Adco Cefazolin Injection

Treatment of HIV - 1 Infections

DIDIVIR is indicated in combination with other antiretroviral medicines (such as non-nucleoside reverse transcriptase inhibitors or protease inhibitors) for the treatment of HIV - 1 infections in adults.

Pre - Exposure Prophylaxis (PrEP)

DIDIVIR is indicated in combination with safer sex practices for pre - exposure prophylaxis (PrEP) in proven HIV - 1 uninfected adults, to reduce the risk of sexually acquired HIV - 1 in adults at high risk, provided maximum treatment compliance can be monitored.

Posology

Dosage in adults for treatment of HIV - 1 infection

The dose of DIDIVIR is one tablet (containing 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) once daily.

Dosage for Pre - exposure prophylaxis (PrEP)

The dose of DIDIVIR in HIV - 1 uninfected adults is one tablet (containing 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) once daily. Significantly increased medicine exposures to emtricitabine and tenofovir occur when DIDIVIR is administered to patients with moderate to severe renal impairment (see section 4.3).

Table 1: Dosage for HIV - 1 infected adult patients with creatinine clearance u2265 50 mL/min.

Creatinine Clearance (mL/min) a >50 Recommended dosing interval Every 24 hours

a Calculated using ideal (lean) body weight

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

Pre - exposure prophylaxis: Do not use DIDIVIR for PrEP in HIV - 1 uninfected individuals with a creatinine clearance below 60 mL/min (See section 4.3 and 4.4).

Paediatric population

Treatment of HIV - 1 infection

The dose of DIDIVIR in paediatric patients 12 years of age and older with body weight greater than or equal to 35 kg is one tablet (containing 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) once daily taken.

Method of administration

Oral use

It is recommended that DIDIVIR be swallowed whole with water. DIDIVIR can usually be taken with food or without food.

DIDIVIR is contraindicated in:

• patients with known hypersensitivity to tenofovir, emtricitabine or to any of the excipients in DIDIVIR (see section 6.1).
• creatinine clearance < 60 mL/min when used for HIV PrEP
• creatinine clearance < 50 mL/min when used for HIV - 1 treatment
• individuals with unknown or positive HIV - 1 status, for PrEP use
• DIDIVIR should not be used for PrEP in individuals not fully committed to full treatment compliance
• patients who are pregnant or breastfeeding (see section 4.6)
• DIDIVIR should not be co-administered with other tenofovir-containing products, or with other products containing emtricitabine
• DIDIVIR should not be administered with lamivudine-containing products due to similarities between emtricitabine and lamivudine.

Patients with HIV - 1 harbouring mutations

DIDIVIR should be avoided in antiretroviral-experienced patients with HIV - 1 harbouring the K65R mutation (see section 5.1).

Overall HIV - 1 infection prevention strategy

DIDIVIR is not always effective in preventing the acquisition of HIV - 1. The time to onset of protection after commencing DIDIVIR disoproxil is unknown.

DIDIVIR should only be used for pre - exposure prophylaxis as part of an overall HIV - 1 infection prevention strategy including the use of other HIV - 1 prevention measures (e.g. consistent and correct condom use, knowledge of HIV - 1 status, regular testing for other sexually transmitted infections).

Risk of resistance with undetected HIV - 1 infection

DIDIVIR should only be used to reduce the risk of acquiring HIV - 1 in individuals confirmed to be HIV negative (see section 4.3). Individuals should be re-confirmed to be HIV negative at frequent intervals (e.g. at least every 3 months) using a combined antigen/antibody test while taking DIDIVIR for pre - exposure prophylaxis.

DIDIVIR alone does not constitute a complete regimen for the treatment of HIV - 1 and HIV - 1 resistance mutations have emerged in individuals with undetected HIV - 1 infection who are only taking DIDIVIR.

If clinical symptoms consistent with acute viral infection are present and recent (< 1 month) exposures to HIV - 1 are suspected, use of DIDIVIR should be delayed for at least one month and HIV - 1 status reconfirmed before starting DIDIVIR for pre - exposure prophylaxis.

