Source: Health Products Regulatory Authority (ZA) Revision Year: 2022 Publisher: Adcock Ingram Limited, 1 New Road, Erand Gardens, Midrand, 1685 Customer Care: 0860 ADCOCK (232625)
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 ANTIRETROVIRALS (SEE SECTION 4.4). NUVACO IS NOT INDICATED FOR THE TREATMENT OF CHRONIC HEPATITIS B VIRUS (HBV) INFECTION. SAFETY AND EFFICACY OF NUVACO HAS NOT BEEN ESTABLISHED IN PATIENTS CO-INFECTED WITH HBV AND HIV. SEVERE ACUTE EXACERBATIONS OF HEPATITIS B HAVE BEEN REPORTED IN PATIENTS WHO ARE CO-INFECTED WITH HBV AND HIV AND HAVE DISCONTINUED THE COMBINATION TABLET. HEPATIC FUNCTION SHOULD BE MONITORED CLOSELY WITH BOTH CLINICAL AND LABORATORY FOLLOW-UP FOR AT LEAST SEVERAL MONTHS IN PATIENTS WHO DISCONTINUE NUVACO AND ARE CO-INFECTED WITH HIV AND HBV IF APPROPRIATE, INITIATION OF ANTI-HEPATITIS B THERAPY MAY BE WARRANTED (SEE SECTION 4.4).
Safety and efficacy of the individual active ingredients in various antiretroviral combination regimens with similar dosages as contained in NUVACO have been established in clinical studies for the treatment of HIV patients. However, safety and efficacy of the fixed-drug combination as in NUVACO for the treatment of HIV have not been established in clinical studies.
The complete professional information of the other medicines used in combination should be consulted before initiation of therapy.
Combination antiretroviral therapy, including NUVACO has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia.
Combination antiretroviral therapy, including NUVACO, has also 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.
A higher risk of lipodystrophy has been associated with individual factors such as older age, and with medicine related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Fasting serum lipids and blood glucose levels should be monitored. Lipid disorders should be managed as clinically appropriate.
Patients with evidence of lipodystrophy should also have a thorough cardiovascular risk assessment.
In HIV infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (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, cryptococcal meningitis and Pneumocystis jirovecii (carinii) pneumonia. Any inflammatory symptoms should be evaluated, treatment instituted when necessary 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, Guillain-Barre syndrome, polymyositis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.
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), including components of NUVACO. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.
Patients receiving NUVACO may continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close clinical observation by healthcare providers experienced in the treatment of patients with HIV-associated disease.
Patients must be advised that treatment with NUVACO, has not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions must continue to be used.
Lactic acidosis, usually associated with hepatic steatosis, including fatal cases, has been reported with the use of nucleoside analogues, such as in NUVACO. Early symptoms (symptomatic hyperlactataemia) include benign digestive symptoms (nausea, vomiting and abdominal pain), non-specific malaise, loss of appetite, weight loss, respiratory symptoms (rapid and/or deep breathing) or neurological symptoms (including motor weakness). Lactic acidosis has a high mortality and may be associated with pancreatitis, liver failure or renal failure.
Lactic acidosis generally occurs after a few or several months of treatment. Treatment with nucleoside analogues should be discontinued in the setting of symptomatic hyperlactataemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating aminotransferase levels.
Suspicious biochemical features include mild raised transaminases, raised lactate dehydrogenase (LDH) and/or creatine kinase.
In patients with suspicious symptoms or biochemistry, measure the venous lactate level (normal <2 mmol/L) and respond as follows:
The above lactate values may not be applicable to paediatric patients.
Diagnosis of lactic acidosis is confirmed by demonstrating metabolic acidosis with an increased anion gap and raised lactate level. Therapy should be stopped in any acidotic patient with a raised lactate level.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of NUVACO alone or in combination, in the treatment of HIV infection. Most cases were women.
Caution should be exercised when administering NUVACO to patients with known risk factors for liver disease.
Treatment with NUVACO should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity.
Caution should be exercised when administering nucleoside analogues as contained in NUVACO to any patient (particularly obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease and hepatic steatosis (including certain medicines and alcohol). Patients co-infected with hepatitis C and treated with alpha interferon and ribavirin may constitute a special risk. Patients at increased risk should be followed closely. However, cases have also been reported in patients with no known risk factors.
There are no study results demonstrating the effect of NUVACO on clinical progression of HIV-1.
Nucleoside and nucleotide analogues as contained in NUVACO 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 postnatally 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, convulsion, abnormal behaviour). 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 lamivudine, as in NUVACO. It is unclear whether this is due to lamivudine or to underlying HIV disease. Pancreatitis must be considered whenever a patient develops abdominal pain, nausea, vomiting or elevated biochemical markers. Discontinue use of NUVACO until diagnosis of pancreatitis is excluded.
In patients with renal impairment, the terminal half-life of NUVACO is increased due to decreased clearance (see section 4.3).
NUVACO is a combination medicine and the dose of the individual components cannot be altered. Tenofovir disoproxil fumarate and lamivudine are principally eliminated by the kidney. NUVACO is not recommended for patients with creatinine clearance <50 mL/min or patients who require haemodialysis. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia) has been reported with the use of tenofovir disoproxil fumarate in clinical practice. Careful monitoring of renal function (serum creatinine and serum phosphate) is therefore recommended before taking NUVACO.
