KOMYCITAF Film-coated tablet Ref.[51212] Active ingredients: Dolutegravir Emtricitabine Tenofovir alafenamide

WARNING: 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.

WARNING: POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B

Tenofovir alafenamide, one component of KOMYCITAF tablets, is approved for the treatment of chronic hepatitis B virus (HBV) infection. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of KOMYCITAF tablets.

Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue KOMYCITAF tablets. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

Hepatotoxicity

Safety of the mono-component medicines are well established, but the safety of the FDC combination have not been established. Hepatic adverse events have been reported in patients receiving a dolutegravircontaining regimen. Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with use of KOMYCITAF tablets [see section 4.8]. In some cases, the elevations in transaminases were consistent with immune reconstitution syndrome or hepatitis B reactivation particularly in the setting where antihepatitis therapy was withdrawn. Cases of hepatic toxicity, including elevated serum liver biochemistries, hepatitis, and acute liver failure have been reported in patients receiving a dolutegravir-containing regimen without pre-existing hepatic disease or other identifiable risk factors. Medicine-induced liver injury leading to liver transplant has been reported with fixed-dose abacavir, dolutegravir, and lamivudine. Monitoring for hepatotoxicity is recommended.

Hypersensitivity reactions

Hypersensitivity reactions have been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury. The events were reported in less than 1% of subjects receiving dolutegravir in Phase 3 clinical trials.

Discontinue KOMYCITAF tablets and other suspect medicines immediately 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 or peeling of the skin, oral blisters or lesions, conjunctivitis, facial oedema, hepatitis, eosinophilia, angioedema, difficulty breathing). Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated. Delay in stopping treatment with KOMYCITAF tablets or other suspect medicines after the onset of hypersensitivity may result in a lifethreatening reaction. KOMYCITAF tablets are contraindicated in patients who have experienced a previous hypersensitivity reaction to dolutegravir.

Risk of adverse reactions or loss of virologic response due to interactions

The concomitant use of KOMYCITAF tablets and other medicines may result in known or potentially significant interactions, some of which may lead to [see section 4.3 and section 4.5]:

• Loss of therapeutic effect of KOMYCITAF tablets and possible development of resistance.
• Possible clinically significant adverse reactions from greater exposures of concomitant medicines.

Consider the potential for interactions prior to and during therapy with KOMYCITAF tablets; review concomitant medications during therapy with KOMYCITAF tablets; and monitor for the adverse reactions associated with the concomitant medicines.

Lipodystrophy and metabolic abnormalities

Combination antiretroviral therapy has been associated with the redistribution/accumulation of body fat, including central obesity, dorsocervical 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

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.

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.

Bone mineral density

During therapy with KOMYCITAF 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 was not studied. If bone abnormalities are suspected then appropriate consultation should be obtained.

Opportunistic infections

Patients receiving KOMYCITAF 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.

The risk of HIV transmission to others

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

New onset or worsening renal impairment

Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphataemia), has been reported with the use of tenofovir prodrugs in both animal toxicology studies and human trials. In clinical trials of FTC + TAF with cobicistat (COBI) plus elvitegravir (EVG), there have been no cases of Fanconi syndrome or Proximal Renal Tubulopathy (PRT).

In clinical trials of FTC + TAF with EVG + COBI in treatment-naïve subjects and in virally suppressed subjects switched to FTC + TAF with EVG + COBI with eGFRs greater than 50 mL per minute, renal serious adverse events or discontinuations due to renal adverse reactions were encountered in less than 1% of participants treated with FTC + TAF with EVG + COBI. In a study of virally suppressed subjects with baseline eGFRs between 30 and 69 mL per minute treated with FTC + TAF with EVG + COBI for a median duration of 43 weeks, FTC + TAF with EVG + COBI was permanently discontinued due to worsening renal function in two of 80 (3%) subjects with a baseline eGFR between 30 and 50 mL per minute [see section 4.8]. KOMYCITAF tablets are not recommended in patients with estimated creatinine clearance below 30 mL per minute because data in this population are insufficient (see section 4.3).

