Komycitaf 120 mg FC tablets

KOMYCITAF tablets are indicated for use alone as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and paediatric patients weighing at least 40 kg.

Testing prior to initiation of KOMYCITAF Tablets

Prior to initiation of KOMYCITAF tablets, patients should be tested for hepatitis B virus infection [see section 4.4]. 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 [see section 4.4]. Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in all individuals.

Adults and paediatric patients weighing at least 40 kg

The recommended dosage of KOMYCITAF is one tablet taken orally once daily with or without food in adults and paediatric patients weighing at least 40 kg and creatinine clearance greater than or equal to 30 mL per minute.

Paediatric use

KOMYCITAF tablets should only be administered to paediatric patients with a body weight of at least 40 kg because they are a fixed-dose combination that cannot be adjusted. The safety and efficacy have been established for the individual components in this weight group.

Elderly

Dolutegravir: Clinical trials of dolutegravir did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. Caution should be exercised in the administration of dolutegravir in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other medicine therapy.

Emtricitabine and tenofovir alafenamide: In clinical trials, 80 of the 97 subjects enrolled aged 65 years and over received FTC + TAF and EVG + COBI. No differences in safety or efficacy have been observed between elderly subjects and adults between 18 and less than 65 years of age.

Hepatic impairment

No dosage adjustment of KOMYCITAF tablets is recommended in patients with mild (Child-Pugh Class A) hepatic impairment. The effect of moderate or severe hepatic impairment (Child-Pugh Class B or C) on the pharmacokinetics of dolutegravir, emtricitabine and tenofovir alafenamide has not been studied. Therefore, KOMYCITAF tablets are not recommended for use in patients with moderate or severe hepatic impairment (see section 4.3).

Renal impairment

KOMYCITAF tablets are not recommended for patients with severe renal impairment (estimated creatinine clearance below 30 mL per min) because KOMYCITAF tablets are a fixed-dose combination and the dosage of the individual components cannot be adjusted. No dosage adjustment of KOMYCITAF tablets is recommended in patients with mild or moderate renal impairment (estimated creatinine clearance greater than or equal to 30 mL per minute).

KOMYCITAF tablets are contraindicated in patients:

• with previous hypersensitivity reaction to dolutegravir [see section 4.4]
• receiving dofetilide and pilsicainide
• with moderate and severe hepatic impairment (Child-Pugh B or C)
• with severe renal impairment, CrCl < 30 ml/min
• Metformin is contraindicated in patients taking KOMYCITAF.
• Antiretroviral-experienced patients with HIV-1 harbouring the K65R mutation
• KOMYCITAF is contraindicated in pregnancy and lactation (see section 4.6).

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

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 dolutegravir-containing 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 anti-hepatitis 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 life-threatening 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.

...

Effect of dolutegravir on the pharmacokinetics of other medicines

In vitro, dolutegravir demonstrated no direct, or weak inhibition (IC50 > 50 u03bcm) 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 fixed-dose 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].

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 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. 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 patientu2019s 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.

Blood and the lymphatic system disorders

Frequent Neutropenia

Frequency unknown Anaemia

Immune system disorders

Frequent Allergic reaction, including angioedema

Less frequent Hypersensitivity, Immune Reconstitution Syndrome (see section 4.4)

Metabolism and nutrition disorders

Frequent Hypertriglyceridaemia, hyperglycaemia

Frequency unknown Hypophosphataemia, lactic acidosis, hypokalaemia

Psychiatric disorders

Frequent Insomnia, abnormal dreams, suicidal ideation, attempt, behaviour, or completion. These events were observed primarily in subjects with a pre-existing history of depression or other psychiatric illness

Nervous system disorders

Frequent Headache, dizziness

Respiratory, thoracic and mediastinal disorders

Frequent Dyspnoea

Gastrointestinal disorders

Frequent Nausea, diarrhoea, vomiting, flatulence, upper abdominal pain, Dyspepsia, amylase elevation, lipase elevation

Less frequent Abdominal pain, abdominal discomfort

Frequency unknown Pancreatitis

Hepatobiliary disorders

Frequent Hyperbilirubinaemia, increased liver enzymes (including increased AST, increased ALT and/or gamma GT)

Less frequent Hepatitis

Frequency unknown Hepatic steatosis

Skin and subcutaneous tissue disorders

Frequent Rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, pustular rash, skin discolouration

Musculoskeletal, connective tissue and bone disorders

Frequent Creatine kinase elevation, myositis

Frequency unknown Myopathy, osteomalacia, rhabdomyolysis, muscular weakness

Renal and urinary disorders

Frequent Renal impairment

Frequency unknown Increased creatinine, renal insufficiency, renal failure, acute renal failure, Fanconi syndrome, proximal tubulopathy, nephrogenic diabetes insipidus, proteinuria, acute tubular necrosis, polyuria, interstitial nephritis

General disorders and administration site conditions

Frequent Fatigue, pain, asthenia

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 nau00efve patients a mean change from baseline of 9,96 u03bc mol/l (range: -53 u03bcmol/l to 54,8 u03bc mol/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 u201c6.04 Adverse Drug Reactions & Quality Problem Reporting Formu201d, found online under SAHPRAu2019s publications:

https://sahpra.org.za/wp-content/uploads/2020/01/6.04_ARF1_v5.1_27Jan2020.pdf

There is no known specific treatment for overdose with KOMYCITAF tablets. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required.

Dolutegravir: As dolutegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.

Emtricitabine (FTC): Limited clinical experience is available at doses higher than the recommended dose of FTC. Haemodialysis treatment removes approximately 30 % of the FTC dose over a 3-hour dialysis period starting within 1,5 hours of FTC dosing (blood flow rate of 400 mL per minute and a dialysate flow rate of 600 mL per minute). It is not known whether FTC can be removed by peritoneal dialysis.

Tenofovir alafenamide (TAF): Limited clinical experience is available at doses higher than the recommended dose of TAF. Tenofovir is efficiently removed by haemodialysis with an extraction coefficient of approximately 54 %.