Since NUVACO is primarily eliminated by the kidneys, co-administration of NUVACO with medicines that reduce renal function or compete for active tubular secretion may increase serum concentrations of NUVACO and/or increase the concentrations of other renally eliminated medicines. Some examples include, but are not limited to adefovir dipivoxil, cidofovir, acyclovir, valaciclovir, ganciclovir and valganciclovir.
Renal safety with tenofovir has only been studied to a very limited degree in adult patients with impaired renal function (creatinine clearance <80 mL/min).
It is recommended that renal function (creatinine clearance and serum phosphate) is assessed in all patients prior to initiating therapy with tenofovir disoproxil fumarate and that it is also monitored every four weeks during the first year of tenofovir disoproxil fumarate therapy, and then every three months. In patients at risk for renal impairment, including patients who have previously experienced renal events while receiving adefovir dipivoxil, consideration should be given to more frequent monitoring of renal function.
Use of tenofovir disoproxil fumarate should be avoided with concurrent or recent use of a nephrotoxic medicine (e.g. aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2). If concomitant use of tenofovir disoproxil fumarate and nephrotoxic medicines is unavoidable, renal function should be monitored weekly.
Tenofovir disoproxil fumarate has not been clinically evaluated in patients receiving medicines 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 medicine). These renal transport proteins may be responsible for tubular secretion and in part, renal elimination of tenofovir and cidofovir.
Consequently, the pharmacokinetics of these medicines, 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 medicines which are secreted by the same renal pathway is not recommended, but if such use is unavoidable, renal function should be monitored weekly.
NUVACO should be avoided with concurrent or recent use of a nephrotoxic medicine. Patients at risk of, or with a history of, renal dysfunction and patients receiving concomitant nephrotoxic substances should be carefully monitored for changes in serum creatinine and phosphorus.
NUVACO should be avoided in antiretroviral experienced patients with HIV-1 harbouring the K65R mutation.
Decreases in bone mineral density of spine and changes in bone biomarkers from baseline are significantly greater with tenofovir disoproxil fumarate as contained in NUVACO. Decreases in bone mineral density of the hip are significantly greater. Clinically relevant bone fractures are reported. If bone abnormalities are suspected, then appropriate consultation should be obtained. Bone monitoring should be considered for HIV infected patients who have a history of pathologic bone fracture or are at risk of osteopenia.
NUVACO may cause a reduction in bone mineral density. The effects of tenofovir disoproxil fumarate-associated changes in bone mineral density on long-term bone health and future fracture risk are currently unknown.
Bone monitoring should be considered for HIV infected patients who have a history of pathologic bone fracture or are at risk for osteopenia. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected, then appropriate consultation should be obtained.
Bone abnormalities (infrequently contributing to fractures) may be associated with proximal renal tubulopathy.
Use of NUVACO can result in hepatomegaly due to non-alcoholic fatty liver disease (hepatic steatosis). The safety and efficacy of NUVACO 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 according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.
NUVACO is not indicated for the treatment of chronic HBV infection. The safety and efficacy of NUVACO has not been established for the treatment of patients co-infected with HBV and HIV.
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 relevant professional information for these medicines.
Patients co-infected with HIV and HBV who discontinue NUVACO 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 NUVACO therapy in patients co-infected with HIV and HBV may be associated with severe, acute exacerbations of hepatitis.
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. 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.
Acute exacerbations of hepatitis have been reported in patients after the discontinuation of 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.
Dolutegravir, as in NUVACO is associated with a risk for hypersensitivity reactions (HSR) and share some common features such as fever and/or rash with other symptoms indicating multi-organ involvement.
Discontinue dolutegravir, as in NUVACO and other suspect agents if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial oedema, hepatitis, eosinophilia, angioedema).
Clinical status including liver aminotransferases should be monitored and appropriate therapy initiated. Delay in stopping treatment with dolutegravir, as in NUVACO and other suspect agents after the onset of hypersensitivity may result in a life-threatening reaction.
Safety and effectiveness in paediatric patients and patients <18 years of age have not been established.
Clinical studies did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.
The likelihood of metabolic interactions is low due to limited metabolism as plasma protein binding and almost complete renal clearance.
Zidovudine plasma levels are not significantly altered when co-administered with lamivudine, as in NUVACO. Zidovudine has no effect on the pharmacokinetics of lamivudine, as in NUVACO.
