhabdomyolysis1, muscular weakness1 osteomalacia (manifested as bone pain and infrequently contributing to fractures)1, Rare:               2
, myopathy1
Renal and urinary disorders:
Uncommon:           increased creatinine, proximal renal tubulopathy (including Fanconi syndrome) acute renal failure, renal failure, acute tubular necrosis, nephritis (including acute Rare: interstitial nephritis)2, nephrogenic diabetes insipidus
General disorders and administration site conditions:
Very common:        Asthenia
Common:             Fatigue
1 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.
2 This adverse reaction was identified through post-marketing surveillance but not observed in randomised controlled clinical
 trials or the tenofovir disoproxil expanded access program. The frequency category was estimated from a statistical calculation based on the total number of patients exposed to tenofovir disoproxil in randomised controlled clinical trials and the expanded access program (n = 7,319).

Description of selected adverse reactions
HIV-1 and hepatitis B:
Renal impairment
As Viread may cause renal damage monitoring of renal function is recommended (see sections 4.4 and 4.8 Summary of the safety profile). Proximal renal tubulopathy generally resolved or improved after tenofovir disoproxil discontinuation. However, in some patients, declines in creatinine clearance did not completely resolve despite tenofovir disoproxil discontinuation. Patients at risk of renal impairment (such as patients with baseline renal risk factors, advanced HIV disease, or patients receiving concomitant nephrotoxic medications) are at increased risk of experiencing incomplete recovery of renal function despite tenofovir disoproxil discontinuation (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 medications known to induce lactic acidosis are at increased risk of experiencing severe lactic acidosis during tenofovir disoproxil treatment, including fatal outcomes.

HIV-1:
Metabolic parameters
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4).

Immune reactivation syndrome
In HIV infected patients with severe immune deficiency at the time of initiation of 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).



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

Hepatitis B:
Exacerbations of hepatitis during treatment
In studies with nucleoside-naïve patients, on-treatment ALT elevations > 10 times ULN (upper limit of normal) and > 2 times baseline occurred in 2.6% of tenofovir disoproxil-treated patients. ALT elevations had a median time to onset of 8 weeks, resolved with continued treatment, and, in a majority of cases, were associated with a ≥ 2 log10 copies/ml reduction in viral load that preceded or coincided with the ALT elevation. Periodic monitoring of hepatic function is recommended during treatment (see section 4.4).

Exacerbations of hepatitis after discontinuation of treatment
In HBV infected patients, clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of HBV therapy (see section 4.4).

Paediatric population
HIV-1:
Assessment of adverse reactions is based on one randomised trial (study GS-US-104-0321) in 87 HIV-1 infected adolescent patients (aged 12 to < 18 years) who received treatment with tenofovir disoproxil fumarate (n = 45) or placebo (n = 42) in combination with other antiretroviral agents for 48 weeks (see section 4.2). The adverse reactions observed in paediatric patients who received treatment with tenofovir disoproxil were consistent with those observed in clinical studies of tenofovir disoproxil in adults (see section 4.8 Tabulated summary of adverse reactions and 5.1).

Reductions in BMD have been reported in paediatric patients. In HIV-1 infected adolescents, the BMD Z-scores observed in subjects who received tenofovir disoproxil were lower than those observed in subjects who received placebo.


Other special population(s)
Elderly
Tenofovir disoproxil has not been studied in patients over the age of 65. Elderly patients are more likely to have decreased renal function, therefore caution should be exercised when treating elderly patients with tenofovir disoproxil (see section 4.4).

Patients with renal impairment
Since tenofovir disoproxil can cause renal toxicity, close monitoring of renal function is recommended in adult patients with renal impairment treated with Viread (see sections 4.2, 4.4 and 5.2). The use of tenofovir disoproxil is not recommended in paediatric patients with renal impairment (see sections 4.2 and 4.4).

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.

You can report any side effects to the Ministry of Health by clicking on the link "Report side effects due to medical treatment" that is located on the Ministry of Health homepage (www.health.gov.il) which redirects to the online form for reporting side effects or by clicking on the link: https://sideeffects.health.gov.il .

You can also report any side effects directly to the registration holder via email: DrugSafety.Israel@gilead.com.

By reporting side effects, you can help provide more information on the safety of this medicine.