Tenofovir disoproxil Zentiva - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Tenofovir disoproxil Zentiva 245 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains tenofovir disoproxil phosphate (equivalent to 245 mg of tenofovir disoproxil).

Excipient with known effect: Each tablet contains 214.5 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet

Oblong-shaped, light blue colored film-coated tablets with dimensions approx. 17.2 × 8.2 mm.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

HIV-1 infection

Tenofovir disoproxil Zentiva is indicated in combination with other antiretroviral medicinal products for the treatment of HIV-1 infected adults.

In adults, the demonstration of the benefit of tenofovir disoproxil in HIV-1 infection is based on results of one study in treatment-naïve patients, including patients with a high viral load (> 100,000 copies/ml) and studies in which tenofovir disoproxil was added to stable background therapy (mainly tritherapy) in antiretroviral pre-treated patients experiencing early virological failure (< 10,000 copies/ml, with the majority of patients having < 5,000 copies/ml).

Tenofovir disoproxil Zentiva is also indicated for the treatment of HIV-1 infected adolescents, with NRTI resistance or toxicities precluding the use of first line agents, aged 12 to < 18 years.

The choice of Tenofovir disoproxil Zentiva to treat antiretroviral-experienced patients with HIV-1 infection should be based on individual viral resistance testing and/or treatment history of patients.

Hepatitis B infection

Tenofovir disoproxil Zentiva is indicated for the treatment of chronic hepatitis B in adults with:

• – compensated liver disease, with evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active inflammation and/or fibrosis (see section 5.1).

• – evidence of lamivudine-resistant hepatitis B virus (see sections 4.8 and 5.1).

• – decompensated liver disease (see sections 4.4, 4.8 and 5.1).

Tenofovir disoproxil Zentiva is indicated for the treatment of chronic hepatitis B in adolescents 12 to < 18 years of age with:

• – compensated liver disease and evidence of immune active disease, i.e. active viral replication and persistently elevated serum ALT levels, or histological evidence of moderate to severe inflammation and/or fibrosis. With respect to the decision to initiate treatment in paediatric patients, see sections

• 4.2 , 4.4, 4.8 and 5.1.

4.2 Posology and method of administration

Therapy should be initiated by a physician experienced in the management of HIV infection and/or treatment of chronic hepatitis B.

Posology

HIV-1 and chronic hepatitis B

Adults and adolescents aged 12 to < 18 years and weighing > 35 kg

The recommended dose of Tenofovir disoproxil Zentiva for the treatment of HIV or for the treatment of chronic hepatitis B is 245 mg (one tablet) once daily taken orally with food.

The decision to treat paediatric patients (adolescents) should be based on careful consideration of individual patient needs and with reference to current paediatric treatment guidelines including the value of baseline histological information. The benefits of long-term virologic suppression with continued therapy must be weighed against the risk of prolonged treatment, including the emergence of resistant hepatitis B virus and the uncertainties as regards the long term impact of bone and renal toxicity (see section 4.4).

Serum ALT should be persistently elevated for at least 6 months prior to treatment of paediatric patients with compensated liver disease due to HBeAg positive chronic hepatitis B; and for at least 12 months in patients with HBeAg negative disease.

Duration of therapy in adult and adolescent patients with chronic hepatitis B

The optimal duration of treatment is unknown. Treatment discontinuation may be considered as follows:

• – In HBeAg positive patients without cirrhosis, treatment should be administered for at least 12 months after HBe seroconversion (HBeAg loss and HBV DNA loss with anti-HBe detection on two consecutive serum samples at least 3–6 months apart) is confirmed or until HBs seroconversion or there is loss of efficacy (see section 4.4). Serum ALT and HBV DNA levels should be followed regularly after treatment discontinuation to detect any late virological relapse.

• – In HBeAg negative patients without cirrhosis, treatment should be administered at least until HBs seroconversion or there is evidence of loss of efficacy. Treatment discontinuation may also be considered after stable virological suppression is achieved (i.e. for at least 3 years) provided serum ALT and HBV DNA levels are followed regularly after treatment discontinuation to detect any late virological relapse. With prolonged treatment for more than 2 years, regular reassessment is recommended to confirm that continuing the selected therapy remains appropriate for the patient.

In adult patients with decompensated liver disease or cirrhosis, treatment cessation is not recommended.

Paediatric population

Reduced doses of tenofovir (the active ingredient of Tenofovir disoproxil Zentiva) are also used for the treatment of HIV-1 infection and chronic hepatitis B in paediatric patients aged 2 to < 12 years. Tenofovir disoproxil Zentiva is available only as 245 mg film-coated tablets, it is not suitable for the use in paediatric patients aged 2 < 12 years. Other suitable formulations should be checked for their availability.