Table 2. Medicine interactions: Changes in pharmacokinetic parameters for coadministered medicine in the presence of lamivudine:
| Co-administered medicine | Dose of co-administered medicine | Change of co-administered medicine pharmacokinetic parameters | |
| Zidovudine | No dosage adjustments necessary | 13% ↑ in zidovudine exposure 28% ↑ in peak plasma levels | |
| Zalcitabine | Do not use in combination | May inhibit intracellular phosphorylation of zalcitabine | |
| Trimethoprim (a constituent of co-trimoxazole) | No dosage adjustments necessary, unless the patient has renal impairment. NUVACO has no effect on the pharmacokinetics of co-trimoxazole. | ↑ in NUVACO plasma levels | ↔ |
| Etravirine (ETR) | Co-administration is not recommended, unless the patient is also receiving concomitant atazanavir + ritonavir (ATV + RTV), lopinavir + ritonavir (LPV + RTV) or darunavir + ritonavir (DRV + RTV) | ||
| Emtricitabine | Due to similarities, lamivudine as in NUVACO should not be administered concomitantly with other cytidine analogues, such as emtricitabine. Moreover, lamivudine as in NUVACO should not be taken with any other medicinal products containing lamivudine. | ||
| Cladribine | In vitro, lamivudine inhibits the intracellular phosphorylation of cladribine leading to a potential risk of cladribine loss of efficacy in case of combination in the clinical setting. Some clinical findings also support a possible interaction between lamivudine and cladribine. Therefore, the concomitant use of lamivudine with cladribine is not recommended. | ||
| Ranitidine or cimetidine | Do not interact with lamivudine. No dosage adjustments necessary. | ||
| Products containing sorbitol or osmotic acting poly-alcohols or monosaccharide alcohols (e.g. xylitol, mannitol, lactitol, maltitol). | Studies conducted demonstrated that co-administration of sorbitol solution (3,2 g, 10,2 g, 13,4 g) with a single 300 mg dose of lamivudine oral solution resulted in dosedependent decreases of 14%, 32%, and 36% in lamivudine exposure (AUC∞) and 28%, 52%, and 55% in the Cmax of lamivudine in adults. Where possible, avoid chronic co-administration of lamivudine, as in NUVACO, with medicinal products containing sorbitol or other osmotic acting poly-alcohols or monosaccharide alcohols (e.g. xylitol, mannitol, lactitol, maltitol). Consider more frequent monitoring of HIV-1 viral load when chronic coadministration cannot be avoided. | ||
Abbreviations: ↑ = increase; ↓ = decrease; ↔ = no effect The possibility of interactions with other medicines administered concurrently should be considered, particularly when the main route is renal.
No medicine interaction studies have been conducted using NUVACO. As NUVACO contains tenofovir disoproxil fumarate and lamivudine, any interactions that have been identified with these individual medicines may occur with NUVACO. Important medicine interaction information for NUVACO is summarised in Tables 2, 3, 4 and 5.
The medicine interactions described are based on studies conducted with tenofovir disoproxil fumarate or lamivudine as individual medicines or are potential medicine interactions. While the tables include potentially significant interactions, they are not all inclusive. Based on the results of in vitro experiments and the known elimination pathway of tenofovir disoproxil fumarate, the potential for CYP450 mediated interactions involving tenofovir with other medicines is low. An interaction with trimethoprim, a constituent of cotrimoxazole, causes a 40% increase in lamivudine exposure at therapeutic doses. This does not require dose adjustment unless the patient also has renal impairment. Administration of co-trimoxazole with the lamivudine/zidovudine combination in patients with renal impairment should be carefully assessed.
Tenofovir disoproxil fumarate is primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. Co-administration of tenofovir disoproxil fumarate with medicines that are eliminated by active tubular secretion may increase serum concentrations of either tenofovir disoproxil fumarate or the co-administered medicines, due to competition for this elimination pathway. Medicines that decrease renal function may also increase serum concentrations of tenofovir disoproxil fumarate, as in NUVACO.
Tenofovir disoproxil fumarate has been evaluated in healthy volunteers in combination with abacavir, adefovir dipivoxil, atazanavir, didanosine, efavirenz, emtricitabine, indinavir, lamivudine, Iopinavir/ritonavir, methadone, oral contraceptives and ribavirin. Tables 3 and 4 summarise pharmacokinetic effects of co-administered medicine on tenofovir disoproxil fumarate pharmacokinetics and effects of tenofovir disoproxil fumarate on the pharmacokinetics of co-administered medicine.
When administered with multiple doses of tenofovir disoproxil fumarate, the Cmax and AUC of didanosine 400 mg increased significantly. The mechanism of this interaction is unknown.
When didanosine 250 mg enteric-coated capsules were administered with tenofovir,
systemic exposures to didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions.