Importance of adherence

The effectiveness of DIDIVIR in reducing the risk of acquiring HIV - 1 is strongly correlated with adherence as demonstrated by measurable drug levels in blood (see section 5.1). HIV - 1 uninfected individuals should be counselled at frequent intervals to strictly adhere to the recommended DIDIVIR daily dosing schedule.

Patients with hepatitis B or C virus infection

See boxed u201cWARNINGSu201d

HIV - 1 infected patients with chronic hepatitis B or C treated with antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions. Medical practitioners should refer to current HIV treatment guidelines for the management of HIV infection in patients co-infected with hepatitis B virus (HBV) or hepatitis C virus (HCV). The safety and efficacy of DIDIVIR for pre - exposure prophylaxis in patients with HBV or HCV infection has not been established.

In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant Summary of Product Characteristics for these medicinal products. See also under Use with ledipasvir and sofosbuvir or sofosbuvir and velpatasvir below.

Discontinuation of DIDIVIR therapy in patients infected with HBV may be associated with severe acute exacerbations of hepatitis. Patients infected with HBV who discontinue DIDIVIR should be closely monitored with both clinical and laboratory follow - up for at least several months after stopping treatment. 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.

Lactic acidosis / Severe hepatomegaly with steatosis

See boxed u201cWARNINGSu201d

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues such as DIDIVIR alone or in combination with other antiretrovirals. 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 DIDIVIR 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 DIDIVIR should be suspended in any patient or uninfected individual 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 DIDIVIR 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, 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 DIDIVIR to patients with known risk factors for liver disease. Treatment with DIDIVIR 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 DIDIVIR. Pancreatitis must be considered whenever a patient develops abdominal pain, nausea, vomiting or elevated biochemical markers. Discontinue treatment with DIDIVIR until diagnosis of pancreatitis is excluded.

Liver disease

Treatment with DIDIVIR can cause hepatomegaly due to non-alcoholic fatty liver disease (hepatitis steatosis). The safety and efficacy of DIDIVIR has not been established in patients with significant underlying liver disorders/diseases. The pharmacokinetics of tenofovir has been studied in patients with hepatic impairment and no dose adjustment is required. The pharmacokinetics of emtricitabine has not been studied in patients with hepatic impairment. Based on minimal hepatic metabolism and the renal route of elimination for emtricitabine, it is unlikely that a dose adjustment would be required for DIDIVIR in patients with hepatic impairment (see section 5.2).

HIV - 1 infected 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.

Mitochondrial dysfunction following exposure in utero

Nucleoside and nucleotide analogues such as DIDIVIR have been demonstrated in vitro and in vivo to cause variable degree of damage to mitochondriae. 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/hyperlactataemia (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. These findings should be considered for any foetus exposed in utero to nucleoside and nucleotide analogues, including HIV-negative infants/children, who present with severe clinical findings of unknown etiology, particularly neurologic findings.

Renal impairment

Emtricitabine and tenofovir, the active ingredients in DIDIVIR, are principally eliminated by the kidney by a combination of glomerular filtration and active tubular secretion. Renal failure, renal impairment, elevated creatinine, hypophosphataemia and proximal tubulopathy (including Fanconi syndrome) (renal tubular injury with severe hypophosphataemia), have been reported in association with the use of tenofovir disoproxil (see section 4.3 and 4.8).

Prior to initiating DIDIVIR for the treatment of HIV - 1 infection or for use in pre - exposure prophylaxis, it is recommended that creatinine clearance should be calculated in all individuals. Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients without risk factors for renal impairment after two to four weeks of use, after three months of use and every three to six months thereafter (see section 4.3). In individuals at risk for renal disease more frequent monitoring of renal function is required.