The safety and efficacy of tenofovir disoproxil in HIV-1 infected children or children with chronic hepatitis B under 2 years of age have not been established. No data are available.

Missed dose

If a patient misses a dose of Tenofovir disoproxil Zentiva within 12 hours of the time it is usually taken, the patient should take Tenofovir disoproxil Zentiva with food as soon as possible and resume their normal dosing schedule. If a patient misses a dose of Tenofovir disoproxil Zentiva by more than 12 hours and it is almost time for their next dose, the patient should not take the missed dose and simply resume the usual dosing schedule.

If the patient vomits within 1 hour of taking Tenofovir disoproxil Zentiva another tablet should be taken. If the patient vomits more than 1 hour after taking Tenofovir disoproxil Zentiva they do not need to take another dose.

Special populations

Elderly

No data are available on which to make a dose recommendation for patients over the age of 65 years (see section 4.4).

Renal impairment

Tenofovir is eliminated by renal excretion and the exposure to tenofovir increases in patients with renal dysfunction.

Adults

There are limited data on the safety and efficacy of tenofovir disoproxil in adult patients with moderate and severe renal impairment (creatinine clearance < 50 ml/min) and long-term safety data has not been evaluated for mild renal impairment (creatinine clearance 50 – 80 ml/min). Therefore, in adult patients with renal impairment tenofovir disoproxil should only be used if the potential benefits of treatment are considered to outweigh the potential risks.

Mild renal impairment (creatinine clearance 50 – 80 ml/min)

Limited data from clinical studies support once daily dosing of 245 mg tenofovir disoproxil in patients with mild renal impairment.

Moderate renal impairment (creatinine clearance 30 – 49 ml/min)

If administration of a lower dose is not possible, prolonged dose intervals using the 245 mg film-coated tablets may be used.

Administration of 245 mg tenofovir disoproxil every 48 hours can be used based on modelling of single-dose pharmacokinetic data in HIV-negative and non-HBV infected subjects with varying degrees of renal impairment, including end-stage renal disease requiring haemodialysis, but has not been confirmed in clinical studies. Therefore, clinical response to treatment and renal function should be closely monitored in these patients (see sections 4.4 and 5.2).

Severe renal impairment (creatinine clearance < 30 ml/min) and haemodialysis patients

Adequate dose adjustments cannot be applied with this product due to lack of alternative tablet strengths, therefore use in this group of patients is not recommended. If no alternative treatment is available, prolonged dose intervals using the 245 mg film-coated tablets may be used as follows:

Severe renal impairment: 245 mg tenofovir disoproxil may be administered every 72 – 96 hours (dosing twice a week).

Haemodialysis patients: 245 mg tenofovir disoproxil may be administered every 7 days following completion of a haemodialysis session*.

These dose interval adjustments have not been confirmed in clinical studies. Simulations suggest that the prolonged dose interval using Tenofovir disoproxil Zentiva 245 mg film-coated tablets is not optimal and could result in increased toxicity and possibly inadequate response. Therefore clinical response to treatment and renal function should be closely monitored (see sections 4.4 and 5.2).

*Generally, once weekly dosing assuming three haemodialysis sessions per week, each of approximately 4 hours duration or after 12 hours cumulative haemodialysis.

No dosing recommendations can be given for non-haemodialysis patients with creatinine clearance < 10 ml/min.

Paediatric population

The use of tenofovir disoproxil is not recommended in paediatric patients with renal impairment (see section 4.4).

Hepatic impairment

No dose adjustment is required in patients with hepatic impairment (see sections 4.4 and 5.2).

If Tenofovir disoproxil Zentiva is discontinued in patients with chronic hepatitis B with or without HIV co-infection, these patients should be closely monitored for evidence of exacerbation of hepatitis (see section 4.4).

Method of administration

Tenofovir disoproxil Zentiva tablets should be taken once daily, orally with food.

In exceptional circumstances in patients having particular difficulty in swallowing, Tenofovir disoproxil Zentiva can be administered following disintegration of the tablet in at least 100 ml of water, orange juice or grape juice.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

General

HIV antibody testing should be offered to all HBV infected patients before initiating tenofovir disoproxil therapy (see below Co-infection with HIV-1 and hepatitis B ).

HIV-1

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.

Hepatitis B

Patients must be advised that tenofovir disoproxil has not been proven to prevent the risk of transmission of HBV to others through sexual contact or contamination with blood. Appropriate precautions must continue to be used.

Co-administration of other medicinal products

• – Tenofovir disoproxil Zentiva should not be administered concomitantly with other medicinal products containing tenofovir disoproxil or tenofovir alafenamide.

• – Tenofovir disoproxil Zentiva should not be administered concomitantly with adefovir dipivoxil.

• – Co-administration of tenofovir disoproxil and didanosine is not recommended (see section 4.5).