Table 3. Medicine interactions: Changes in pharmacokinetic parameters for tenofovir1 in the presence of co-administered medicines:
| Co-administered medicine | Dose of coadministered medicine (mg) | N | % Changes of tenofovir pharmacokinetic parameters² (90% CI) | ||
| Cmax | AUC | Cmin | |||
| Abacavir | 300 once | 8 | ↔ | ↔ | NC |
| Adefovir dipivoxil | 10 once | 22 | ↔ | ↔ | ↔ |
| Atazanavir | 400 once daily x 14 days | 33 | ↑14 | Atazanavir | 400 once daily x 14 days |
| Didanosine (entericcoated) | 400 once | 25 | ↔ | ↔ | ↔ |
| Didanosine (buffered) | 250 or 400 once daily x 7 days | 14 | ↔ | ↔ | ↔ |
| Efavirenz | 600 once daily x 14 days | 29 | ↔ | ↔ | ↔ |
| Emtricitabine | 200 once daily x 7 days | 17 | ↔ | ↔ | ↔ |
| Indinavir | 800 three times daily x 7 days | 13 | ↑14 | Indinavir | 800 three times daily x 7 days |
| Lamivudine | 150 twice daily x 7 days | 15 | ↔ | ↔ | ↔ |
| Lopinavir/Ritonavir | 400/100 twice daily x 14 days | 24 | ↔ | ↑32 | Lopinavir/Ritonavir |
| Nelfinavir | 1250 twice daily x 14 days | 29 | ↔ | ↔ | ↔ |
| Saquinavir/Ritonavir | 1000/100 twice daily x 14 days | 35 | ↔ | ↔ | ↑23 (↑16 to ↑30) |
1 Patients received tenofovir disoproxil fumarate 300 mg once daily
2 Increase = ↑; Decrease = ↓; No effect = ↔; NC = Not calculated
Following multiple dosing to HIV-negative subjects receiving either chronic methadone maintenance therapy, oral contraceptives, or single doses of ribavirin, steady-state tenofovir pharmacokinetics were similar to those observed in previous studies, indicating a lack of clinically significant medicine interactions between these medicines and tenofovir disoproxil fumarate.
Table 4. Medicine interactions: Changes in pharmacokinetic parameters for coadministered medicines in the presence of tenofovir disoproxil fumarate:
| Co-administered medicine | Dose of co-administered medicine (mg) | N | % Change of co-administered medicine pharmacokinetic parameters1 (90% Cl) | ||
| Cmax | AUC | Cmin | |||
| Abacavir | 300 once | 8 | ↑12 (↓1 to ↑26) | ↔ | NA |
| Adefovir dipivoxil | 10 once | 22 | ↔ | ↔ | NA |
| Efavirenz | 600 once daily x 14 days | 30 | ↔ | ↔ | ↔ |
| Emtricitabine | 200 once daily x 7 days | 17 | ↔ | ↔ | ↑20 (↑12 to ↑29) |
| Indinavir | 800 three times daily x 7 days | 12 | ↓11 (↓30 to ↑12) | ↔ | ↔ |
| Lamivudine | 150 twice daily x 7 days | 15 | ↓24 (↓34 to ↓12) | ↔ | ↔ |
| Lopinavir/Ritonavir | 400/100 twice daily × 14 days | 21 | ↔ | ↔ | ↔ |
| Methadone2 | 40-110 once daily x 14 days3 | 13 | ↔ | ↔ | ↔ |
| Oral contraceptives4 | Ethinyl oestradiol/norgestimate once daily x 7 days | 20 | ↔ | ↔ | ↔ |
| Ribavirin | 600 once | 22 | ↔ | ↔ | NA |
| Ritonavir | Lopinavir/Ritonavir 400/100 twice daily x 14 days | 24 | ↔ | ↔ | ↔ |
| Atazanavir5 | 400 once daily x 14 days | 34 | ↓21 (↓27 to ↓14) | ↓25 (↓30 to ↓19) | ↓40 (↓48 to ↓32) |
| Atazanavir5 | Atazanavir/Ritonavir 300/100 once daily x 42 days | 10 | ↓28 (↓50 to ↑5) | ↓25 (↓42 to ↓3) | ↓236 (↓46 to ↑10) |
| Saquinavir | Saquinavir/Ritonavir 1000/100 twice daily x 14 days | 32 | ↑22 (↑6 to ↑41) | ↑297 (↑12 to ↑48) | ↑477 (↑23 to ↑76) |
| Ritonavir | ↔ | ↔ | ↑23 (↑3 to ↑46) | ||
1 Abbreviations: ↑ = increase; ↓ = decrease; ↔ = no effect; NA = Not applicable
2 R-(active), S-and total methadone exposures were equivalent when dosed alone or with tenofovir as tenofovir disoproxil fumarate 300 mg.
3 Individual subjects were maintained on their stable methadone dose. No pharmacodynamic alterations (opiate toxicity or withdrawal signs or symptoms were reported).
4 Ethinyl oestradiol and 17-deacetyl norgestimate (pharmacologically active metabolite) exposures were equivalent when dosed alone or with tenofovir as tenofovir disoproxil fumarate 300 mg.
5 REYATAZ US Prescribing Information (Bristol-Myers Squibb).
6 In HIV-infected patients, addition of tenofovir disoproxil fumarate to atazanavir 300 mg plus ritonavir 100 mg, resulted in AUC and Cmin values of atazanavir that were 2,3 and 4-fold higher than the respective values observed for atazanavir 400 mg when given alone.
7 Increase in AUC and Cmin are not expected to be clinically relevant; hence no dose adjustments are required when tenofovir disoproxil fumarate and ritonavir-boosted saquinavir are co-administered.
Rifampicin decreases the blood levels of dolutegravir. A supplementary dose of dolutegravir should be given to patients taking NUVACO.
There is evidence that the concentration of isoniazid is increased by dolutegravir as contained in NUVACO.
NUVACO should not be co-administered with polyvalent cation-containing antacids. NUVACO is recommended to be administered 2 hours before or 6 hours after these medicines (see section 4.5).
