Source: Health Products Regulatory Authority (ZA) Revision Year: 2022 Publisher: Adcock Ingram Limited, 1 New Road, Erand Gardens, Midrand, 1685
LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS INCLUDING FATAL CASES HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION WITH OTHER ANTI-RETROVIRALS (SEE SECTION 4.4).
RIZENE IS NOT INDICATED FOR THE TREATMENT OF CHRONIC INFECTION WITH HEPATITIS B VIRUS (HBV). THE SAFETY AND EFFICACY OF RIZENE IN PATIENTS CO-INFECTED WITH HBV AND HIV HAS NOT BEEN ESTABLISHED. PATIENTS ON TENOFOVIR AND EMTRICITABINE HAVE DISPLAYED SEVERE EXACERBATIONS OF HEPATITIS B UPON DISCONTINUATION OF TREATMENT. LIVER FUNCTION SHOULD BE MONITORED CLOSELY FOR SEVERAL MONTHS AFTER DISCONTINUATION OF RIZENE IN PATIENTS WITH HIV AND HBV CO-INFECTION. CLINICAL AND LABORATORY FOLLOW-UP IS NECESSARY AND IF APPROPRIATE ANTI-HEPATITIS B THERAPY MAY BE WARRANTED (SEE SECTION 4.4).
Lactic acidosis and severe hepatomegaly with steatosis have been reported, including fatal cases, with the use of nucleoside analogues alone or in combination with other anti-retrovirals, with the majority being in women. Obesity and prolonged nucleoside exposure are potential risk factors. Patients with known risk factors for liver disease should only be given nucleoside analogues under cautious observation.
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:
The above lactate values may not be applicable to paediatric patients.
Any patient that 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) should immediately cease RIZENE treatment.
Use of RIZENE can result in hepatomegaly due to non-alcoholic fatty liver disease (hepatic steatosis). The safety and efficacy of RIZENE has not been established in patients with significant underlying liver disorders/diseases. In case of concomitant antiviral therapy for hepatitis B or C, please also consult the relevant professional information for these medicines.
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.
RIZENE is not recommended in patients with moderate to severe hepatic impairment because there are insufficient data to determine whether dose adjustments are required.
There is some evidence that efavirenz is associated with three clinical pathological patterns of drug induced liver failure in HIV positive patients of which the sub massive necrosis histological pattern seems to be associated with high morbidity/mortality risk and may present many months after therapy has been initiated or even stopped. Risk factor include younger age, CD4+ counts ≥350 cell/µl and female gender.
Early detection and treatment of the liver failure and the immediate discontinuation of RIZENE or efavirenz containing medicines should be stressed. Patients who discontinued treatment with RIZENE should be followed up for symptoms/signs of liver failure for up to 12 months.
In patients with a known or suspected history of Hepatitis B or C infection and in patients treated with other medications associated with liver toxicity, monitoring of liver enzymes is recommended. Caution should be exercised and the risk weighed against the benefits of therapy for patients fitting the above profile as well as those with hepatic impairment.
Patients on RIZENE or efavirenz containing antiretroviral treatment (ART) should be regularly monitored for jaundice (including a laboratory bilirubin and liver enzymes) and bleeding tendencies.
Patients with chronic hepatitis B or C and 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 optimal management of HIV infection in patients co-infected with hepatitis B virus (HBV). In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the professional information for these medicines. Patients co-infected with HIV and HBV who discontinue RIZENE should be closely monitored with both clinical and laboratory follow-up after stopping treatment. 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 RIZENE therapy in patients co-infected with HIV and HBV may be associated with severe, acute exacerbations of hepatitis.
Efavirenz is not predominantly excreted by the kidneys while tenofovir disoproxil fumarate and emtricitabine are excreted by the kidneys. Since RIZENE is a fixed-dose combination product and the dose of the individual components cannot be altered, patients with creatinine clearance less than 50 ml/min should not receive RIZENE.