Triple therapy with nucleosides/nu­cleotides

There have been reports of a high rate of virological failure and of emergence of resistance at an early stage in HIV patients when tenofovir disoproxil was combined with lamivudine and abacavir as well as with lamivudine and didanosine as a once daily regimen.

Renal and bone effects in adult population

Renal effects

Tenofovir is principally eliminated via the kidney. Renal failure, renal impairment, elevated creatinine, hypophosphataemia and proximal tubulopathy (including Fanconi syndrome) have been reported with the use of tenofovir disoproxil in clinical practice (see section 4.8).

Renal monitoring

It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy with tenofovir disoproxil and renal function (creatinine clearance and serum phosphate) is also monitored after two to four weeks of treatment, after three months of treatment and every three to six months thereafter in patients without renal risk factors. In patients at risk for renal impairment, a more frequent monitoring of renal function is required.

Renal management

If serum phosphate is < 1.5 mg/dl (0.48 mmol/l) or creatinine clearance is decreased to < 50 ml/min in any adult patient receiving tenofovir disoproxil, renal function should be re- evaluated within one week, including measurements of blood glucose, blood potassium and urine glucose concentrations (see section 4.8, proximal tubulopathy). Consideration should also be given to interrupting treatment with tenofovir disoproxil in adult patients with creatinine clearance decreased to < 50 ml/min or decreases in serum phosphate to < 1.0 mg/dl (0.32 mmol/l). Interrupting treatment with tenofovir disoproxil should also be considered in case of progressive decline of renal function when no other cause has been identified.

Co-administration and risk of renal toxicity

Use of tenofovir disoproxil should be avoided with concurrent or recent use of a nephrotoxic medicinal product (e.g. aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2). If concomitant use of tenofovir disoproxil and nephrotoxic agents is unavoidable, renal function should be monitored weekly.

Cases of acute renal failure after initiation of high dose or multiple non-steroidal anti-inflammatory drugs (NSAIDs) have been reported in patients treated with tenofovir disoproxil and with risk factors for renal dysfunction. If tenofovir disoproxil is co-administered with an NSAID, renal function should be monitored adequately.

A higher risk of renal impairment has been reported in patients receiving tenofovir disoproxil in combination with a ritonavir or cobicistat boosted protease inhibitor. A close monitoring of renal function is required in these patients (see section 4.5). In patients with renal risk factors, the co-administration of tenofovir disoproxil with a boosted protease inhibitor should be carefully evaluated.

Tenofovir disoproxil has not been clinically evaluated in patients receiving medicinal products which are secreted by the same renal pathway, including the transport proteins human organic anion transporter (hOAT) 1 and 3 or MRP 4 (e.g. cidofovir, a known nephrotoxic medicinal product). These renal transport proteins may be responsible for tubular secretion and in part, renal elimination of tenofovir and cidofovir. Consequently, the pharmacokinetics of these medicinal products which are secreted by the same renal pathway including transport proteins hOAT 1 and 3 or MRP 4, might be modified if they are co-administered. Unless clearly necessary, concomitant use of these medicinal products which are secreted by the same renal pathway is not recommended, but if such use is unavoidable, renal function should be monitored weekly (see section 4.5).

Renal impairment

Renal safety with tenofovir disoproxil has only been studied to a very limited degree in adult patients with impaired renal function (creatinine clearance < 80 ml/min).

Adult patients with creatinine clearance < 50 ml/min, including haemodialysis patients

There are limited data on the safety and efficacy of tenofovir disoproxil in patients with impaired renal function. Therefore, tenofovir disoproxil should only be used if the potential benefits of treatment are considered to outweigh the potential risks. In patients with severe renal impairment (creatinine clearance < 30 ml/min) and in patients who require haemodialysis use of tenofovir disoproxil is not recommended. If no alternative treatment is available, the dosing interval must be adjusted and renal function should be closely monitored (see sections 4.2 and 5.2).

Bone effects

Bone abnormalities such as osteomalacia which can manifest as persistent or worsening bone pain and, which can infrequently contribute to fractures may be associated with tenofovir disoproxil-induced proximal renal tubulopathy (see section 4.8).

Tenofovir disoproxil may also cause a reduction in bone mineral density (BMD). In HIV infected patients, in a 144- week controlled clinical study (GS-99–903) that compared tenofovir disoproxil with stavudine in combination with lamivudine and efavirenz in antiretroviral-naïve adult patients, small decreases in BMD of the hip and spine were observed in both treatment groups. Decreases in BMD of spine and changes in bone biomarkers from baseline were significantly greater in the tenofovir disoproxil treatment group at 144 weeks. Decreases in BMD of hip were significantly greater in this group until 96 weeks. However, there was no increased risk of fractures or evidence for clinically relevant bone abnormalities over 144 weeks in this study.