Patients taking tenofovir prodrugs who have impaired renal function and those taking nephrotoxic medicines including non-steroidal antiinflammatory medicines are at increased risk of developing renal-related adverse reactions.

Estimated creatinine clearance, urine glucose, and urine protein should be assessed before initiating KOMYCITAF tablets therapy and should be monitored during therapy in all patients.

Serum phosphorus should be monitored in patients with chronic kidney disease because these patients are at greater risk of developing Fanconi syndrome on tenofovir prodrugs. Discontinue KOMYCITAF tablets in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.

Lactic acidosis / hyperlactataemia

Use of KOMYCITAF can result in potentially fatal lactic acidosis as a consequence of mitochondrial dysfunction. Clinical features are nonspecific, 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 2-5 mmol/ℓ with minimum symptoms: switch to medicines that are less likely to cause lactic acidosis.
• Lactate 5-10 mmol/ℓ with symptoms and/or with reduced standard bicarbonate: Stop NRTIs and change treatment option. Once lactate has settled, use medicines that are less likely to cause lactic acidosis. Exclude other causes, (e.g. sepsis, uraemia, diabetic ketoacidosis, thyrotoxicosis and hyperthyroidism.
• Lactate >10 mmol/ℓ: STOP all therapy (80% mortality).

The above lactate values may not be applicable to paediatric patients. Caution should be exercised when administering KOMYCITAF to patients with known risk factors for liver disease.

Treatment with KOMYCITAF should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity.

Mitochondrial dysfunction

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-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 lateonset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). It is not known whether the neurological disorders are transient or permanent. Any fetus 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 sign and symptoms.

Pancreatitis

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

Patients with moderate to severe renal impairment

In patients with moderate to severe renal impairment, the terminal half-life of KOMYCITAF is increased due to decreased clearance. The dose of KOMYCITAF should therefore be adjusted (see section 4.2).

Liver disease

Use of KOMYCITAF can result in hepatomegaly due to nonalcoholic fatty liver disease (hepatic steatosis). The safety and efficacy of KOMYCITAF 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 package inserts for these medicines. Patients with preexisting 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.

Patients with HIV and hepatitis B or C virus co-infection

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 package inserts for these medicines.

Patients co-infected with HIV and HBV who discontinue KOMYCITAF 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 posttreatment exacerbation of hepatitis may lead to hepatic decompensation. Discontinuation of KOMYCITAF therapy in patients coinfected with HIV and HBV may be associated with severe, acute exacerbations of hepatitis.

Excipient warnings

KOMYCITAF contains lactose. Patients with the rare hereditary conditions of galactose intolerance e.g. galactosaemia, total lactase deficiency, glucose-galactose malabsorption should not take KOMYCITAF. KOMYCITAF also contains mannitol and may have a laxative effect.

Effect of dolutegravir on the pharmacokinetics of other medicines

In vitro, dolutegravir demonstrated no direct, or weak inhibition (IC50 >50 μm) of the enzymes cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, uridine diphosphate (UDP)-glucuronosyl transferase 1A1 (UGT1A1), UGT2B7, or the transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), (OATP)1B1, OATP1B3, OCT1, multidrug resistance protein (MRP)2.

In vitro, dolutegravir did not induce CYP1A2, CYP2B6, or CYP3A4. In vivo, dolutegravir did not have an effect on midazolam, a CYP3A4 probe. Based on these data, dolutegravir 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 agents (such as sildenafil, tadalafil, vardenafil), alafenamide, valaciclovir, sitagliptin, adefovir).

In medicine interaction studies, dolutegravir did not have a clinically relevant effect on the pharmacokinetics of the following: tenofovir, methadone, efavirenz, lopinavir, atazanavir, darunavir, etravirine, fosamprenavir, rilpivirine, telaprevir and oral contraceptives containing norgestimate and ethinyl estradiol.