Metformin concentrations may be increased by NUVACO. Metformin is contraindicated in patients taking NUVACO (see section 4.3).
In vitro, NUVACO demonstrated no direct, or weak inhibition (IC50 > 50 µM) of the cytochrome P450 enzymes: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, uridine diphosphate glucuronosyl transferase UGT1A1 or UGT2B7, or the transporters Pgp, BCRP, OATP1B1, OATP1B3, OCT1 or MRP2. In vitro, dolutegravir as in NUVACO did not induce CYP1A2, CYP2B6 or CYP3A4. In vivo, dolutegravir as in NUVACO did not have an effect on midazolam, a CYP3A4 probe.
Based on these data, dolutegravir as in NUVACO is not expected to affect the pharmacokinetics of medicines that are substrates of these enzymes or transporters (e.g. reverse transcriptase and protease inhibitors, opioid analgesics, antidepressants, statins, azole antifungals (such as fluconazole, itraconazole, clotrimazole), proton pump inhibitors (such as esomeprazole, lansoprazole, omeprazole), anti-erectile dysfunction medicines (such as sildenafil, tadalafil, vardenafil), aciclovir, valaciclovir, sitagliptin, adefovir).
Dolutegravir, as in NUVACO, did not have a clinically relevant effect on the pharmacokinetics of the following: tenofovir disoproxil fumarate, methadone, efavirenz, lopinavir, atazanavir, darunavir, etravirine, fosamprenavir, rilpivirine, telaprevir and oral contraceptives containing norgestimate and ethinylestradiol.
In vitro, dolutegravir as in NUVACO inhibited the renal organic cation transporter 2 (OCT2). Based on this observation, dolutegravir as in NUVACO may increase plasma concentrations of medicines in which excretion is dependent upon OCT2 (dofetilide, metformin) (see Table 5).
Dolutegravir, as in NUVACO, is eliminated mainly through metabolism by UGT1A1. Dolutegravir as in NUVACO, is also a substrate of UGT1A3, UGT1A9, CYP3A4, Pgp and BCRP; therefore, medicines that induce those enzymes may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir (see Table 5).
Co-administration of dolutegravir, as in NUVACO and other medicines that inhibit UGT1A1, UGT1A3, UGT1A9, CYP3A4, and/or Pgp may increase dolutegravir plasma concentration.
Efavirenz, nevirapine, rifampicin and tipranavir in combination with ritonavir each reduced the plasma concentrations of dolutegravir significantly and require dolutegravir dose adjustment to 50 mg twice daily.
Etravirine also reduced plasma concentrations, but the effect of etravirine was mitigated by co-administration of CYP3A4 inhibitors lopinavir/ritonavir, darunavir/ritonavir and is expected to be mitigated by atazanavir/ritonavir.
Therefore, no dolutegravir as in NUVACO dose adjustment is necessary when coadministered with etravirine and either lopinavir/ritonavir, darunavir/ritonavir, or atazanavir/ritonavir. Another inducer, fosamprenavir in combination with ritonavir decreased plasma concentrations of dolutegravir but does not require a dosage adjustment of dolutegravir as in NUVACO. Caution is warranted, and clinical monitoring is recommended when these combinations are given in INI-resistant patients (see Table 5: Medicine Interactions – HIV-1 Antiviral medicines). A medicine interaction study with the UGT1A inhibitor, atazanavir, did not result in clinically meaningful increase in the plasma concentrations of dolutegravir. Tenofovir disoproxil fumarate, ritonavir, lopinavir/ritonavir, darunavir/ritonavir, rilpivirine, boceprevir, telaprevir, prednisone, rifabutin and omeprazole had no or minimal effect on dolutegravir pharmacokinetics, therefore no dolutegravir as in NUVACO dose adjustment is required when co-administered with these medicines.
