Abacavir and Lamivudine in a single-pill as part of combination therapy

Before initiating treatment with abacavir-containing products, HLA-B*5701 status must always be documented. Abacavir should not be used in patients known to carry the HLA-B*5701 allele due to the risk of hypersensitivity reaction1.

 

Indication and Dosing

Once-Daily KIVEXA As Part Of Combination Therapy**†‡

KIVEXA is indicated in antiretroviral combination therapy for the treatment of HIV infection in adults, adolescents and children weighing at least 25 kg1.

Before initiating treatment with abacavir-containing products, HLA-B*5701 status must always be documented. Abacavir should not be used in patients known to carry the HLA-B*5701 allele due to the risk of hypersensitivity reaction1.

 

**In a study supporting KIVEXA (abacavir/lamivudine – fixed-dose-combination), ABC 2 x 150 mg / 3TC 2 x 150 mg were used. Bioequivalence has been demonstrated1

KIVEXA is a fixed-dose tablet and should not be prescribed for patients requiring dose adjustments. Separate preparations of abacavir or lamivudine are available in cases where discontinuation or dose adjustment is required1

KIVEXA is not recommended for co-administration with products containing lamivudine or medicinal products containing emtricitabine1

Dosing recommendations for KIVEXA (adults, adolescents and children weighing ≥25 kg)1*†‡

 

One tablet, Once Daily

  • One tablet, once daily
  • No time-of-day restrictions
  • No food restrictions
  • Few clinically significant DDIs
  • No additional renal monitoring required

Drug-Drug Interactions

KIVEXA has few clinically significant drug-drug interactions1

Interactions identified for abacavir and lamivudine individually are relevant to KIVEXA1

 

 

HIV-1 Antiviral Agents

NRTI

Medical Products by therapeutic areas

Interaction Geometric mean change (%)

Recommendations concerning co-administration

Didanosine

Interaction with abacavir or lamivudine not studied

No KIVEXA dosage adjustment necessary

Zidovudine

Lamivudine: AUC

 

Zidovudine : AUC

 

Zidovudine 300 mg single dose,
lamivudine 150 mg single dose

 

Interaction with abacavir not studied

No KIVEXA dosage adjustment necessary

Emtricitabine

 

Due to similarities, KIVEXA should not be administered concomitantly with other cytidine analogues, such as emtricitabine.

Medical Products by therapeutic areas

Interaction

Geometric mean change (%)

Recommendations concerning co-administration

Ranitidine

Interaction with abacavir and lamivudine not studied

Clinically significant interaction unlikely with lamivudine. Ranitidine eliminated only in part by renal organic cation transport system

No dosage adjustment necessary

Cimetidine

Interaction with abacavir and lamivudine not studied

Cimetidine eliminated only in part by renal organic cation transport system. Clinically significant interaction with lamivudine unlikely.

No dosage adjustment necessary

Medical Products by therapeutic areas

Interaction

Geometric mean change (%)

Recommendations concerning co-administration

Phenobarbital

Interaction with abacavir and lamivudine not studied

Potential to slightly decrease abacavir plasma concentrations through UGT induction.

Insufficient data to recommend dose adjustment

Phenytoin

Interaction with abacavir and lamivudine not studied

Potential to slightly decrease abacavir plasma concentrations through UGT induction.

Monitor phenytoin concentrations

Insufficient data to recommend dose adjustment

Medical Products by therapeutic areas

Interaction

Geometric mean change (%)

Recommendations concerning co-administration

Rifampicin

Interaction with abacavir and lamivudine not studied

Potential to slightly decrease abacavir plasma concentrations through UGT induction

Insufficient data to recommend dose adjustment

Medical Products by therapeutic areas

Interaction

Geometric mean change (%)

Recommendations concerning co-administration

Trimethoprim/sulfamethoxazole (co-trimoxazole) (160 mg/800 mg once daily for 5 days/300 mg single dose)

Lamivudine: AUC ↑40%

Trimethoprim: AUC

Sulfamethoxazole: AUC

(organic cation transporter inhibition)

Interaction with abacavir not studied

No KIVEXA dosage adjustment necessary

Patients should be monitored during therapy as lamivudine concentrations are increased.

High doses of trimethoprim/ sulfamethoxazole for the treatment of Pneumocystis jirovecii pneumonia (PCP) and toxoplasmosis have not been studied and should be avoided

Medical Products by therapeutic areas

Interaction

Geometric mean change (%)

Recommendations concerning co-administration

Retinoid compounds
(e.g. Isotretinoin)

Interaction with abacavir and lamivudine not studied

Possible interaction with abacavir given common pathway of elimination of abacavir via alcohol dehydrogenase.