CrCl (ml/min) = 140-age (years) x weight (kg) (x 0,85 if female) / 72 x serum creatinine (mg/dL)
Renal impairment, has been reported in association with the use of tenofovir disoproxil fumarate (see section 4.8).
It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy and as clinically appropriate during therapy with RIZENE. Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients at risk for renal impairment. RIZENE should be avoided with concurrent or recent use of a nephrotoxic agent.
In patients with moderate to severe renal impairment, the terminal half-life of RIZENE is increased due to decreased clearance. The dose of RIZENE should therefore be adjusted (see section 4.2).
QTc prolongation has been observed with the use of efavirenz (see sections 4.3 and 4.5). For patients at increased risk of Torsade de Pointes or who are receiving medicinal products with a known risk for Torsade de Pointes, the administration of RIZENE is contraindicated (see section 4.3).
There have been reports of patients treated with efavirenz, which is a component of RIZENE, experiencing serious side effects such as severe depression, suicidal ideation, suicide attempts, aggressive behaviour, paranoid reactions and manic reactions.
Although efavirenz was associated with an increase in these psychiatric experiences, there are other associated factors such as a history of injection medicine use, psychiatric history and the use of psychiatric medication. Other adverse events such as death by suicide, psychosis like behaviour and delusions have been reported.
Patients with psychiatric adverse experiences should seek medical evaluation for an assessment on whether their symptoms are related to the use of efavirenz, and thus RIZENE (see section 4.8).
Nervous system symptoms that may be reported during treatment with RIZENE are related to efavirenz, which has the potential to cause: dizziness, insomnia, impaired concentration, somnolence, abnormal dreams, hallucinations, euphoria, confusion, agitation, amnesia, stupor, abnormal thinking and depersonalisation.
Nervous system symptoms are more likely to abate after the first 2 to 4 weeks of therapy. It is important to inform patients that they can expect an improvement with continued therapy and that dosing at bedtime may improve the tolerability of nervous system symptoms.
Co-administration of RIZENE with alcohol or psychoactive medicines can result in additive central nervous system effects.
Patients receiving RIZENE 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 providers experienced in the treatment of patients with associated HIV disease. Regular monitoring of viral load and CD4 counts need to be done.
Patients should be advised that current antiretroviral therapy, including RIZENE, does not prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be employed.
There have been reports of a high rate of virological failure and of emergence of resistance at an early stage when tenofovir disoproxil fumarate as in RIZENE, was combined with lamivudine and abacavir as well as with lamivudine and didanosine as a once daily regimen.
Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV negative infants exposed in utero and/or post-natal 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. It is not known whether the neurological disorders are transient or permanent. Any foetus exposed in utero to nucleoside and nucleotide analogues, even 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.
Pancreatitis has been observed in some patients receiving RIZENE. Pancreatitis must be considered whenever a patient develops abdominal pain, nausea, vomiting or elevated biochemical markers. Discontinue use of RIZENE until diagnosis of pancreatitis is excluded.
Rashes may occur and are usually mild to moderate maculopapular skin eruptions that occur within the first two weeks of initiating efavirenz therapy. In most cases the rash resolves after one month of continuing efavirenz therapy. If treatment is interrupted due to the rash, it may be re-initiated later. The various skin rashes may be treated with antihistamines and/or corticosteroids if indicated. This may result in faster resolution and improved tolerability of the rash.
RIZENE should be discontinued in patients experiencing the following skin rashes: rashes associated with blistering, desquamation, mucosal involvement, or rashes associated with fever.
The effects of when tenofovir disoproxil fumarate associated changes in bone mineral density and biochemical markers on long-term bone health and future fracture risk, are not known.
Osteomalacia associated with the use of tenofovir has been reported associated with proximal renal tubulopathy (see section 4.8).
HIV patients who have a history of pathologic bone fracture or are at risk for osteopenia should be considered for bone monitoring. Supplementation with Vitamin D and calcium may be beneficial. If bone abnormalities are suspected, then appropriate consultation must be sought.
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.
Patients with a history of convulsions must be monitored for possible convulsions when using efavirenz therapy. Please see section 4.5 for anticonvulsants such as phenytoin and phenobarbital, for the precautions and plasma level monitoring that may be required.
