Erestz 245 mg FC tablets

ERESTZ, is indicated for the use as a complete regimen for the treatment of HIV-1 infection in adult patients weighing at least 35 kg as initial therapy in those with no antiretroviral treatment history and with HIV-1 RNA less than or equal to 100 000 copies/mL at the start of therapy, or to replace a stable antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA < 50 copies/mL) on a stable antiretroviral regimen for at least 6 months with no treatment failure and no known substitutions associated with resistance to the individual components of ERESTZ.

Therapy should be initiated by a doctor experienced in the management of HIV infection. Testing prior to or when initiating ERESTZ, test for hepatitis B virus infection. Prior to initiation and during treatment with ERESTZ, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus.

Recommended dosage in adult patients weighing at least 35 kg: One tablet taken orally once daily with food (see section 5.2). If a patient misses a dose of ERESTZ within 12 hours of the time it is usually taken, the patient should take ERESTZ with food as soon as possible and resume the normal dosing schedule. If a patient misses a dose of ERESTZ by more than 12 hours, the patient should not take the missed dose and simply resume the usual dosing schedule. If a patient vomits within 4 hours of taking ERESTZ another ERESTZ tablet should be taken with food. If a patient vomits more than 4 hours after taking ERESTZ they do not need to take another dose of ERESTZ until the next regularly scheduled dose.

Special Population

• Elderly: ERESTZ has not been studied in patients over the age of 65 years. ERESTZ should be administered with caution to elderly patients.
• Paediatric use: The safety and effectiveness of ERESTZ in children under the age of 18 years have not been established. ERESTZ should only be administered to adult patients with a body weight greater than or equal to 35 kg. Because ERESTZ is a fixed-dose combination tablet, the dose of ERESTZ cannot be adjusted for patients of a lower weight.

Dosage for HIV-1 infected adult patients with creatinine clearance u2265 50 (mL/min)

• Creatinine Clearance (mL/min)
• Recommended dosing interval
• u2265 50
• Every 24 hours

Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in all individuals (see section 4.3 and 4.4 - Renal impairment)

Renal impairment: Because ERESTZ is a fixed-dose combination, and cannot be dose adjusted, it is not for use in patients with moderate, severe, or end-stage renal impairment (estimated creatinine clearance below 50 mL per minute) or that require dialysis (see section 4.3).

Hepatic impairment: No dose-adjustment of ERESTZ is required in patients with mild or moderate hepatic impairment (Child-Pugh score A or B). ERESTZ has not been studied in patients with severe hepatic impairment (Child-Pugh score C). Therefore, ERESTZ is not recommended in patients with severe hepatic impairment (see section 4.3).

If ERESTZ is discontinued in patients co-infected with HIV and hepatitis B virus (HBV), these patients should be closely monitored for evidence of exacerbation of hepatitis (see section 4.4).

Method of administration

ERESTZ must be taken orally, once daily with food. It is recommended that ERESTZ be swallowed whole with water. The film-coated tablet should not be chewed, crushed or split as it may impact the absorption of ERESTZ.

ERESTZ is contraindicated in patients with previously demonstrated hypersensitivity to tenofovir, emtricitabine or rilpivirine. It is not recommended that ERESTZ be co-administered with other Non-Nucleoside Reverse Transcriptase inhibitors (NNRTIs) e.g. delavirdine, efavirenz, etravirine, nevirapine (see section 4.5). ERESTZ should not be used in combination with carbamazepine, oxcarbazepine, phenobarbitone, phenytoin and dexamethasone (except as a single-dose treatment) as co-administration may cause significant decreases in rilpivirine plasma concentrations due to the induction of CYP3A enzymes. This may result in loss of therapeutic effect of ERESTZ. Rifabutin, rifampicin and rifapentine are potent inducers of CYP3A enzymes. ERESTZ should not be used in combination with these medicines as co-administration may cause significant decreases in rilpivirine plasma concentrations. This may result in loss of therapeutic effect of ERESTZ. ERESTZ should not be used concomitantly with products containing St. Johnu2019s Wort because co-administration may cause significant decreases in rilpivirine plasma concentrations. This may result in loss of therapeutic effect of ERESTZ.