See also under Co - administration of other medicinal products below. Patients at risk for, or with a history of, renal dysfunction and patients receiving concomitant nephrotoxic medicines should be carefully monitored for changes in serum creatinine and phosphorus. DIDIVIR should not be administered to patients with creatinine below 50 mL/min or patients requiring haemodialysis or for pre - exposure prophylaxis in patients with creatinine clearance below 60 mL/min. Interrupting treatment with DIDIVIR should also be considered in case of progressive decline of renal function when no other cause has been identified.

Bone mineral density

DIDIVIR decreased bone mineral density (BMD). During therapy bone monitoring should be considered for HIV infected patients and HIV - 1 uninfected individuals who have a history of pathologic bone fracture or other risk factors for osteopenia, osteoporosis or bone loss. The effect of supplementation with calcium and vitamin D has not been studied. Such supplementation may be beneficial for all patients. If bone abnormalities are suspected, appropriate consultation should be obtained. If bone abnormalities are suspected or detected then appropriate consultation should be obtained.

Bone mineral density monitoring should be considered for HIV infected patients who have a history of pathologic bone fracture or are at risk of osteopenia. Tenofovir combination therapy associated with decrease in bone mineral density. In clinical trials of HIV - 1 uninfected individuals, decreases in BMD were also observed. In a pre - exposure trial of men having sex with men (MSM), a sub study of 503 subjects found mean changes from baseline in BMD ranging from -0.4 % to -1.0 % across total hip, spine, femoral neck, and trochanter in the Emtricitabine / tenofovir disoproxil group compared with the placebo group. Bone fractures were reported in 1.7 % of the Emtricitabine / tenofovir disoproxil group compared with 1.4 % in the placebo group. No correlation between BMD and fractures was noted. A pre - exposure study in heterosexual couples where one of the partners was HIV - 1 infected, found similar fracture rates between treatment and placebo groups (0.8 % and 0.6 %, respectively). No BMD evaluations were conducted during this trial. Cases of osteomalacia (associated with proximal renal tubulopathy) have been reported in association with the use of tenofovir disoproxil fumarate (tenofovir disoproxil fumarate), such as DIDIVIR (see section 4.8). When using DIDIVIR for pre - exposure prophylaxis individuals should be reassessed at each visit to ascertain whether they remain at high risk of HIV - 1 infection. The risk of HIV - 1 infection should be balanced against the potential for renal and bone effects with long - term use of DIDIVIR.

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 combination antiretroviral therapy (cART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Mineralisation defects

Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of tenofovir disoproxil fumarate as in DIDIVIR (see section 4.8). During therapy with DIDIVIR assessment of bone mineral density (BMD) should be considered for patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. The effect of supplementation with calcium and vitamin D has not been studied. If bone abnormalities are suspected, appropriate consultation should be obtained. In cases of proximal renal tubulopathy, arthralgias and muscle pain or weakness have also been reported. Hypophosphataemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing tenofovir disoproxil fumarate (see section 4.4 Renal impairment).

Lipodystrophy and metabolic abnormalities

Combination antiretroviral therapy such as DIDIVIR has been associated with the redistribution/accumulation of body fat, including central obesity, dorso-cervical fat, enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement and u201ccushingoid appearanceu201d and elevated serum lipid and glucose levels in HIV patients. 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. Clinical examination should include evaluation for physical signs of fat redistribution. Patients with evidence of lipodystrophy should have a thorough cardiovascular risk assessment.

Immune reconstitution syndrome (IRIS)

Immune reconstitution inflammatory syndrome (IRIS) is an immunopathological response resulting from the rapid restoration of pathogen-specific immune responses to pre-existing antigens combined with immune dysregulation, which occurs shortly after starting combination Anti-Retroviral Therapy (cART). Typically such reaction presents by paradoxical deterioration of opportunistic infections being treated or with unmasking of an asymptomatic opportunistic disease, often with an atypical inflammatory presentation. IRIS usually develops within the first few weeks or months of initiation of cART and occurs more commonly in patients with low CD4 counts. Common examples of IRIS reactions to opportunistic diseases are tuberculosis, cytomegalovirus retinitis, cryptococcal meningitis, and atypical mycobacterial infections and Pneumocystis jiroveci pneumonia (PCP).