In other studies (prospective and cross-sectional), the most pronounced decreases in BMD were seen in patients treated with tenofovir disoproxil as part of a regimen containing a boosted protease inhibitor. Overall, in view of the bone abnormalities associated with tenofovir disoproxil and the limitations of longterm data on the impact of tenofovir disoproxil on bone health and fracture risk, alternative treatment regimens should be considered for patients with osteoporosis that are at a high risk for fractures.

If bone abnormalities are suspected or detected then appropriate consultation should be obtained.

Renal and bone effects in paediatric population

There are uncertainties associated with the long-term effects of bone and renal toxicity. Moreover, the reversibility of renal toxicity cannot be fully ascertained. Therefore, a multidisciplinary approach is recommended to adequately weigh on a case by case basis the benefit/risk balance of treatment, decide the appropriate monitoring during treatment (including decision for treatment withdrawal) and consider the need for supplementation.

Renal effects

Renal adverse reactions consistent with proximal renal tubulopathy have been reported in HIV-1 infected paediatric patients aged 2 to < 12 years in clinical study GS-US-104–0352 (see sections 4.8 and 5.1).

Renal monitoring

Renal function (creatinine clearance and serum phosphate) should be evaluated prior to treatment, and monitored during treatment as in adults (see above).

Renal management

If serum phosphate is confirmed to be < 3.0 mg/dl (0.96 mmol/l) in any paediatric patient receiving tenofovir disoproxil renal function should be re-evaluated within one week, including measurements of blood glucose, blood potassium and urine glucose concentrations (see section 4.8, proximal tubulopathy). If renal abnormalities are suspected or detected then consultation with a nephrologist should be obtained to consider interruption of tenofovir disoproxil treatment.

Interrupting treatment with tenofovir disoproxil should also be considered in case of progressive decline of renal function when no other cause has been identified.

Co-administration and risk of renal toxicity

The same recommendations apply as in adults (see above).

Renal impairment

The use of tenofovir disoproxil is not recommended in paediatric patients with renal impairment (see section 4.2). Tenofovir disoproxil should not be initiated in paediatric patients with renal impairment and should be discontinued in paediatric patients who develop renal impairment during tenofovir disoproxil therapy.

Bone effects

Tenofovir disoproxil Zentiva may cause a reduction in BMD. The effects of tenofovir disoproxil-associated changes in BMD on long-term bone health and future fracture risk are uncertain (see section 5.1).

If bone abnormalities are detected or suspected in paediatric patients, consultation with an endocrinologist and/or nephrologist should be obtained.

Liver disease

Safety and efficacy data are very limited in liver transplant patients.

There are limited data on the safety and efficacy of tenofovir disoproxil in HBV infected patients with decompensated liver disease and who have a Child- Pugh- Turcotte (CPT) score > 9. These patients may be at higher risk of experiencing serious hepatic or renal adverse reactions. Therefore, hepatobiliary and renal parameters should be closely monitored in this patient population.

Exacerbations of hepatitis

Flares on treatment: Spontaneous exacerbations in chronic hepatitis B are relatively common and are characterised by transient increases in serum ALT. After initiating antiviral therapy, serum ALT may increase in some patients (see section 4.8). In patients with compensated liver disease, these increases in serum ALT are generally not accompanied by an increase in serum bilirubin concentrations or hepatic decompensation. Patients with cirrhosis may be at a higher risk for hepatic decompensation following hepatitis exacerbation, and therefore should be monitored closely during therapy.

Flares after treatment discontinuation: Acute exacerbation of hepatitis has also been reported in patients who have discontinued hepatitis B therapy. Post-treatment exacerbations are usually associated with rising HBV DNA, and the majority appears to be self-limited. However, severe exacerbations, including fatalities, have been reported. Hepatic function should be monitored at repeated intervals with both clinical and laboratory follow-up for at least 6 months after discontinuation of hepatitis B therapy. If appropriate, resumption of hepatitis B therapy may be warranted. In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation.

Liver flares are especially serious, and sometimes fatal in patients with decompensated liver disease.

Co -infection with hepatitis C or D: There are no data on the efficacy of tenofovir in patients co-infected with hepatitis C or D virus.

Co -infection with HIV -1 and hepatitis B: Due to the risk of development of HIV resistance, tenofovir disoproxil should only be used as part of an appropriate antiretroviral combination regimen in HIV/HBV co-infected patients. Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy (CART) and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered. However, it should be noted that increases of ALT can be part of HBV clearance during therapy with tenofovir, see above Exacerbations of hepatitis.