The proton-pump inhibitors (PPIs) lansoprazole, omeprazole, rabeprazole, pantoprazole and esomeprazole should not be administered concurrently with ERESTZ as this may result in significant decreases in rilpivirine plasma concentration due to gastric pH increase. This may result in loss of therapeutic effect of ERESTZ.

• ERES TZ should not be co-administered with other tenofovir-containing medicines, or with other emtricitabine, or rilpivirine-containing medicines.
• ERESTZ should not be administered with lamivudine-containing medicines due to similarities between emtricitabine and lamivudine.
• ERESTZ should not be administered to patients with moderate, severe, or end-stage renal impairment (estimated creatinine clearance below 50 mL per minute) or that require dialysis.
• ERESTZ is not for patients with severe hepatic impairment. (Child-Pugh score C).
• Pregnancy and lactation (see section 4.6).

Patients should be advised that current antiretroviral therapy does not cure HIV and has not been proven to prevent the transmission of HIV to others through blood, other bodily secretion or sexual contact. Appropriate precautions to prevent the transmission of HIV should continue to be employed.

• There are no study results demonstrating the effect of ERESTZ on clinical progression of HIV-1.
• It is not recommended that ERESTZ be used as a component of a triple nucleoside regimen.
• Individuals should be warned that full compliance with treatment is essential to the efficacy in preventing HIV-1 transmission and should be fully informed about the use of other preventative measures including barrier contraception (condoms).

Lactic acidosis/severe hepatomegaly with steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues such as ERESTZ alone or in combination with other antiretrovirals. This is caused by mitochondrial dysfunction. The majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogues such as ERESTZ to any patient with known risk factors for liver disease. However, cases have also been reported in patients with no known risk factors. Treatment with ERESTZ should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). Clinical features are non-specific, and include nausea, vomiting, abdominal pain, dyspnoea, fatigue and weight loss. In patients with suspicious symptoms or biochemistry, measure the venous lactate level (normal < 2 mmol/L) and the serum bicarbonate, and respond as follows:

• Lactate 2 to 5 mmol/L with minimum symptoms: Switch to medicines that are less likely to cause lactic acidosis.
• Lactate 5 to 10 mmol/L with symptoms and/or with reduced standard bicarbonate: Stop ERESTZ and change treatment option. Once lactate has settled, use medicines that are less likely to cause lactic acidosis. Exclude other causes (e.g. sepsis, uraemia, diabetic ketoacidosis, thyrotoxicosis and hyperthyroidism).
• Lactate > 10 mmol/L: Stop all therapy (80 % mortality).

The above lactate values may not be applicable to paediatric patients. Caution should be exercised when administering ERESTZ to patients with known risk factors for liver disease. Treatment with ERESTZ should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity.

Pancreatitis: Pancreatitis has been observed in some patients receiving ERESTZ. Pancreatitis must be considered whenever a patient develops abdominal pain, nausea, vomiting or elevated biochemical markers (serum lipase). Discontinue use of ERESTZ until diagnosis of pancreatitis is excluded.

Liver disease: Use of ERESTZ can result in hepatomegaly due to non-alcoholic fatty liver disease (hepatic steatosis). The safety and efficacy of ERESTZ has not been established in patients with significant underlying liver disorders/diseases. Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored. If there is evidence of worsening liver disease in such patients, temporary or permanent discontinuation of treatment must be considered.