Appropriate treatment of the opportunistic disease should be instituted or continued and ART continued. Any inflammatory symptoms should be evaluated and treatment instituted when necessary. Severe cases may respond to glucocorticoids, but there is only limited evidence for this in patients with tuberculosis IRIS.

Opportunistic infections

Patients receiving DIDIVIR should be advised that they may continue to develop opportunistic infections and other complications of HIV infection, and therefore they should remain under close observation by healthcare professionals experienced in the treatment of patients with associated HIV disease. Regular monitoring of viral load and CD4 counts needs to be done.

Co - administration of other medicinal products

Use of DIDIVIR should be avoided with concurrent or recent use of a nephrotoxic medicinal product (see section 4.5). If concomitant use with nephrotoxic medicine 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 HIV - 1 infected patients treated with tenofovir disoproxil and with risk factors for renal dysfunction. If DIDIVIR is co-administered with an NSAID, renal function should be monitored adequately.

A higher risk of renal impairment has been reported in HIV - 1 infected patients receiving tenofovir disoproxil in combination with a ritonavir or cobicistat boosted protease inhibitor. Close monitoring of renal function is required in these patients (see section 4.5). In HIV - 1 infected patients with renal risk factors, the co-administration of tenofovir disoproxil with a boosted protease inhibitor should be carefully evaluated.

DIDIVIR should not be administered concomitantly with other medicinal products containing emtricitabine, tenofovir disoproxil, tenofovir alafenamide, or other cytidine analogues, such as lamivudine (see section 4.5). DIDIVIR should not be administered concomitantly with adefovir dipivoxil.

Use with ledipasvir and sofosbuvir, sofosbuvir and velpatasvir or sofosbuvir, velpatasvir and voxilaprevir

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 when co-administered with 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 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.

Co-administration of tenofovir disoproxil and didanosine

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

Triple nucleoside therapy

There have been reports of a high rate of virological failure and of emergence of resistance at an early stage in HIV - 1 infected patients when tenofovir disoproxil was combined with lamivudine and abacavir as well as with lamivudine and didanosine as a once daily regimen. There is close structural similarity between lamivudine and emtricitabine and similarities in the pharmacokinetics and pharmacodynamics of these two medicines.

The risk of HIV transmission to others

Patients should be advised that current antiretroviral therapy, including DIDIVIR, does not prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be employed.

Comprehensive management to reduce the risk of acquiring HIV - 1

Use DIDIVIR for pre - exposure prophylaxis only as part of a comprehensive prevention strategy that includes other preventative measures, such as safer sex practices, because DIDIVIR is not always effective in preventing the acquisition of HIV - 1.

• Counsel uninfected individuals about safer sex practices that include consistent and correct use of condoms, knowledge of their HIV - 1 status and that of their partner(s), and regular testing for other sexually transmitted infections that can facilitate HIV - 1 transmission (such as syphilis and gonorrhoea).
• Inform uninfected individuals about and support their efforts in reducing sexual risk behaviour. Use DIDIVIR to reduce the risk of acquiring HIV - 1 only in individuals confirmed to be HIV negative. HIV - 1 resistance substitutions may emerge in individuals with undetected HIV - 1 infection who are taking only DIDIVIR, because DIDIVIR alone does not constitute a complete treatment regime for HIV - 1 treatment. Therefore, care should be taken to avoid DIDIVIR exposure in HIV - infected individuals (see section 4.3).
• Many HIV - 1 tests, such as rapid tests, detect anti - HIV antibodies and may not identify HIV - 1 during the acute stage of infection. Prior to initiating DIDIVIR for a PrEP indication, evaluate seronegative individuals for current or recent signs or symptoms consistent with acute viral infections (e.g., fever, fatigue, myalgia, skin rash, etc.) and ask about potential exposure events (e.g. unprotected sex, or condom broken during sex with an HIV - 1 infected partner) that may have occurred within the last month.
• If clinical symptoms consistent with acute viral infection are present and recent (< 1 month) exposures are suspected, delay starting PrEP for at least one month and reconfirm HIV - 1 status or use an approved test as an aid in the diagnosis of HIV - 1 infection, including acute or primary HIV - 1 infection.
• While using DIDIVIR for a PrEP indication, HIV - 1 screening tests should be repeated at least once every 3 months. If symptoms consistent with acute HIV - 1 infection develop following a potential exposure event, PrEP should be discontinued until negative infection status is confirmed, using an approved test as an aid in the diagnosis of HIV - 1, including acute or primary HIV - 1 infection.
• Counsel uninfected individuals to strictly adhere to the recommended DIDIVIR dosing schedule. The effectiveness of DIDIVIR in reducing the risk of acquiring HIV - 1 is strongly correlated with adherence, as demonstrated by measurable levels of tenofovir and emtricitabine in clinical trials.