Combination antiretroviral therapy 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 elevated serum lipid and glucose levels in HIV patients. 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 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 three months of initiation of ART and occurs more commonly in patients with low CD4 counts. Common examples of IRIS reactions to opportunistic diseases are tuberculosis, cytomegalovirus retinitis, and cryptococcal meningitis.
Appropriate treatment of the opportunistic disease should be instituted or continued and ART continued. Inflammatory manifestations generally subside after a few weeks. Severe cases may respond to glucocorticoids, but there is only limited evidence for this in patients with tuberculosis IRIS. Autoimmune disorders (such as Graves' disease) have also been reported as IRIS reactions; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.
Tenofovir disoproxil fumarate has not been adequately investigated for use in paediatric patients and therefore RIZENE is not recommended for use in patients under the age of 18 years.
In general, elderly patients should be treated cautiously, with heightened awareness that this population group tends to experience decreased hepatic, renal or cardiac function and that they usually have concomitant disease or other medicine therapy. There are insufficient studies on the use of efavirenz, emtricitabine and tenofovir by subjects 65 years and older to determine whether they to respond differently than younger subjects.
Do not co-administer RIZENE with the following related medicines:
RIZENE is not recommended for use with products containing St. John’s wort (Hypericum perforatum). Co-administration of NNRTIs, including efavirenz, with St. John’s wort is expected to substantially decrease NNRTI concentrations and this may result in suboptimal levels of efavirenz and lead to loss of virologic response and cause possible resistance to efavirenz or to the class of NNRTls.
Efavirenz is contraindicated for use with medicines that are eliminated predominantly by CYP3A4 hepatic enzymes and that rely on this isoenzyme for clearance (see section 4.3). Altered plasma concentrations may result after co-administration of efavirenz with medicines that are metabolised by isoenzymes 2C9, 2C19, and 3A4 (which are reportedly inhibited by efavirenz) and CYP3A4 (which is reportedly induced by efavirenz). Appropriate dose adjustments may be necessary. Inducers of the CYP3A4 isoenzyme can be expected to increase elimination of efavirenz resulting in lowered plasma concentrations. Medicines regarded as inducers of CYP3A4 include phenobarbital, rifampicin and rifabutin.
Medicines such as acyclovir, adefovir, dipivoxil, cidofovir, ganciclovir, valacyclovir and valganciclovir may cause an increase in serum concentrations of emtricitabine and tenofovir. Emtricitabine and tenofovir are primarily eliminated by the kidneys, and therefore have the potential to interact with medicines that reduce renal function or compete for active tubular secretion. Caution should be exercised when RIZENE is given with medicines with potential for this interaction since the serum concentrations of each medicine may increase.
Tenofovir increases the plasma concentrations of didanosine. Suppression of CD4 cell counts have been observed in patients on a combination regimen of tenofovir disoproxil fumarate with didanosine at a daily dose of 400 mg. Patients receiving tenofovir disoproxil fumarate and didanosine should be monitored closely for didanosine-associated adverse events. This combination should be undertaken with caution. Didanosine should be discontinued in patients who develop didanosine-associated adverse events (Table 2 in section 4.5 can be consulted for didanosine dosing adjustment recommendations).
Although the mechanism of interaction is not clearly understood, atazanavir and lopinavir/ritonavir have been shown to increase tenofovir concentrations.
The impact of raised tenofovir serum concentrations may involve a higher incidence of tenofovir-related adverse events including renal disorders. RIZENE should be discontinued immediately in patients that experience tenofovir-related side effects. Table 2 in section 4.5 can be consulted for atazanavir dosing adjustment recommendations.
Important medicine interactions for RIZENE are summarised in this leaflet and further tabulated in Table 1, based upon investigations of interaction profiles for the individual active ingredients efavirenz, emtricitabine and tenofovir disoproxil fumarate. Please also see section 4.3. Interaction studies for RIZENE have not been conducted and therefore the information herein is not all inclusive but highlights potentially significant interactions.