Mitochondrial dysfunction: Nucleoside and nucleotide analogues such as ERESTZ have been demonstrated in vitro and in vivo to cause variable degrees of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV negative infants exposed in utero and/or post-natally to nucleoside analogues. Apart from lactic acidosis/hyperlactatemia (see above), other manifestations of mitochondrial dysfunction include haematological disorders (anaemia, neutropenia) and peripheral neuropathy. Some late-onset neurological disorders have been reported (hypertonia, convulsions, abnormal behaviour). It is not known whether the neurological disorders are transient or permanent. Any foetus exposed in utero to nucleoside and nucleotide analogues, including HIV-negative infants/children, should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant signs and symptoms.

Patients with HIV and Hepatitis B or C Virus co-infection: Patients with chronic hepatitis B or C and treated with antiretroviral therapy such as ERESTZ, are at an increased risk for severe and potentially fatal hepatic adverse reactions. Patients co-infected with HBV to discontinue ERESTZ should be closely monitored, with both clinical and laboratory follow-up, after stopping treatment. Medical practitioners should refer to current HIV treatment guidelines for the optimal management of HIV infection in patients co-infected with hepatitis B virus (HBV). ERESTZ is not indicated for the treatment of chronic HBV infection. The safety and efficacy of ERESTZ have not been established in patients co-infected with HBV and HIV. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant professional information for these medicines. In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended, since post-treatment exacerbation of hepatitis may lead to hepatic decompensation. Discontinuation of ERESTZ therapy in patients co-infected with HIV and HBV may be associated with severe, acute exacerbations of hepatitis which may lead to liver decompensation and liver failure.

All patients with HIV should be tested for the presence of chronic hepatitis B virus (HBV) before initiating ERESTZ therapy. Hepatic function should be closely monitored with both clinical and laboratory follow-up for at least several months, in patients who are co-infected with HIV and HBV and who discontinue ERESTZ. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

Renal impairment: ERESTZ is principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphataemia), has been reported in association with the use of tenofovir disoproxil fumarate (see section 4.3). It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy and as clinically appropriate during therapy with ERESTZ. Routine monitoring or calculated creatinine clearance and serum phosphorus should be performed in patients at risk for renal impairment (see section 4.3). ERESTZ should be avoided with concurrent or recent use of a nephrotoxic medicine. ERESTZ should not be administered to patients with creatinine clearance below 50 mL/min or to patients requiring haemodialysis or for pre-exposure prophylaxis in patients with creatinine clearance below 60 mL/min (see section 4.3). If a decrease in creatinine clearance develops in uninfected individuals, ERESTZ should be discontinued (see section 4.3).

As ERESTZ contains emtricitabine, rilpivirine hydrochloride and tenofovir fumarate, any interactions that have been identified with these active substances individually may occur with ERESTZ. Interaction studies with these active substances have only been performed in adults. Rilpivirine is primarily metabolised by cytochrome P450 (CYP3A). Medicinal products that induce or inhibit CYP3A may thus affect the clearance of rilpivirine (see section 5.2).

Concomitant use contraindicated

Co-administration of ERESTZ and medicines that induce CYP3A have been observed to decrease the plasma concentrations of rilpivirine which could potentially lead to loss of therapeutic effect of ERESTZ (see section 4.3). Co-administration of ERESTZ with proton pump inhibitors has been observed to decrease the plasma concentrations of rilpivirine (due to an increase in gastric pH) which could potentially lead to loss of therapeutic effect of ERESTZ (see section 4.3).

Concomitant use not recommended

ERESTZ should not be administered concomitantly with other medicines containing emtricitabine, tenofovir disoproxil fumarate or tenofovir alafenamide. ERESTZ should not be administered concomitantly with rilpivirine hydrochloride unless needed for dose adjustment with rifabutin (see section 4.2). Due to similarities with emtricitabine, ERESTZ should not be administered concomitantly with other cytidine analogues, such as lamivudine (see section 4.4). ERESTZ should not be administered concomitantly with adefovir dipivoxil.

Didanosine

The co-administration of ERESTZ and didanosine is not recommended (see section 4.4 and Table 1).