Table 5. Medicine interactions:
| Concomitant medicine class: Medicine name | Effect on concentration of NUVACO or concomitant medicine | Clinical comment |
| HIV-1 Antiviral medicines | ||
| Non-nucleoside reverse transcriptase inhibitors | ||
| Etravirine (ETR) | Dolutegravir ↓ AUC ↓ 71% Cmax ↓ 52% Cτ ↓ 88% ETR ↔ | Etravirine decreased dolutegravir plasma concentration, which may result in loss of virologic response and possible resistance to dolutegravir. Dolutegravir should not be used with etravirine without co-administration of atazanavir/ ritonavir, darunavir/ritonavir or lopinavir/ritonavir. |
| Efavirenz (EFV) | Dolutegravir ↓ AUC ↓ 57% Cmax ↓ 39% Cτ ↓ 75% EFV ↔ | Efavirenz decreased dolutegravir plasma concentrations. The recommended dose of dolutegravir is 50 mg twice daily when coadministered with efavirenz. Alternative combinations that do not include efavirenz should be used where possible in INI-resistant patients. |
| Nevirapine | Dolutegravir ↓ | Co-administration with nevirapine has the potential to decrease dolutegravir plasma concentration due to enzyme induction and has not been studied. Effect of nevirapine on dolutegravir exposure is likely similar to or less than that of efavirenz. The recommended dose of dolutegravir is 50 mg twice daily when co-administered with nevirapine. Alternative combinations that do not include nevirapine should be used where possible in INI-resistant patients. |
| Protease inhibitors | ||
| Atazanavir (ATV) | Dolutegravir ↑ AUC ↑ 91% Cmax ↑ 49% Cτ ↑ 180% ATV ↔ | Atazanavir increased dolutegravir plasma concentration. No dose adjustment is necessary. |
| Atazanavir/ritonavir (ATV + RTV) | Dolutegravir ↑ AUC ↑ 62% Cmax ↑ 33% Cτ ↑ 121% ATV ↔ RTV ↔ | Atazanavir/ritonavir increased dolutegravir plasma concentration. No dose adjustment is necessary. |
| Tipranavir/ritonavir (TPV + RTV) | Dolutegravir ↓ AUC ↓ 59% Cmax ↓ 47% Cτ ↓ 76% TPV ↔ RTV ↔ | Tipranavir/ritonavir decreases dolutegravir concentrations. The recommended dose of dolutegravir is 50 mg twice daily when coadministered with tipranavir/ritonavir. Alternative combinations that do not include tipranavir/ritonavir should be used where possible in INI resistant patients. |
| Fosamprenavir/ritonavir (FPV + RTV) | Dolutegravir ↓ AUC ↓ 35% Cmax ↓ 24% Cτ ↓ 49% FPV ↔ RTV ↔ | Fosamprenavir/ritonavir decreases dolutegravir concentrations, but based on limited data, did not result in decreased efficacy in Phase III studies. No dose adjustment is necessary in INI-naïve patients. Alternative combinations that do not include Fosamprenavir/ritonavir should be used where possible in INI resistant patients. |
| Nelfinavir | Dolutegravir ↔ | This interaction has not been studied. Although an inhibitor of CYP3A4, based on data from other inhibitors, an increase is not expected. No dose adjustment is necessary. |
| Lopinavir/ritonavir (LPV + RTV) | Dolutegravir ↔ AUC ↔ Cmax ↔ Cτ ↔ LPV ↔ RTV ↔ | Lopinavir/ritonavir did not change dolutegravir plasma concentration to a clinically relevant extent. No dose adjustment is necessary. |
| Darunavir/ritonavir (DRV + RTV) | Dolutegravir ↓ AUC ↓ 32% Cmax ↓ 11% Cτ ↓ 38% DPV ↔ RTV ↔ | Darunavir/ritonavir did not change dolutegravir plasma concentration to a clinically relevant extent. No dose adjustment is necessary. |
| Lopinavir/ritonavir + Etravirine (LPV/RTV + ETR) | Dolutegravir ↔ AUC ↑ 10% Cmax ↑ 7% Cτ ↑ 28% LPV ↔ RTV ↔ ETR ↔ | Lopinavir/ritonavir and etravirine did not change dolutegravir plasma concentration to a clinically relevant extent. No dose adjustment is necessary. |
| Darunavir/ritonavir + Etravirine (DRV/RTV + ETR) | Dolutegravir ↓ AUC ↓ 25% Cmax ↓ 12% Cτ ↓ 36% DRV ↔ RTV ↔ | Darunavir/ritonavir and etravirine did not change dolutegravir plasma concentration to a clinically relevant extent. No dose adjustment is necessary. |
| Nucleoside reverse transcriptase inhibitor | ||
| Tenofovir (TDV) | Dolutegravir ↔ TDV ↔ | Tenofovir did not change dolutegravir plasma concentration to a clinically relevant extent. No dose adjustment is necessary. |
| Antidysrhythmics | ||
| Dofetilide Pilsicainide | Dofetilide Pilsicainide | Co-administration of dolutegravir has the potential to increase dofetilide or pilsicainide plasma concentration via inhibition of OCT2 transporter; co-administration has not been studied. Dofetilide or pilsicainide coadministration with NUVACO is contraindicated due to the potential lifethreatening toxicity caused by high dofetilide or pilsicainide concentration (see section 4.3). |
| Oxcarbazepine Phenytoin Phenobarbitone Carbamazepine St John’s wort | Dolutegravir ↓ | Co-administration may decrease dolutegravir plasma concentration and has not been studied. Co-administration with these metabolic inducers should be avoided. |
| Antacids containing polyvalent cations (e.g. Mg, Al or Ca) | Dolutegravir ↓ AUC ↓ 74% Cmax ↓ 72% C24 ↓ 74% | Co-administration of antacids containing polyvalent cations decreased dolutegravir plasma concentration. NUVACO is recommended to be administered 2 hours before or 6 hours after taking antacids containing polyvalent cations. |
| Calcium supplements | Dolutegravir ↓ AUC ↓ 39% Cmax ↓ 37% C24 ↓ 39% | NUVACO is recommended to be administered 2 hours before or 6 hours after taking products containing calcium, or alternatively, administered with food. |
| Iron supplements | Dolutegravir ↓ AUC ↓ 54% Cmax ↓ 57% C24 ↓ 56% | NUVACO is recommended to be administered 2 hours before or 6 hours after taking products containing iron, or alternatively, administered with food. |
| Metformin | Metformin ↑ | Co-administration of dolutegravir increased metformin plasma concentration. Metformin is contraindicated in patients taking NUVACO (see section 4.3). |
| Rifampicin | Dolutegravir ↓ AUC ↓ 54% Cmax ↓ 43% Cτ ↓ 72% | Rifampicin decreased dolutegravir plasma concentration. Alternatives to rifampicin should be used where possible for INI-resistant patients. |
| Oral contraceptives (ethinylestradiol (EE) and norgestromin (NGMN) | Effect of dolutegravir: EE ↔ AUC ↑ 3% Cmax ↓ 1% Cτ ↑ 2% Effect of dolutegravir: NGMN ↔ AUC ↓ 2% Cmax ↓ 11% Cτ ↓ 7% | Dolutegravir did not change ethinylestradiol and norgestromin plasma concentrations to a clinically relevant extent. No dose adjustment of oral contraceptives is necessary when co-administered with NUVACO. |
| Methadone | Effect of dolutegravir: Methadone ↔ AUC ↓ 2% Cmax ↔ 0% Cτ ↓ 1% | Dolutegravir did not change methadone plasma concentrations to a clinically relevant extent. No dose adjustment of methadone is necessary when co-administered with NUVACO. |
Abbreviations: ↑ = increase; ↓ = decrease; ↔ = no significant change; AUC = area under the concentration versus time curve; Cmax = maximum observed concentration; Cτ = concentration at the end of dosing interval
Women of childbearing potential should be counselled about the potential risk of neural tube defects with dolutegravir (see below), including consideration of using effective contraceptive measures.