Table 1. Contraindicated medicines or medicines not recommended for use with RIZENE:
| Medicine name | Clinical comment |
|---|---|
| Antifungal: Voriconazole | Co-administration is contraindicated as efavirenz decreases voriconazole plasma concentrations and therapeutic efficacy, whereas voriconazole increases efavirenz plasma concentrations and thereby increasing the risk of efavirenz- related side effects. |
| Antihistamine: Astemizole | Contraindicated as life-threatening adverse events like cardiac dysrhythmias may occur. |
| Ergot derivatives: Dihydroergotamine Ergonovine Ergotamine Methylergonovine | Contraindicated as life-threatening adverse events like acute ergot toxicity characterised by peripheral vasospasm and extreme ischaemia may occur. |
| Anti-retrovirals: Efavirenz Emtricitabine Tenofovir disoproxil fumarate Lamivudine | Use is not recommended as emtricitabine, tenofovir disoproxil fumarate, emtricitabine-tenofovir disoproxil fumarate and efavirenz are already active ingredients in RIZENE. Lamivudine is similar to emtricitabine. |
| Benzodiazepines: Midazolam Triazolam | Contraindicated as life-threatening adverse events such as prolonged or increased sedation or respiratory depression may occur. |
| Calcium channel blockers: Bepridil | Contraindicated as life-threatening adverse events like cardiac dysrhythmias may occur. |
| Gastrointestinal motility agent: Cisapride | Contraindicated as life-threatening adverse events like cardiac dysrhythmias may occur. |
| Neuroleptic: Pimozide | Contraindicated as life-threatening adverse events like cardiac dysrhythmias may occur. |
| St. John’s wort (Hypericum parforatum) | Co-administration is not recommended as efavirenz plasma concentrations may be lowered significantly. |
Table 2. Medicines with established interactions and dose recommendations due to known or predicted interactions:
| Concomitant Medicine Class: Medicine name | Effect | Clinical comment |
|---|---|---|
| Antiretroviral agents: | ||
| Protease inhibitors | ||
| Amprenavir | ↓ amprenavir concentration | Efavirenz may decrease serum concentrations of amprenavir. |
| Fosamprenavir calcium | ↓ amprenavir concentration | Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and RIZENE with respect to safety and efficacy have not been established. An additional 100 mg/day (300 mg total of ritonavir) is recommended when RIZENE is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when RIZENE is administered with fosamprenavir plus ritonavir twice daily. |
| Atazanavir | ↓ atazanavir concentration ↑ tenofovir concentration | Atazanavir concentrations are decreased by both Tenofovir disoproxil fumarate and efavirenz. Therefore, co-administration of RIZENE and atazanavir is not recommended due to concerns regarding decreased atazanavir concentrations. |
| Indinavir | ↓ indinavir concentration | The optimal dose of indinavir when given in combination with efavirenz is not known. Increasing the dose to 1 000 mg/8 hours does not compensate for the increased indinavir metabolism due to efavirenz. |
| Lopinavir/ritonavir | ↓ lopinavir concentration ↑ tenofovir concentration | A dose increase of lopinavir/ritonavir to 600/150 mg (3 tablets) twice daily may be considered when used in combination with efavirenz. In treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). If patient monitoring reveals an increased incidence of tenofovir-related side effects RIZENE should be discontinued. |
| Ritonavir | ↑ efavirenz and ritonavir concentrations | The combination of ritonavir 500 mg every 12 hours and efavirenz 600 mg once daily, is associated with a higher frequency of adverse clinical experiences (e.g. dizziness, nausea, paraesthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when RIZENE is used in combination with ritonavir. |
| Saquinavir | ↓ saquinavir concentration | If co-administered with RIZENE, saquinavir should not be used as the sole protease inhibitor. |
| NRTI’s | ||