Renally eliminated medicines

Since emtricitabine and tenofovir are primarily eliminated by the kidneys, co-administration of ERESTZ with medicines that reduce renal function or compete for active tubular secretion (e.g. cidofovir) may increase serum concentrations of emtricitabine, tenofovir and/or the co-administered medicines. Use of ERESTZ should be avoided with concurrent or recent use of nephrotoxic medicines. Some examples include, but are not limited to, aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2 (also called aldesleukin).

Other NNRTIs

It is not recommended to co-administer ERESTZ with other NNRTIs.

Concomitant use where caution is recommended

Cytochrome P450 enzyme inhibitors

Co-administration of ERESTZ with medicines that inhibit CYP3A enzyme activity have been observed to increase rilpivirine plasma concentrations.

QT prolonging medicines

ERESTZ should be used with caution when co-administered with medicines with a known risk of Torsade de Pointes. There is limited information available on the potential for a pharmacodynamic interaction between rilpivirine and medicines that prolong the QTc interval of the electrocardiogram. In a study of healthy subjects, supratherapeutic doses of rilpivirine (75 mg daily and 300 mg daily) have been shown to prolong the QTc interval of the electrocardiogram (see sections 4.5 and 5.1).

Other interactions

Interactions between ERESTZ or its individual component(s) and co-administered medicines are listed in Table 1 below. Interactions between rilpivirine and co-administered medicines are listed in Table 1 and Table 2 below.

ERESTZ should not be used in pregnancy and lactation as safety and efficacy has not been established (see section 4.3). A reliable method of contraception should be used to avoid pregnancy while taking ERESTZ.

Contraception in females

The effect of ERESTZ when co-administered with oral contraceptives demonstrated that ERESTZ is unlikely to decrease the effectiveness of oral contraceptives. ERESTZ and oestrogen and/or progesterone-based contraceptives can be used without dose adjustments.

Pregnancy: Safe use in pregnancy has not been proven. ERESTZ should not be used in pregnancy (see section 4.3).

Lactation: Nursing Mothers: HIV-infected mothers should not breastfeed their infants, to avoid risk of postnatal transmission of HIV. Because of the potential for HIV transmission and serious adverse reactions in nursing infants, mother should be instructed not to breastfeed if they are receiving ERESTZ. Emtricitabine and tenofovir disoproxil are excreted in human milk. It is not known whether rilpivirine is excreted in human milk. Rilpivirine is excreted in the milk of rats. Because of both the potential for HIV transmission and the potential for adverse events in nursing infants, mothers should be instructed not to breastfeed if they are receiving ERESTZ.

Fertility: No human data on the effect of ERESTZ on fertility are available. Animal studies do not indicate harmful effects of emtricitabine, rilpivirine hydrochloride or tenofovir disoproxil on fertility.

Patients should be informed that fatigue, dizziness and somnolence have been reported during treatment with components of ERESTZ. This should be considered when assessing a patientu2019s ability to drive or operate machinery.

Side effects have been reported. The combination of emtricitabine, rilpivirine and tenofovir disoproxil fumarate have been studied as the component products in treatment-nau00efve patients. The single-tablet regimen, ERESTZ, has been studied in virologically suppressed patients who switched from a regiment containing a ritonavir-boosted protease inhibitor or from efavirenz/emtricitabine/tenofovir disoproxil fumarate. In treatment-nau00efve patients, the most frequently reported adverse reactions considered possibly or probably related to rilpivirine hydrochloride and emtricitabine/tenofovir disoproxil fumarate were nausea (9 %), dizziness (8 %), abnormal dreams (8 %), headache (6 %), diarrhoea (5 %) and insomnia (5 %). In virologically suppressed patients switching to ERESTZ, the most frequently reported adverse reactions considered possibly or probably related to ERESTZ were fatigue (3 %), diarrhoea (3 %), nausea (2 %) and insomnia (2 %). The safety profile of emtricitabine and tenofovir disoproxil fumarate in these studies were consistent with the previous experience with agents when each was administered with other antiretroviral agents. In patients receiving tenofovir disoproxil fumarate, rare events of renal impairment, renal failure and 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 ERESTZ (see section 4.4). Discontinuation of ERESTZ therapy in patients co-infected with HIV and HBV may be associated with severe acute exacerbations of hepatitis (see section 4.4).