Insufficient data to recommend dose adjustment

Medical Products by therapeutic areas

Interaction

Geometric mean change (%)

Recommendations concerning co-administration

Methadone

(40 to 90mg once daily for 14 days/600mg single dose, then 600mg twice daily for 14 days)

Abacavir: AUC

Cmax ↓ 35 %

Methadone: CL/F ↑ 22 %

Interaction with lamivudine not studied

No KIVEXA dosage adjustment necessary

Methadone dosage adjustment unlikely in majority of patients; occasionally methadone re-titration may be required

Medical Products by therapeutic areas

Interaction

Geometric mean change (%)

Recommendations concerning co-administration

Cladribine

Interaction with lamivudine not studied

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

The concomitant use of lamivudine with cladribine is not recommended

Medical Products by therapeutic areas

Interaction

Geometric mean change (%)

Recommendations concerning co-administration

Ethanol

Abacavir: AUC ↑ 41 %

Ethanol: AUC

(Inhibition of alcohol dehydrogenase)

Interaction with lamivudine not studied

No KIVEXA dosage adjustment necessary

Abbreviations:
↑ = Increase; ↓ = decrease; = no significant change;
AUC = area under the concentration versus time curve;
Cmax = maximum observed concentration;
CL/F = apparent oral clearance

 

In a study supporting KIVEXA (abacavir/lamivudine – fixed-dose-combination), ABC 2 x 150 mg / 3TC 2 x 150 mg were used. Bioequivalence has been demonstrated1

KIVEXA is a fixed-dose tablet and should not be prescribed for patients requiring dose adjustments. Separate preparations of abacavir or lamivudine are available in cases where discontinuation or dose adjustment is required1

KIVEXA is not recommended for co-administration with products containing lamivudine or medicinal products containing emtricitabine. The combination of lamivudine with cladribine is not-recommended1

 

KIVEXA Metabolism and Clearance

 

The abacavir component of KIVEXA is metabolised by UDP-glucuronyltransferase (UGT) enzymes and alcohol dehydrogenase. Co-administration of inducers or inhibitors of UGT enzymes and co-administration with compounds eliminated through alcohol dehydrogenase could alter abacavir exposure.1

The lamivudine component of KIVEXA is cleared renally. Active renal secretion of lamivudine in the urine is mediated through organic cation transporters (OCTs). Co-administration of lamivudine with OCT inhibitors may increase lamivudine exposure.1

KIVEXA is not significantly metabolised by cytochrome P450 enzymes (such as CYP 3A4, CYP 2C9 or CYP 2D6). KIVEXA does not inhibit or induce this enzyme system; there is little potential for interactions with antiretroviral protease inhibitors, non-nucleosides and other medicinal products metabolised by major CYP P450 enzymes.1

 

Safety and Tolerability

                 Graph based on pooled trial data 3

                              a The numbers of adverse events may exceed the total number of patients because some patients reported more than one event
                              b During the blinded portion of the study, investigators reported 3% incidence of suspected ABC hypersensitivity reaction in the ZDV/ 3TC/EFV arm
                              c 3TC/ZDV/EFV

 

Frequency of adverse drug reactions with abacavir or lamivudine, by body system

Frequency of adverse drug reactions with abacavir or lamivudine, by body system
Body system Abacavir Lamivudine
Blood and lymphatic systems disorders
 
Uncommon: Neutropenia and anaemia (both occasionally severe), thrombocytopenia

Very rare: Pure red cell aplasia

Immune system disorders Common: hypersensitivity
 
Metabolism and nutrition disorders Common: anorexia

Very rare: lactic acidosis

Very rare: lactic acidosis
Nervous system disorders Common: headache Common: Headache, insomnia

Very rare: Cases of peripheral neuropathy (or paraesthesia) have been reported

Respiratory, thoracic and mediastinal disorders
 
Common: Cough, nasal symptoms
Gastrointestinal disorders Common: nausea, vomiting, diarrhoea

Rare: pancreatitis has been reported, but a causal relationship to abacavir treatment is uncertain

Common: Nausea, vomiting, abdominal pain or cramps, diarrhoea

Rare: Rises in serum amylase. Cases of pancreatitis have been reported

Hepatobiliary disorders
 
Uncommon: Transient rises in liver enzymes (AST, ALT)

Rare: Hepatitis

Skin and subcutaneous tissue disorders Common: rash (without systemic symptoms)

Very rare: erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis

Common: Rash, alopecia

Rare: Angioedema

Musculoskeletal and connective tissue disorders
 
Common: Arthralgia, muscle disorders

Rare: Rhabdomyolysis

General disorders and administration site conditions Common: fever, lethargy, fatigue. Common: fatigue, malaise, fever.
Frequencies are defined as very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1000 to < 1/100), rare (> 1/10,000 to < 1/1000), very rare (< 1/10,000)1.

Resistance Data

Triple therapies including NNRTIs and boosted PIs in treatment-naïve patients1
M184V or M184I mutations were seen in HIV-1 infected patients treated with 3TC-containing antiretroviral therapy.
Total M184V or M184I mutations were high, at 54%; fewer mutations were observed for L74V (5%), K65R (1%) and Y115F (1%). Combined pivotal trial data: in vivo resistance in therapy-naïve patients treated with ABC, 3TC and a third agent 1

Therapy ABC + ZDV/3TC ABC + 3TC + NNRTI ABC + 3TC + PI (or PI/ritonavir) Total
Number of subjects, n 282 1094 909 2285
Virological failures, n (%) 43 (15) 90 (8) 158 (17) 306 (13)
On-therapy genotypes,

n (%)

40 (100) 51 (100) 141 (100) 232 (100)
K65R, n (%) 0 1 (2) 2 (1) 3 (1)
L74V, n (%) 0 9 (18) 3 (2) 12 (5)
Y115F, n (%) 0 2 (4) 0 2 (1)
M184V/I, n (%) 34 (85) 22 (43) 70 (50) 126 (54)
TAMSs, n (%) 3 (8) 2 (4) 4 (3) 9 (4)

Includes three non-virological failures and four unconfirmed virological failures

≥ 1Thymidine Analogue Mutations.