Paediatric population

Safety and effectiveness of DIDIVIR in paediatric patients have not been established. DIDIVIR should only be administered to HIV - 1 infected paediatric patients 12 years of age and older with body weight greater than or equal to 35 kg. Because it is a fixed - dose combination tablet, DIDIVIR cannot be adjusted for patients of lower age and weight.

Geriatric use

Clinical studies of fixed dose combinations of emtricitabine and tenofovir, as in DIDIVIR, did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for the elderly patient should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other medicinal therapy.

Lactose

DIDIVIR contains lactose. Patients with rare hereditary conditions of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take DIDIVIR.

No medicine interaction studies have been conducted using DIDIVIR tablets. Emtricitabine and tenofovir disoproxil fumarate

The steady state pharmacokinetics of emtricitabine and tenofovir, as in DIDIVIR, were unaffected when administered together versus each medicine dosed alone. In vitro and clinical pharmacokinetic interaction studies have shown the potential for CYP450-mediated interactions involving emtricitabine and tenofovir, as in DIDIVIR, with other medicines is low. DIDIVIR are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. No interactions due to competition for renal excretion have been observed. However, co-administration of DIDIVIR with medicines that are eliminated by active tubular secretion may increase concentrations of emtricitabine, tenofovir, and/or the co-administered medicine, and is therefore not recommended. Medicines that decrease renal function may increase concentrations of emtricitabine and/or tenofovir.

Women of childbearing potential

A reliable method of contraception should be used to avoid pregnancy while taking DIDIVIR.

Pregnancy

DIDIVIR should not be used during pregnancy as safety and efficacy have not been established (see section 4.3). If an uninfected individual becomes pregnant while taking DIDIVIR for a PrEP indication, careful consideration should be given to whether use of DIDIVIR should be continued, taking into account the potential increased risk of HIV - 1 infection during pregnancy.

Breastfeeding

HIV - infected mothers should not breastfeed their infants, to avoid risking postnatal transmission of HIV. Animal studies show that tenofovir is excreted in milk. It is not known whether tenofovir and emtricitabine are excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed their infants if they are receiving DIDIVIR.

Fertility

No human data on the effect of DIDIVIR are available. Reported animal studies do not indicate harmful effects of emtricitabine or tenofovir disoproxil on fertility.

No studies on the effects of either tenofovir disoproxil fumarate or emtricitabine on the ability to drive and use machines have been performed. However, dizziness has been reported during treatment with both tenofovir disoproxil fumarate and emtricitabine. If this happens, patients must avoid driving or operating machinery.

HIV - 1 infection: The most frequently reported adverse reactions considered possibly or probably related to emtricitabine and/or tenofovir disoproxil as contained in DIDIVIR were nausea and diarrhoea in a clinical study in adults. The safety profile of emtricitabine and tenofovir disoproxil as contained in DIDIVIR in this study was consistent with the previous experience with these medicines when each was administered with other antiretroviral medicine.