| Didanosine | ↑ didanosine concentration | Didanosine-associated side effects such as pancreatitis and neuropathy may result from higher concentrations of didanosine. There is insufficient data to guide dose-adjustment in adult patients weighing less than 60 kg but for those over 60 kg the dose of didanosine must be decreased to 250 mg if co administered with RIZENE. Caution must be exercised if co- administration is desired and patients must be monitored closely for didanosine-related side effects. More information will appear on the didanosine professional information. When co-administered, efavirenz and didanosine may be taken under fasted conditions or with a light meal (less than 400 kcal, 20% fat). Co-administration of RIZENE and a buffered didanosine formulation should be under fasting conditions. |
| Anticoagulant: | ||
| Warfarin | ↑ or ↓ warfarin concentration | Monitor anti-coagulation levels (INR) as efavirenz has the potential to alter coagulation times. |
| Anticonvulsants | ||
| Carbamazepine | ↓ carbamazepine concentration | Alternative anticonvulsant treatment should be selected as the data is insufficient to guide dosing adjustment. |
| Phenytoin Phenobarbital | ↓ anticonvulsant concentration and ↓ efavirenz concentration | Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted. |
| Antidepressants | ||
| Sertraline | ↓ sertraline concentrations | Clinical responses must guide an increase in the sertraline dose. |
| Antifungals | ||
| Itraconazole | ↓ itraconazole concentration ↓ hydroxy-itraconazole concentration | Consider alternative antifungal treatment because clinical dose recommendations are unknown. |
| Ketoconazole | ↓ ketoconazole concentration | The effects of ketoconazole and RIZENE are unknown. Efavirenz may decrease plasma concentrations of ketoconazole. |
| Anti-infective | ||
| Clarithromycin | ↓ clarithromycin concentration ↑ 14-OH metabolite concentration | No dose adjustment is needed for RIZENE when used with clarithromycin. Azithromycin should be considered as an alternative to clarithromycin. Erythromycin and other macrolides have not been studied. |
| Antimycobacterials | ||
| Rifabutin | ↓ rifabutin concentration | Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week. |
| Rifampicin | ↓ efavirenz concentration | Dosing recommendations for concomitant use of RIZENE and rifampicin have not been established. Clinical significance of reduced efavirenz concentration is unknown. |
| Calcium channel blockers | ||
| Diltiazem Others (e.g. felodipine, nicardipine, nefedipine, verapamil) | ↓ diltiazem concentration ↓ desacetyl diltiazem Concentration ↓ N-monodesmethyl diltiazem concentration ↓ calcium channel blocker concentration | Diltiazem dose adjustments should be undertaken in consultation with the diltiazem professional information, RIZENE dose need not be adjusted. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response in consultation with the complete professional information for the calcium channel blocker. |
| HMG-CoA reductase inhibitors | ||
| Atorvastatin Pravastatin Simvastatin | ↓ atorvastatin, pravastatin and simvastatin | The concentrations of the HMG-CoA reductase inhibitors are decreased by efavirenz and dose adjustments may be done with reference to the individual product professional information. |
| Narcotic analgesics | ||
| Methadone | ↓ methadone concentrations | Co-administration of efavirenz in HIV- infected individuals with a history of injection medicine use caused a decrease in methadone plasma levels and signs of opiate withdrawal. Close patient monitoring and dose adjustment to increase methadone upon appearance of withdrawal symptoms until alleviation of symptoms is recommended. Concomitant administration with RIZENE is contraindicated due to the risk for QTc prolongation (see sections 4.3 and 4.4). |
| Oral contraceptives | ||
| Ethinyloestradiol | ↑ ethinyloestradiol concentration | As the potential interaction with efavirenz with oral contraceptives has not been studied, a reliable barrier contraceptive must be used in addition to oral contraceptives. |
False positive urine cannabinoid test results have been observed in non-HIV-infected volunteers receiving efavirenz when the Microgenics Cedia DAU Multi-Level THC assay was used for screening, even though efavirenz does not bind to cannabinoid receptors. More specific confirmatory testing was performed with gas chromatography/ mass spectrometry to reveal and confirm negative results. For more information, please consult the professional information for efavirenz.