Perform pregnancy testing before initiation of NUVACO in women of childbearing potential to exclude inadvertent (unintentional) use of NUVACO during the first trimester of pregnancy.
If a woman plans pregnancy, the benefits and the risks of starting or continuing treatment with dolutegravir versus using another antiretroviral regimen should be discussed with her.
Use of dolutegravir during pregnancy was associated with a small increase in the prevalence of neural tube defects (0,19%) compared to non-dolutegravir regimens (0,11%). Most neural tube defects occur within the first 4 weeks of embryonic development after conception (approximately 6 weeks after the last menstrual period).
If a pregnancy is confirmed in the first trimester while on dolutegravir, the benefits and risks of continuing dolutegravir versus switching to another antiretroviral regimen should be discussed with the patient, taking the gestational age and the critical time period of neural tube defect development into account.
Dolutegravir may be used during the second and third trimester of pregnancy when the expected benefit outweighs the potential risk to the foetus. Dolutegravir was shown to cross the placenta in humans, leading to significant exposure to the foetus, but the implications of such exposure are not yet known.
HIV infected women should not breast-feed their infants in order to avoid transmission of HIV or follow appropriate guidelines.
Dolutegravir is excreted in human breast milk, and there is significant exposure to the neonate/infants due to slow elimination; the half-life of dolutegravir in the new born was 33 hr compared to 14 hr in the adults. There is insufficient information on the effects of dolutegravir in neonates/infants.
There are no data on the effects of dolutegravir on human male or female fertility. Animal studies indicate no effects of dolutegravir on male or female fertility.
NUVACO may affect the ability to drive a vehicle and use machines (see section 4.8). Patients should ensure that they do not engage in driving or using machines until they know how NUVACO affects them.
NUVACO can have side effects. The following side effects have been reported during therapy for HIV disease with NUVACO film-coated tablets alone and in combination with other antiretrovirals.
| System Organ Class | Frequency | Side effects |
|---|---|---|
| Blood and lymphatic system disorders | Less frequent | Neutropenia, anaemia, thrombocytopenia, pure red cell aplasia. |
| Immune system disorders | Less frequent | Immune reconstitution inflammatory syndrome, angioedema. |
| Metabolism and nutrition disorders | Frequent | Hyperlactataemia. |
| Less frequent | Lactic acidosis (see section 4.4), lipodystrophy (redistribution/accumulation of body fat) (see section 4.4), including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, cushingoid appearance, hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia, hyperlipasaemia. | |
| Psychiatric disorders | Less frequent | Anormal behaviour. |
| Nervous system disorders | Frequent | Headache, insomnia. |
| Less frequent | Paraesthesia, peripheral neuropathy (although a causal relationship to treatment is uncertain), convulsions, late onset neurological disorders in children exposed in utero. | |
| Respiratory, thoracic and mediastinal disorders | Frequent | Cough, nasal symptoms. |
| Gastrointestinal disorders | Frequent | Upper abdominal pain or cramps, nausea, vomiting, diarrhoea. |
| Less frequent | Pancreatitis (although a causal relationship to treatment is uncertain), increased serum amylase. | |
| Hepato-biliary disorders | Less frequent | Transient increased liver enzymes (AST, ALT), hepatitis. |
| Skin and subcutaneous tissue disorders | Frequent | Alopecia, rash. |
| Musculoskeletal, connective tissue and bone disorders | Frequent | Arthralgia, muscle disorders, musculoskeletal pain. |
| Less frequent | Rhabdomyolysis, decrease in bone mineral density, osteopenia, fractures, hypertonia, myalgia, myositis, osteonecrosis. | |
| Reproductive system and breast disorders | Less frequent | Breast enlargement. |
| General disorders and administration site conditions | Frequent | Fatigue, fever, malaise. |
| Investigations | Less frequent | Increased serum amylase, increased creatine phosphokinase, increased blood lipids and glucose. |
| System Organ Class | Frequency | Side effects |
|---|---|---|
| Blood and lymphatic system disorders | Less frequent | Neutropenia, anaemia. |
| Immune system disorders | Less frequent | Allergic reaction including angioedema, immune reconstitution inflammatory syndrome. |