Use with certain hepatitis C virus antiviral agents

Co-administration of tenofovir disoproxil with ledipasvir/so­fosbuvir, sofosbuvir/vel­patasvir or sofosbuvir/vel­patasvir/voxi­laprevir has been shown to increase plasma concentrations of tenofovir, especially when used together with an HIV regimen containing tenofovir disoproxil and a pharmacokinetic enhancer (ritonavir or cobicistat).

The safety of tenofovir disoproxil in the setting of ledipasvir/so­fosbuvir, sofosbuvir/vel­patasvir or sofosbuvir/vel­patasvir/voxi­laprevir and a pharmacokinetic enhancer has not been established. The potential risks and benefits associated with co-administration of ledipasvir/so­fosbuvir, sofosbuvir/vel­patasvir or sofosbuvir/vel­patasvir/voxi­laprevir with tenofovir disoproxil given in conjunction with a boosted HIV protease inhibitor (e.g. atazanavir or darunavir) should be considered, particularly in patients at increased risk of renal dysfunction. Patients receiving ledipasvir/so­fosbuvir, sofosbuvir/vel­patasvir or sofosbuvir/vel­patasvir/voxi­laprevir concomitantly with tenofovir disoproxil and a boosted HIV protease inhibitor should be monitored for adverse reactions related to tenofovir disoproxil.

Weight and metabolic parameters

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Mitochondrial dysfunction following exposure in utero

Nucleos(t)ide analogues may impact mitochondrial function to a variable degree, which is most pronounced with stavudine, didanosine and zidovudine. There have been reports of mitochondrial dysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues; these have predominantly concerned treatment with regimens containing zidovudine. The main adverse reactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders (hyperlactataemia, hyperlipasaemia). These events have often been transitory. Late-onset neurological disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour). Whether such neurological disorders are transient or permanent is currently unknown. These findings should be considered for any child exposed in utero to nucleos(t)ide analogues, who present with severe clinical findings of unknown etiology, particularly neurologic findings. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.

Immune reactivation syndrome

In HIV infected patients with severe immune deficiency at the time of institution of CART, an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

Osteonecrosis

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV disease and/or long-term exposure to CART. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

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.

Excipients

Tenofovir disoproxil Zentiva contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the potential for CYP450 mediated interactions involving tenofovir with other medicinal products is low.

Concomitant use not recommended

Tenofovir disoproxil Zentiva should not be administered concomitantly with other medicinal products containing tenofovir disoproxil or tenofovir alafenamide.

Tenofovir disoproxil Zentiva should not be administered concomitantly with adefovir dipivoxil.

Didanosine

Co-administration of tenofovir disoproxil and didanosine is not recommended (see section 4.4 and Table 1).

Renally eliminated medicinal products

Since tenofovir is primarily eliminated by the kidneys, co-administration of tenofovir disoproxil with medicinal products that reduce renal function or compete for active tubular secretion via transport proteins hOAT 1, hOAT 3 or MRP 4 (e.g. cidofovir) may increase serum concentrations of tenofovir and/or the co-administered medicinal products.

Use of tenofovir disoproxil should be avoided with concurrent or recent use of a nephrotoxic medicinal product. Some examples include, but are not limited to, aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2 (see section 4.4).

Given that tacrolimus can affect renal function, close monitoring is recommended when it is co-administered with tenofovir disoproxil.

Other interactions

Interactions between tenofovir disoproxil and other medicinal products are listed in Table 1 below (increase is indicated as “$”, decrease as “I”, no change as “^”, twice daily as “b.i.d.”, and once daily as “q.d.”).

Table 1: Interactions between tenofovir disoproxil and other medicinal products

1 Data generated from simultaneous dosing with ledipasvir/so­fosbuvir. Staggered administration (12 hours apart) provided similar results.

2 The predominant circulating metabolite of sofosbuvir.

3 Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients.

Studies conducted with other medicinal products

There were no clinically significant pharmacokinetic interactions when tenofovir disoproxil was coadministered with emtricitabine, lamivudine, indinavir, efavirenz, nelfinavir, saquinavir (ritonavir boosted), methadone, ribavirin, rifampicin, tacrolimus, or the hormonal contraceptive norgestimate/et­hinyl oestradiol.

Tenofovir disoproxil must be taken with food, as food enhances the bioavailability of tenofovir (see section 5.2).

4.6 Fertility, pregnancy and lactation

Pregnancy

A large amount of data on pregnant women (more than 1,000 pregnancy outcomes) indicate no malformations or foetal/neonatal toxicity associated with tenofovir disoproxil. Animal studies do not indicate reproductive toxicity (see section 5.3). The use of tenofovir disoproxil may be considered during pregnancy, if necessary.

In the literature, exposure to tenofovir disoproxil in the third trimester of pregnancy has been shown to reduce the risk of HBV transmission from mother to infant if tenofovir disoproxil is given to mothers, in addition to hepatitis B immune globulin and hepatitis B vaccine in infants.