Women of childbearing age who are using RIZENE should avoid falling pregnant and should ensure this by using a barrier method of contraception in combination with other methods of contraception. Pregnancy testing should also be conducted prior to initiating RIZENE treatment.
Barrier contraception should always be used in combination with other methods of contraception (for example, oral or other hormonal contraceptives, see section 4.5) while on therapy with RIZENE. Because of the long half-life of efavirenz, use of adequate contraceptive measures for 12 weeks after discontinuation of RIZENE is recommended.
RIZENE should not be used during pregnancy.
Administration of efavirenz in the first trimester has the potential to cause harm to the unborn foetus and should the woman become pregnant, she should be educated on the potential harm to the foetus.
Efavirenz has been associated with teratogenicity in animals. Retrospective studies of pregnancies with first-trimester exposure to efavirenz as part of a combination regimen have noted a few cases of neural tube defects, including meningomyelocele.
RIZENE should not be taken by breast-feeding women. Mothers should be instructed that they may not breastfeed their infants if they are on RIZENE in order to avoid transmission of HIV to the infant.
Efavirenz, emtricitabine and tenofovir have been shown to be excreted in human milk. There is insufficient information on the effects of efavirenz, emtricitabine and tenofovir in newborns/infants. A risk to the infants cannot be excluded.
No human data on the effect of RIZENE are available. Animal studies do not indicate harmful effects of efavirenz, emtricitabine or tenofovir disoproxil on fertility.
Co-administration of RIZENE with alcohol or psychoactive medicines can result in additive central nervous system effects. Patients experiencing central nervous system symptoms such as dizziness, impaired concentration and/or drowsiness should avoid tasks related to operation of machinery and other potentially hazardous tasks.
The professional information for efavirenz, emtricitabine and tenofovir disoproxil fumarate in combination with other anti-retroviral medicines, can be referred to for additional information RIZENE side effects are summarised in the tables below.
Table 3. Side effects associated with the use of RIZENE active ingredients:
| System Organ Class | Side effects observed with efavirenz | Side effects observed with emtricitabine and tenofovir | Efavirenz, emtricitabine and Tenofovir (DF) in combination: The following side effects have been reported to occur |
|---|---|---|---|
| Infections and infestations | Frequent: Sinusitis, upper respiratory tract infections, nasopharyngitis | ||
| Blood and lymphatic system disorders | Frequency unknown: Neutropenia, anaemia | ||
| Immune system disorders | Frequent: Immune reconstitution syndrome | ||
| Endocrine disorders | Frequency unknown: Sweating, nephrogenic diabetes insipidus | Frequency unknown: Cushingoid appearance, accumulation of body fat, dorsocervical fat enlargement (buffalo hump) | |
| Metabolism and nutrition disorders | Frequency unknown: Anorexia | Frequent: Anorexia, lactic acidosis | |
| Psychiatric disorders | Frequent: Impaired concentration, anxiety, nervousness, euphoria, confusion, somnolence, amnesia, abnormal thinking or dreaming Frequency unknown: Aggressive behaviour, suicidal thoughts or attempts | Frequent: Anxiety, headaches Less frequent: Abnormal dreams Frequency unknown: Depression, insomnia | Frequent: Depression, insomnia, abnormal dreams |
| Nervous system disorders | Frequent: Headache, dizziness, insomnia Less frequent: Hypoaesthesia, convulsions, depersonalisation, paraesthesia, nervousness | Less frequent: Paraesthesia, peripheral neuropathy, anxiety, insomnia, dizziness, headache | Frequent: Somnolence, headache, dizziness |
| Ear and labyrinth disorders | Less frequent: Tinnitus | ||
| Respiratory, thoracic and mediastinal disorders | Frequency unknown: Dyspnoea | Frequent: Cough, rhinitis, pneumonia Less frequent: Dyspnoea | |