Pre - exposure prophylaxis: No new adverse reactions to tenofovir disoproxil /emtricitabine as contained in DIDIVIR were identified from reported studies in which HIV - 1 uninfected adults received tenofovir disoproxil /emtricitabine as contained in DIDIVIR once daily for pre - exposure prophylaxis. The most frequent adverse reaction reported in the study was headache.

Tabulated list of adverse reactions:

Emtricitabine and Tenofovir disoproxil

Frequency Emtricitabine Tenofovir disoproxil

Blood and lymphatic system disorders

Frequent Neutropenia

Less frequent Anaemia

Frequency unknown Haematuria

Immune system disorders

Frequent Allergic reactions, including angioedema. Angioedema.

Metabolism and nutrition disorders

Frequent Hypertriglyceridermia, hyperglycaemia Hypophosphataemia.

Less Frequent Lactic acidosis and hypokalaemia.

Psychiatric disorders

Frequent Abnormal dreams, insomnia).

Frequency unknown Depression, insomnia, anxiety

Nervous system disorders

Frequent Headache, dizziness.

Less frequent Neuritis, paraesthesia, and peripheral neuropathy.

Frequency unknown Peripheral neuropathy (including peripheral neuritis and neuropathy).

Respiratory, thoracic and mediastinal disorders

Frequent Increased cough, rhinitis, dyspnoea.

Dyspnoea.

Frequency unknown Chest pain, pneumonia.

Gastrointestinal disorders

Frequent Nausea, diarrhoea, vomiting, flatulence, dyspepsia, abdominal pain, elevated amylase including elevated pancreatic amylase, elevated serum lipase.

Nausea, vomiting, diarrhoea, abdominal pain, abdominal distension, and flatulence.

Less frequent Raised serum amylase concentrations, pancreatitis, abdominal pain, and flatulence.

Frequency unknown Dyspepsia.

Hepatobiliary disorders

Frequent Elevated serum aspartate aminotransferase (AST) and/or elevated serum alanine aminotransferase (ALT) and hyperbilirubinaemia.

Increased transaminases

Less frequent Hepatotoxicity, including lactic acidosis, hepatic steatosis and hepatitis.

Frequency unknown Raised liver enzyme (including ALT, AST and gamma GT).

Skin and subcutaneous tissue disorders

Frequent Rash event (including rash, pruritus rash, maculopapular rash, urticaria, vesiculobullous rash and pruritus and skin discolouration, manifested by hyperpigmentation

Rash (including rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash and pustular rash).

Musculoskeletal and connective tissue disorders

Frequent Creatine kinase elevation.

Less frequent Arthralgia, myalgia.

Rhabdomyolysis, osteomalacia (manifested as bone pain and infrequently contributing to fractures), muscular weakness and myopathy.

Frequency unknown Myopathy, osteomalacia (both associated with proximal renal tubulopathy), rhabdomyolysis, muscular weakness.

Bone density decreased (see section 4.4).

Renal and urinary disorders

Less Frequent Increased creatinine, proteinuria, proximal renal tubulopathy including Fanconi syndrome, renal failure (acute and chronic), acute tubular necrosis, nephritis (including acute interstitial nephritis) and nephrogenic diabetes insipidus.

Frequency unknown Renal insufficiency, renal failure, proteinuria.

General disorders and administration site conditions

Frequent Pain, asthenia

Asthenia

Frequency unknown Fever, sweating, and weight loss.

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.

Anaemia was common and skin discolouration (increased pigmentation).

This adverse reaction was identified through reported post-marketing surveillance.

If overdose occurs the patient must be monitored for evidence of toxicity (see section 4.8), and standard supportive treatment applied as necessary.

Emtricitabine

Haemodialysis treatment removes 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 a 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 with an extraction coefficient of approximately 54 %. Following a single 300 mg dose of tenofovir, a four - hour haemodialysis session removed only approximately 10 % of the administered tenofovir dose.