 

Zidovudine (ZDV) inclusion in regimens demonstrated a reduction in L74V and K65R mutations in the presence of ABC1. TAM mutations were not present in regimens containing ABC without ZDV; TAM mutations might present when thymidine analogs (e.g. ZDV) are associated with ABC.1

 

Treatment-experienced Patient Studies

M184V or M184I mutations in HIV-1 infected patients being treated with 3TC-containing antiretroviral therapy, confer high-level resistance to 3TC. Maintaining 3TC therapy despite emergence of M184V should only be considered in cases where no other active NRTIs are available.1

 

Five clinical trials examined the addition of ABC, as a single agent, to intensify current antiretroviral treatment in 166 subjects. At 4 weeks, the majority of baseline mutations observed were M184V (74%). Virological response to ABC declined where three of more of these mutations were present as baseline; however, many patients responded to ABC even with evidence of resistance to NRTIs.4

4-week meta-analysis data of 5 clinical trials in which therapy was intensified with the addition of ABC in 166 subjects on current ARV therapies4

Baseline RT mutations n <400 copies/mL (%)
None 15 40
M184V alone 75 64
1 NRTI-associated mutation

 

(M184V or TAM)

82 65
2 NRTI-associated mutations
(M184V + TAM or 2 TAMs)
22 32
3 NRTI-associated mutations

(M184V + 2 TAMs or 3 TAMs)

19 5
≥ 4 NRTI-associated mutations

(M184V + 3 TAMs or M184V + >3 TAMs or ≥ 4 TAMs)

28 11

Cross-Resistance1

M184V plus at least one other ABC-selected mutation, or M184V with many TAMs results in ABC resistance.

Either M184V or M184I mutation alone confers minimal cross-resistance to other NRTIs. NRTIs that maintain their antiretroviral activities against these HIV-1 variants include ZDV, didanosine (DDI), stavudine (d4T) and tenofovir (TDF).

Cross-resistance between ABC, TDF, DDI and 3TC is seen when M184V and K65R mutations are present together.

Cross-resistance between ABC, DDI and 3TC is seen when M184V and L47V are present together.

Cross-resistance between ABC and 3TC is seen when M184V with Y115F are present together.

Cross-resistance between ABC or 3TC and antiretrovirals from other classes e.g. PIs or NNRTIs is unlikely.

HLA-B*5701 Screening

Screening for the HLA-B*5701 allele should be performed before Prescribing KIVEXA1

 

 HLA-B*5701 screening significantly reduces the risk of an ABC hypersensitivity reaction5

 

Clinical description of ABC HSRs1

  • Almost all patients developing ABC HSRs will have fever and/or rash
  • Other key symptoms include gastrointestinal, respiratory or constitutional symptoms, such as lethargy and malaise

 

If suspected1:

  • KIVEXA must be stopped without delay, even in the absence of the HLA-B*5701 allele
  • After stopping treatment with KIVEXA for a suspected HSR, KIVEXA or any other medicinal product containing ABC or DTG, must never be re-initiated

 

Guidelines recommended6,7

  • EACS and DHHS guidelines recommend screening for HLA-B*5701 before starting ABC-containing antiretroviral therapy, if not previously tested

 

References

  1. Kivexa film-coated tablets - Summary of Product Characteristics, November 2014 (SPC) - (eMC). Available at: https://www.medicines.org.uk/emc/medicine/15707 (Accessed: 28th November 2016).
  2. Liverpool HIV Interactions. Available at: http://www.hiv-druginteractions.org/. (Accessed: 28th November 2016)
  3. Castillo, S. A., Hernandez, J. E. & Brothers, C. H. Long-term safety and tolerability of the lamivudine/abacavir combination as components of highly active antiretroviral therapy. Drug Saf. 29, 811–826 (2006).
  4. Lanier, E. R. et al. Antiviral efficacy of abacavir in antiretroviral therapy-experienced adults harbouring HIV-1 with specific patterns of resistance to nucleoside reverse transcriptase inhibitors. Antivir. Ther. 9, 37–45 (2004).
  5. Mallal, S. et al. HLA-B*5701 screening for hypersensitivity to abacavir. N. Engl. J. Med. 358, 568–579 (2008).
  6. European AIDS Clinical Society. Guidelines. Version 8.1. October 2016. Available at: http://www.eacsociety.org/files/guidelines_8.1-english.pdf (Accessed February 27, 2017.)
  7. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. January 28, 2016. Available at: https://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf(Accessed: 6th January 2017)

UK/DTGP/0001/17 Date of Prep: March 2017