| Gastrointestinal disorders | Frequent: Dyspepsia, abdominal pain, pancreatitis, diarrhoea, nausea, vomiting Frequency unknown: Constipation, malabsorption | Frequent: Dyspepsia, abdominal pain, diarrhoea, nausea, vomiting, flatulence Less frequent: Pancreatitis | Frequent: Diarrhoea, nausea, vomiting |
| Hepato-biliary disorders | Frequent: Raised liver enzymes Frequency unknown: Hepatic failure | Less frequent: Hepatotoxicity Frequency unknown: Hepatitis | |
| Skin and subcutaneous tissue disorders | Frequent: Pruritis, skin rash Less frequent: Erythema multiforme, Stevens- Johnson syndrome, photo-allergic dermatitis, skin discolouration | Frequent: Rash event, pruritis Less frequent: Hyper-pigmentation of soles and/or palms, maculopapular and vesiculobullous rash, urticaria | Frequent:: Rash |
| Musculoskeletal, connective tissue and bone disorders | Frequent: Arthralgia, myalgia Frequency unknown: Myopathy | Frequent: Back pain Less frequent: Myalgia, bone pain, osteomalacia, arthralgia, myopathy | |
| Renal and urinary disorders | Frequency unknown: Nephritis, acute renal failure, renal impairment, Fanconi’s syndrome, acute tubular necrosis, polyuria, proximal renal tubulopathy | ||
| Reproductive system and breast disorders | Frequency unknown: Breast enlargement | ||
| General disorders and administrative site conditions | Frequency unknown: Fatigue | Frequency unknown: Fatigue | Frequent: Fatigue |
| Investigations | Less frequent: Raised serum cholesterol and triglycerides, raised serum amylases | Frequency unknown: Elevations of bilirubin, pancreatic amylase, serum glucose, urine glucose, raised serum amylase, hypophosphataemia, raised liver enzymes | Frequency unknown: Laboratory abnormalities related to fasting cholesterol, creatine kinase, serum amylase, alkaline phosphatise, AST, ALT, haemoglobin, hyperglycaemia, haematuria, neutrophils, fasting triglycerides, hyper- triglyceridaemia, hypercholesterolaem ia, insulin resistance, hyperlactataemia, hyperlipidaemia |
Table 4. Side effects reported from post-marketing surveillance of RIZENE:
| System Organ Class | Efavirenz | Tenofovir | Emtricitabine |
|---|---|---|---|
| Immune system disorders | Allergic reactions, immuno-allergic liver injury/failure | Allergic reactions | No additional events have been identified for inclusion in this section. |
| Endocrine disorders | Gynaecomastia | ||
| Metabolism and nutrition disorders | Redistribution/ accumulation of body fat (see section 4.4), hyper-cholesterolemia, hyper-triglyceridemia | Hypophosphataemia, lactic acidosis | |
| Psychiatric disorders | Aggressive reactions, agitation, delusions, emotional lability, mania, neurosis, paranoia, psychosis, suicide | ||
| Nervous system disorders | Abnormal co- ordination, ataxia, convulsions, hypoesthesia, tremor | ||
| Eye disorders | Abnormal vision | ||
| Ear and labyrinth disorders | Tinnitus | ||
| Cardiac disorders | Palpitations | ||
| Respiratory, thoracic and mediastinal disorders | Dyspnoea | Dyspnoea | |
| Gastrointestinal disorders | Constipation, malabsorption | ||
| Hepato-biliary disorder | Hepatic enzyme increases in hepatic failure, hepatitis | Increased liver enzymes, hepatitis | |
| Skin and subcutaneous tissue disorders | Flushing, erythema multiforme, nail disorders, photoallergic dermatitis, skin discolouration, Stevens-Johnson syndrome | Rash | |
| Musculo-skeletal, connective tissue and bone disorders | Myopathy | Myopathy, osteomalacia (both associated with proximal renal tubulopathy) | |
| Renal and urinary disorders | Renal insufficiency, renal failure, acute renal failure, Fanconi syndrome, proximal tubulopathy, proteinuria, increased creatinine, acute tubular necrosis, nephrogenic diabetes insipidus, polyuria, interstitial nephritis (including acute cases) | ||
| General disorders and administrative site conditions | Asthenia | Asthenia |
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reactions Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8
Not applicable.
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