In three controlled clinical trials, a total of 327 pregnant women with chronic HBV infection were administered tenofovir disoproxil (245 mg) once daily from 28 to 32 weeks gestation through 1 to 2 months postpartum; women and their infants were followed for up to 12 months after delivery. No safety signal has emerged from these data.

Breast-feeding

Generally, if the newborn is adequately managed for hepatitis B prevention at birth, a mother with hepatitis B may breast-feed her infant.

Tenofovir is excreted in human milk at very low levels and exposure of infants through breast milk is considered negligible. Although long-term data is limited, no adverse reactions have been reported in breast-fed infants, and HBV-infected mothers using tenofovir disoproxil may breast-feed.

As a general rule, it is recommended that HIV infected mothers do not breast-feed their infants in order to avoid transmission of HIV to the infant.

Fertility

There are limited clinical data with respect to the effect of tenofovir disoproxil on fertility. Animal studies do not indicate harmful effects of tenofovir disoproxil on fertility.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. However, patients should be informed that dizziness has been reported during treatment with tenofovir disoproxil.

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 Tenofovir disoproxil Zentiva (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

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 Tenofovir disoproxil Zentiva 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 two randomised trials (studies GS-US-104–0321 and GS-US-104–0352) in 184 HIV-1 infected paediatric patients (aged 2 to < 18 years) who received treatment with tenofovir disoproxil (n = 93) or placebo/active comparator (n = 91) in combination with other antiretroviral agents for 48 weeks (see section 5.1). 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 sections 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 Zscores observed in subjects who received tenofovir disoproxil were lower than those observed in subjects who received placebo. In HIV-1 infected children, the BMD Z-scores observed in subjects who switched to tenofovir disoproxil were lower than those observed in subjects who remained on their stavudine- or zidovudine-containing regimen (see sections 4.4 and 5.1).

In study GS-US-104–0352, 8 out of 89 paediatric patients (9.0%) exposed to tenofovir disoproxil (median tenofovir disoproxil exposure 331 weeks) discontinued study drug due to renal adverse events. Five subjects (5.6%) had laboratory findings clinically consistent with proximal renal tubulopathy, 4 of whom discontinued tenofovir disoproxil therapy. Seven patients had estimated glomerular filtration rate (GFR) values between 70 and 90 ml/min/1.73 m2. Among them, 3 patients experienced a clinically meaningful decline in estimated GFR which improved after discontinuation of tenofovir disoproxil.

Chronic hepatitis B

Assessment of adverse reactions is based on a randomised study (study GS-US-174–0115) in 106 adolescent patients (12 to < 18 years of age) with chronic hepatitis B receiving treatment with tenofovir disoproxil 245 mg (n = 52) or placebo (n = 54) for 72 weeks and a randomised study (Study GS-US-174–0144) in 89 patients with chronic hepatitis B (2 to < 12 years of age) receiving treatment with tenofovir disoproxil (n = 60) or placebo (n = 29) for 48 weeks. 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 sections 4.8 Tabulated summary of adverse reactions and 5.1).

Reductions in BMD have been observed in HBV infected paediatric patients 2 to < 18 years of age. The BMD Z-scores observed in subjects who received tenofovir disoproxil were lower than those observed in subjects who received placebo (see sections 4.4 and 5.1).

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 Tenofovir disoproxil Zentiva (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. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in

4.9 Overdose

5.   PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

5.2 Pharmacokinetic properties

Tenofovir disoproxil is a water soluble ester prodrug which is rapidly converted in vivo to tenofovir and formaldehyde.

Tenofovir is converted intracellularly to tenofovir monophosphate and to the active component, tenofovir diphosphate.

Absorption

Following oral administration of tenofovir disoproxil to HIV infected patients, tenofovir disoproxil is rapidly absorbed and converted to tenofovir. Administration of multiple doses of tenofovir disoproxil with a meal to HIV infected patients resulted in mean (%CV) tenofovir Cmax, AUC, and Cmin values of 326 (36.6%) ng/ml, 3,324 (41.2%) ng h/ml and 64.4 (39.4%) ng/ml, respectively. Maximum tenofovir concentrations are observed in serum within one hour of dosing in the fasted state and within two hours when taken with food. The oral bioavailability of tenofovir from tenofovir disoproxil in fasted patients was approximately 25%. Administration of tenofovir disoproxil with a high fat meal enhanced the oral bioavailability, with an increase in tenofovir AUC by approximately 40% and Cmax by approximately 14%. Following the first dose of tenofovir disoproxil in fed patients, the median Cmax in serum ranged from 213 to 375 ng/ml. However, administration of tenofovir disoproxil with a light meal did not have a significant effect on the pharmacokinetics of tenofovir.