| Metabolism and nutrition disorders | Less frequent | Accumulation or redistribution of fat (lipodystrophy), including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, cushingoid appearance, hypercholesterolaemia, hyperlactataemia, lactic acidosis, anorexia, hypophosphatemia, hypokalaemia. |
| Psychiatric disorders | Less frequent | Abnormal behaviour. |
| Nervous system disorders | Frequent | Headache, dizziness. |
| Less frequent | Convulsions. | |
| Respiratory, thoracic and mediastinal disorders | Frequency unknown | Dyspnoea, pneumonia. |
| Gastrointestinal disorders | Frequent | Abdominal pain, anorexia, distention, nausea, vomiting, diarrhoea, dyspepsia, flatulence. |
| Less frequent | Increased amylase, pancreatitis. | |
| Hepato-biliary disorders | Less frequent | Hepatomegaly, steatosis, increased liver enzymes (AST, ALT, gamma-GT) hepatitis. |
| Skin and subcutaneous tissue disorders | Less frequent | Skin rash. |
| Musculoskeletal, connective tissue and bone disorders | Less frequent | Bone pain, osteomalacia, fractures, muscle weakness, myopathy, hypertonia, osteonecrosis. |
| Frequency unknown | Muscle disorders (including rhabdomyolysis). | |
| Renal and urinary disorders | Frequent | Renal insufficiency, renal failure, proximal renal tubulopathy (including Fanconi syndrome), proteinuria, increased creatinine, acute tubular necrosis, nephrogenic diabetes insipidus. |
| Less frequent | Nephritis. | |
| Reproductive system and breast disorders | Less frequent | Breast enlargement. |
| General disorders and administration site conditions | Frequent | Fatigue, asthenia. |
| Investigations | Less frequent | Increased liver enzymes, increased serum amylase, grade 3 and 4 laboratory abnormalities (in total cholesterol, triglycerides, creatine kinase, haematuria, neutrophil, urine glucose and serum glucose). |
| System Organ Class | Frequency | Side effects |
|---|---|---|
| Blood and lymphatic system disorders | Less frequent | Thrombocytopenia, neutropenia. |
| Immune system disorders | Less frequent | Hypersensitivity, immune reconstitution inflammatory syndrome (see section 4.4) |
| Psychiatric disorders | Frequent | Insomnia. |
| Less frequent | Anxiety, depression, paranoia, suicidal ideation. | |
| Nervous system disorders | Frequent | Headache, dizziness, abnormal dreams. |
| Ear and labyrinth disorders | Frequent | Vertigo. |
| Gastrointestinal disorders | Frequent | Nausea, diarrhoea, vomiting, flatulence, upper abdominal pain. |
| Less frequent | Abdominal pain, abdominal discomfort, gastritis. | |
| Hepato-biliary disorders | Less frequent | Hepatitis. |
| Skin and subcutaneous tissue disorders | Frequent | Rash, pruritus. |
| Less frequent | Stevens-Johnson syndrome, toxic epidermal necrolysis. | |
| Musculoskeletal, connective tissue and bone disorders | Less frequent | Myopathy, rhabdomyolysis, arthralgia, myalgia. |
| Renal and urinary disorders | Less frequent | Renal failure, abnormal creatine phosphokinase values. |
| Pregnancy, puerperium and perinatal conditions | Frequency unknown | Neural tube defects, late onset neurological disorders including seizures (see section 4.6). |
| General disorders and administration site conditions | Frequent | Fatigue. |
| Investigations | Less frequent | Increased liver transaminases, increased serum triglyceride concentrations. |
| Frequency unknown | Changes in laboratory chemistries as reported in clinical studies: Increases in serum creatinine occurred within the first week of treatment with dolutegravir and remained stable through 48 weeks. In treatment-naive patients a mean change from baseline of 9,96 μmol/L (range: 53 μmol/L to 54,8 μmol/L) was observed after 48 weeks of treatment. Creatinine increases were comparable by background NRTls and were similar in treatment-experienced patients. These changes are not considered to be clinically relevant since they do not reflect a change in glomerular filtration rate (see section 5.2, Effects on Renal Function). |
Small increases in total bilirubin (without clinical jaundice) were observed on dolutegravir and raltegravir (but not efavirenz) arms in the programme. These changes are not considered clinically relevant as they likely reflect competition between dolutegravir and unconjugated bilirubin for a common clearance pathway 9UGT1A1) (see section 5.2).
Asymptomatic creatine phosphokinase (CPK) elevations mainly in association with exercise have also been reported with dolutegravir therapy.
The safety profile was similar across the treatment-naïve, treatment-experienced (and integrase-naïve) and integrase-resistant patient populations.
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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