In vitro. Dolutegravir inhibited the renal organic cation transporter 2 (OCT2). Based on this observation, dolutegravir may increase plasma concentrations of medicines in which excretion is dependent upon OCT2 (dofetilide, metformin).

Effect of other medicines on the pharmacokinetics of dolutegravir or emtricitabine and tenofovir alafenamide

Dolutegravir

Dolutegravir, one component of KOMYCITAF tablets, is metabolized by UGT1A1 with some contribution from CYP3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, BCRP, and P-gp in vitro. Medicines that induce those enzymes and transporters may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir.

Coadministration of dolutegravir and other medicines that inhibit these enzymes may increase dolutegravir plasma concentration.

Etravirine significantly reduced plasma concentrations of dolutegravir, but the effect of etravirine was mitigated by coadministration of lopinavir/ritonavir or darunavir/ritonavir, and is expected to be mitigated by atazanavir/ritonavir.

In vitro, dolutegravir was not a substrate of OATP1B1 or OATP1B3.

Based on interaction trial results, the following medicines can be coadministered with dolutegravir without a dose adjustment: atazanavir/ritonavir, lopinavir/ritonavir, darunavir/ritonavir, daclatasvir, boceprevir, elbasvir/grazoprevir, methadone, midazolam, omeprazole, oral contraceptives containing norgestimate and ethinyl estradiol, prednisone, rifabutin, rilpivirine, and sofosbuvir/velpatasvir.

Emtricitabine and tenofovir alafenamide

TAF, one component of KOMYCITAF tablets, is a substrate of P-gp, BCRP, OATP1B1, and OATP1B3. Medicines that strongly affect P-gp and BCRP activity may lead to changes in TAF absorption (see Table below). Medicines that induce P-gp activity are expected to decrease the absorption of TAF, resulting in decreased plasma concentration of TAF, which may lead to loss of therapeutic effect of KOMYCITAF tablets and development of resistance.

Coadministration of KOMYCITAF tablets with other medicines that inhibit P-gp and BCRP may increase the absorption and plasma concentration of TAF. TAF is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or UGT1A1. TAF is a weak inhibitor of CYP3A in vitro. TAF is not an inhibitor or inducer of CYP3A in vivo.

Based on interaction studies conducted with the components of emtricitabine and tenofovir alafenamide, no clinically significant interactions have been either observed or are expected when emtricitabine and tenofovir alafenamide is combined with the following antiretroviral medicines: atazanavir with ritonavir or cobicistat, darunavir with ritonavir or cobicistat, dolutegravir, efavirenz, ledipasvir, lopinavir/ritonavir, maraviroc, nevirapine, raltegravir, rilpivirine, and sofosbuvir. No clinically significant interactions have been either observed or are expected when emtricitabine and tenofovir alafenamide is combined with the following medicines: buprenorphine, itraconazole, ketoconazole, lorazepam, methadone, midazolam, naloxone, norbuprenorphine, norgestimate/ethinyl estradiol, and sertraline.

Established and other potentially significant interactions

There were no interaction trials conducted with dolutegravir and fixeddose emtricitabine and tenofovir alafenamide or with the fixed-dose combination of all three components. Information regarding potential interactions with dolutegravir, emtricitabine and tenofovir alafenamide are provided below. These recommendations are based on either interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy [see section 4.3].

Established and other potentially significant interactions for dolutegravir, emtricitabine and tenofovir alafenamide

Alterations in dose may be recommended based on interaction trials or predicted interactions:

Medicines affecting renal function

Because FTC and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion, coadministration of KOMYCITAF tablets with medicines that reduce renal function or compete for active tubular secretion may increase concentrations of FTC, tenofovir, and other renally eliminated medicines and this may increase the risk of adverse reactions. Some examples of medicines that are eliminated by active tubular secretion include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g. gentamicin), and high-dose or multiple NSAIDs [see section 4.4].