Distribution

Following intravenous administration the steady-state volume of distribution of tenofovir was estimated to be approximately 800 ml/kg. After oral administration of tenofovir disoproxil, tenofovir is distributed to most tissues with the highest concentrations occurring in the kidney, liver and the intestinal contents (preclinical studies). In vitro protein binding of tenofovir to plasma or serum protein was less than 0.7 and 7.2%, respectively, over the tenofovir concentration range 0.01 to 25 ^g/ml.

Biotransformation

In vitro studies have determined that neither tenofovir disoproxil nor tenofovir are substrates for the CYP450 enzymes. Moreover, at concentrations substantially higher (approximately 300-fold) than those observed in vivo , tenofovir did not inhibit in vitro drug metabolism mediated by any of the major human CYP450 isoforms involved in drug biotransformation (CYP3A4, CYP2D6, CYP2C9, CYP2E1, or CYP1A1/2). Tenofovir disoproxil at a concentration of 100 ^mol/l had no effect on any of the CYP450 isoforms, except CYP1A1/2, where a small (6%) but statistically significant reduction in metabolism of CYP1A1/2 substrate was observed. Based on these data, it is unlikely that clinically significant interactions involving tenofovir disoproxil and medicinal products metabolised by CYP450 would occur.

Elimination

Tenofovir is primarily excreted by the kidney by both filtration and an active tubular transport system with approximately 70 – 80% of the dose excreted unchanged in urine following intravenous administration. Total clearance has been estimated to be approximately 230 ml/h/kg (approximately 300 ml/min). Renal clearance has been estimated to be approximately 160 ml/h/kg (approximately 210 ml/min), which is in excess of the glomerular filtration rate. This indicates that active tubular secretion is an important part of the elimination of tenofovir. Following oral administration the terminal half-life of tenofovir is approximately 12 to 18 hours.

Studies have established the pathway of active tubular secretion of tenofovir to be influx into proximal tubule cell by the human organic anion transporters (hOAT) 1 and 3 and efflux into the urine by the multidrug resistant protein 4 (MRP 4).

Linearity/non-linearity

The pharmacokinetics of tenofovir were independent of tenofovir disoproxil dose over the dose range 75 to 600 mg and were not affected by repeated dosing at any dose level.

Age

Pharmacokinetic studies have not been performed in the elderly (over 65 years of age).

Gender

Limited data on the pharmacokinetics of tenofovir in women indicate no major gender effect.

Ethnicity

Pharmacokinetics have not been specifically studied in different ethnic groups.

Paediatric population

HIV-1: Steady-state pharmacokinetics of tenofovir were evaluated in 8 HIV-1 infected adolescent patients (aged 12 to < 18 years) with body weight > 35 kg. Mean (± SD) Cmax and AUCtau are 0.38 ± 0.13 ^g/ml and 3.39 ± 1.22 ^g h/ml, respectively. Tenofovir exposure achieved in adolescent patients receiving oral daily doses of tenofovir disoproxil 245 mg was similar to exposures achieved in adults receiving once-daily doses of tenofovir disoproxil 245 mg.

Chronic hepatitis B: Steady-state tenofovir exposure in HBV infected adolescent patients (12 to < 18 years of age) receiving an oral daily dose of tenofovir disoproxil 245 mg was similar to exposures achieved in adults receiving once-daily doses of tenofovir disoproxil 245 mg.

Tenofovir exposure in HBV infected paediatric patients 2 to <12 years of age receiving an oral daily dose of tenofovir disoproxil 6.5 mg/kg of body weight (tablet or granules) up to a maximum dose of 245 mg was similar to exposures achieved in HIV-1 infected paediatric patients 2 to <12 years of age receiving a once daily dose of tenofovir disoproxil 6.5 mg/kg up to a maximum dose of tenofovir disoproxil 245 mg.

Pharmacokinetic studies have not been performed with tenofovir disoproxil 245 mg tablets in children under 12 years or with renal impairment.

Renal impairment

Pharmacokinetic parameters of tenofovir were determined following administration of a single dose of tenofovir disoproxil 245 mg to 40 non-HIV, non-HBV infected adult patients with varying degrees of renal impairment defined according to baseline creatinine clearance (CrCl) (normal renal function when CrCl > 80 ml/min; mild with CrCl = 50–79 ml/min; moderate with CrCl = 30 – 49 ml/min and severe with CrCl = 10 – 29 ml/min). Compared with patients with normal renal function, the mean (%CV) tenofovir exposure increased from 2,185 (12%) ngJVml in subjects with CrCl > 80 ml/min to respectively 3,064 (30%) ng h/ml, 6,009 (42%) ng^h/ml and 15,985 (45%) ng h/ml in patients with mild, moderate and severe renal impairment. The dosing recommendations in patients with renal impairment, with increased dosing interval, are expected to result in higher peak plasma concentrations and lower Cmin levels in patients with renal impairment compared with patients with normal renal function. The clinical implications of this are unknown.