The following frequency classes apply to the Table below: Very common (u2265 1/10); common (u2265 1/100, < 1/10); uncommon (u2265 1/1 000, < 1/100); rare (u2265 1/10 000, < 1/1 000); very rare (< 1/10 000); Not known (cannot be estimated from the available data).

These frequencies are from clinical trials.

Tabulated summary of adverse reactions

Tabulated summary of adverse reactions to ERESTZ and its individual components

Frequency Adverse reaction

Blood and lymphatic system disorders

Common: Neuropenia, decreased white cell count, decreased haemoglobin, decreased platelet count

Uncommon: Anaemia

Immune system disorders

Common: Allergic reactions

Uncommon: Immune reactivation syndrome

Metabolism and nutrition disorders

Very common: Increased total cholesterol (fasted), increased LDL-cholesterol (fasted), hypophosphataemia

Common: Hypertriglyceridaemia, hyperglycaemia, decreased appetite

Uncommon: Hypokalaemia

Rare: Lactic acidosis

Psychiatric disorders

Very common: Insomnia

Common: Depression, depressed mood, sleep disorders, abnormal dreams

Nervous system disorders

Very common: Headache, dizziness

Common: Somnolence

Gastrointestinal disorders

Very common: Increased pancreatic amylase, vomiting, diarrhoea, nausea

Common: Elevated amylase including elevated pancreatic amylase, elevated serum lipase, abdominal pain, abdominal discomfort, abdominal distension, dyspepsia, flatulence, dry mouth

Uncommon: Pancreatitis

Hepatobiliary disorders

Very common: Increased transaminases (AST and/or ALT)

Common: Increased bilirubin

Rare: Hepatitis, hepatic steatosis

Skin and subcutaneous tissue disorders

Very common: Rash

Common: Vesiculobullous rash, pustular rash, urticaria, skin discolouration (increased pigmentation), maculopapular rash, pruritus

Uncommon: Angioedema

Musculoskeletal and connective tissue disorders

Very common: Elevated creatine kinase

Common: Bone mineral density decreased

Uncommon: Rhabdomyolysis, muscular weakness

Rare: Osteomalacia manifested as bone pain and infrequently contributing to fractures, myopathy

Renal and urinary disorders

Uncommon: Proximal renal tubulopathy including Fanconi syndrome, increased creatinine, proteinuria

Rare: Renal failure (acute and chronic), acute tubular necrosis, nephritis (including acute interstitial nephritis), nephrogenic diabetes insipidus

General disorders and administration site conditions

Very common: Asthenia

Common: Pain, fatigue

If overdose occurs the side effects listed will be exacerbated and exaggerated (see section 4.8). The patient must be monitored for evidence of toxicity and standard supportive treatment provided as necessary.

Emtricitabine: Haemodialysis treatment removed approximately 30 % of the emtricitabine dose over a 3-hour dialysis period, starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL/min and dialysate flow rate of 600 mL/min). It is not known whether emtricitabine can be removed by peritoneal dialysis.

Tenofovir disoproxil fumarate: Tenofovir is poorly removed by haemodialysis. Following a single 300 mg dose of tenofovir disoproxil fumarate, a four-hour haemodialysis session removed only approximately 10 % of the administered tenofovir dose.

Rilpivirine: Human experience of overdose with ERESTZ is limited. Treatment of overdose with ERESTZ consists of general supportive measures including monitoring of vital signs and ECG (QT interval) as well as observation of clinical status of the patient. If indicated, elimination of unabsorbed active substance may be achieved by gastric lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed active substance. Since rilpivirine is highly bound to plasma protein, dialysis is unlikely to result in significant removal of the active substance.