Women of childbearing potential

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 KOMYCITAF in women of childbearing potential to exclude inadvertent (unintentional) use of KOMYCITAF 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.

Pregnancy

KOMYCITAF is contraindicated during pregnancy (see section 4.3) A urine pregnancy test should be carried out within 24 hours before commencing treatment with dolutegravir containing medicines. Use of dolutegravir during pregnancy was associated with a small increase in the prevalence of neural tube defects (0.19%) compared to nondolutegravir 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.

Once treatment has started, pregnancy testing should be repeated every 4 weeks. Pregnancy testing and counselling should be performed if a patient misses her periods or if there are any abnormalities in the menstrual bleeding.

Nucleotide analogues, as in KOMYCITAF may impact on mitochondrial function to a variable degree. There have been reports of mitochondrial dysfunction in HIV negative infants exposed in utero and/or post-natally to nucleotide analogues. The main adverse reactions reported are haematological disorders (anaemia, neutropenia) peripheral neuropathy and metabolic disorders (hyperlactataemia, hyperlipasaemia). These events have often been transitory. Late onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether such neurological disorders are transient or permanent is unknown. These findings should be considered and investigated for any baby/infant/child exposed in utero to nucleos(t)ide analogues who present with severe clinical findings of unknown aetiology, particularly neurologic findings.

Breast-feeding

HIV-1-infected mothers should not breastfeed their infants to avoid risking transmission of HIV-1 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.

Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants) and (3) adverse reactions in a breastfed infant similar to those seen in adults, mothers should not breastfeed if they are receiving KOMYCITAF tablets.

Fertility

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 (see section 5.3).

The clinical status of the patient and the adverse event profile of KOMYCITAF should be borne in mind when considering the patient’s ability to drive or operate machinery.

Dizziness has been reported during treatment with emtricitabine.

Clinical trial data

Adverse reactions identified in an analysis of pooled data from clinical studies are listed below by system organ class and by frequency.

Changes in laboratory chemistries

Increases in serum creatinine occurred within the first week of treatment with dolutegravir and remained stable through 48 weeks. In treatment naïve 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 NRTIs 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.

Small increases in total bilirubin (without clinical jaundice) were observed with dolutegravir. These changes are not considered clinically relevant as they likely reflect competition between dolutegravir and unconjugated bilirubin for a common clearance pathway (UGT1A1).

Asymptomatic creatine phosphokinase (CPK) elevations mainly in association with exercise have also been reported with dolutegravir therapy.

Hepatitis B and/or Hepatitis C Virus Co-infection

In Phase 3 trials, subjects with hepatitis B and/or C virus co-infection were permitted to enrol provided that baseline liver chemistry tests did not exceed 5 times the upper limit of normal. Overall, the safety profile in subjects with hepatitis B and/or C virus co-infection was similar to that observed in subjects without hepatitis B or C co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis B and/or C virus co-infection for all treatment groups. Grades 2 to 4 ALT abnormalities in hepatitis B and/or C co-infected compared with HIV mono-infected subjects receiving dolutegravir were observed in 18% vs. 3% with the 50 mg once-daily dose and 13% vs. 8% with the 50 mg twice-daily dose. Liver chemistry elevations consistent with immune reconstitution syndrome were observed in some subjects with hepatitis B and/or C at the start of therapy with dolutegravir, particularly in the setting where anti-hepatitis therapy was withdrawn [see section 4.4].

Not for use in subjects <40 kg.

Postmarketing experience

In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postmarketing use.

Psychiatric disorders

Frequency unknown: Anxiety.

Hepatobiliary disorders

Frequency unknown: Acute liver failure, hepatotoxicity.

Musculoskeletal disorders

Frequency unknown: Arthralgia, myalgia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reactions & Quality Problem Reporting Form”, found online under SAHPRA’s publications.

Not applicable.