In patients with end-stage renal disease (ESRD) (CrCl < 10 ml/min) requiring haemodialysis, between dialysis tenofovir concentrations substantially increased over 48 hours achieving a mean Cmax of 1,032 ng/ml and a mean AUC0–48h of 42,857 ng h/ml.

It is recommended that the dosing interval for tenofovir disoproxil 245 mg is modified in adult patients with creatinine clearance < 50 ml/min or in patients who already have ESRD and require dialysis (see section 4.2).

The pharmacokinetics of tenofovir in non-haemodialysis patients with creatinine clearance < 10 ml/min and in patients with ESRD managed by peritoneal or other forms of dialysis have not been studied.

The pharmacokinetics of tenofovir in paediatric patients with renal impairment have not been studied. No data are available to make dose recommendations (see sections 4.2 and 4.4).

Hepatic impairment

A single 245 mg dose of tenofovir disoproxil was administered to non-HIV, non-HBV infected adult patients with varying degrees of hepatic impairment defined according to Child-Pugh-Turcotte (CPT) classification. Tenofovir pharmacokinetics were not substantially altered in subjects with hepatic impairment suggesting that no dose adjustment is required in these subjects. The mean (%CV) tenofovir Cmax and AUCo-v values were 223 (34.8%) ng/ml and 2,050 (50.8%) ngJVml, respectively, in normal subjects compared with 289 (46.0%) ng/ml and 2,310 (43.5%) ngJVml in subjects with moderate hepatic impairment, and 305 (24.8%) ng/ml and 2,740 (44.0%) ngJVml in subjects with severe hepatic impairment.

Intracellular pharmacokinetics

In non-proliferating human peripheral blood mononuclear cells (PBMCs) the half-life of tenofovir diphosphate was found to be approximately 50 hours, whereas the half-life in phytohaemagglutinin-stimulated PBMCs was found to be approximately 10 hours.

5.3 Preclinical safety data

Non-clinical safety pharmacology studies reveal no special hazard for humans. Findings in repeated dose toxicity studies in rats, dogs and monkeys at exposure levels greater than or equal to clinical exposure levels and with possible relevance to clinical use include renal and bone toxicity and a decrease in serum phosphate concentration. Bone toxicity was diagnosed as osteomalacia (monkeys) and reduced bone mineral density (BMD) (rats and dogs). The bone toxicity in young adult rats and dogs occurred at exposures > 5-fold the exposure in paediatric or adult patients; bone toxicity occurred in juvenile infected monkeys at very high exposures following subcutaneous dosing (> 40-fold the exposure in patients). Findings in the rat and monkey studies indicated that there was a substance-related decrease in intestinal absorption of phosphate with potential secondary reduction in BMD.

Genotoxicity studies revealed positive results in the in vitro mouse lymphoma assay, equivocal results in one of the strains used in the Ames test, and weakly positive results in an UDS test in primary rat hepatocytes. However, it was negative in an in vivo mouse bone marrow micronucleus assay.

Oral carcinogenicity studies in rats and mice only revealed a low incidence of duodenal tumours at an extremely high dose in mice. These tumours are unlikely to be of relevance to humans.

Reproductive studies in rats and rabbits showed no effects on mating, fertility, pregnancy or foetal parameters. However, tenofovir disoproxil reduced the viability index and weight of pups in peri-postnatal toxicity studies at maternally toxic doses.

Environmental Risk Assessment (ERA)

The active substance tenofovir disoproxil phosphate and its main transformation products are persistent in the environment.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Tablet core

Lactose monohydrate

Microcrystalline cellulose Croscarmellose sodium Povidone

Magnesium stearate

Film-coating

Lactose monohydrate

Hypromellose

Titanium dioxide

Triacetin

Indigo Carmine Aluminum lake

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

Shelf-life after first opening is 60 days.

6.4 Special precautions for storage

Do not store above 30 °C. Store in the original package in order to protect from moisture.

6.5 Nature and contents of container

High density polyethylene (HDPE) bottle with a polypropylene child-resistant cap and induction heat sealing (with aluminium foil).

The bottle contains 30 film-coated tablets and a silica gel desiccant (in a container).

The following pack sizes are available:

Outer cartons containing 1 bottle of 30 film-coated tablets and outer cartons containing 90 (3 bottles of 30) film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Open bottles by pressing the child proof cap down and turning it counter-clock wise.

7. MARKETING AUTHORISATION HOLDER

Zentiva, k.s.

U Kabelovny 130 102 37 Prague 10

Czech Republic

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/16/1127/001

EU/1/16/1127/002

Date of first authorisation: 15 September 2016 Date of latest renewal: