Tenofovir Disoproxil Fumarate/ Emtricitabine/ Rilpivirine

Registered South African indications:

• HIV-1 infection

Contraindications

• Hypersensitivity to the active ingredients or any of the excipients in this combination product
• Pregnancy
• Breastfeeding
• Renal impairment (CrCl<50 mL/minute) or patients on dialysis
• Severe hepatic impairment (Child-Pugh Class C)
• Coadministration with other Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) (e.g. delavirdine, efavirenz, etravirine, nevirapine)
• Coadministration with other medicines containing tenofovir, emtricitabine, lamivudine or rilpivirine
• Coadministration with CYP3A inducers (e.g. carbamazepine, oxcarbazepine, phenobarbitone, phenytoin)
• Coadministration with rifabutin, rifampicin and rifapentine
• Coadministration with the systemic glucocorticoid dexamethasone (except as a single-dose treatment)
• Coadministration with proton-pump inhibitors (PPIs) (e.g. lansoprazole, omeprazole, rabeprazole, pantoprazole and esomeprazole)
• Coadministration with products containing St. John’s Wort (Hypericum perforatum)

Cautions

• Renal impairment (CrCl≥50 mL/minute)
• Mild to moderate hepatic impairment (Child-Pugh Class A or B)
• Elderly
• Previous virologic failure to antiretroviral therapy
• Risk factors for osteoporosis, osteopenia or bone loss
• Bone abnormalities
• Mitochondrial dysfunction
• Hepatitis B or C co-infection
• Underlying liver disorders
• Chronic active hepatitis
• Risk factors for liver disease
• Pronounced hepatotoxicity
• Hepatomegaly
• Hepatic steatosis
• Pancreatitis
• Lipid disorders
• Lactic acidosis
• Severe immune deficiency
• Residual opportunistic pathogens
• Autoimmune disorders
• Advanced HIV progression
• Long-term exposure to combination ART
• Prolonged nucleoside exposure
• Obesity
• Diabetes mellitis
• Galactose intolerance
• Lapp lactase deficiency
• Glucose-galactose malabsorption
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: tab

HIV infection

Tenofovir disoproxil fumarate/ Emtricitabine/ Rilpivirine 

300mg/200mg/27.5mg

• Oral (tab): 1 tab, dly

Not recommended for patients <35kg

Tablets are to be swallowed whole and taken with food

Therapy should be initiated by a doctor experienced in the management of HIV infection

Not established for use in children below 18 years

Consult HIV/infectious disease specialists prior to any decisions related to ARV regimen termination/switch

Pregnancy

• Contraindicated
• Safety and efficacy has not been established in pregnancy
• The use of effective contraception is recommended to avoid pregnancy

Breastfeeding

• Contraindicated
• Tenofovir penetrates breast milk to a small degree, but is undetectable in breastfeeding infants. Emtricitabine is secreted in breast milk. It is unknown whether rilpivirine is secreted in breast milk
• Due to the potential for postnatal HIV transmission and serious adverse reactions in breastfeeding infants, mothers should not breastfeed if receiving HIV treatment

Renal Impairment

• CrCl≥50 mL/minute: Caution; no dose adjustment recommended
  Use is recommended only if the potential benefits of treatment outweigh the potential risks
• CrCl<50 mL/minute or on dialysis: Contraindicated

Hepatic impairment

• Mild to moderate (Child-Pugh Class A or B): Caution; no dose adjustment recommended
• Severe (Child-Pugh Class C): Contraindicated

Elderly

• Caution; no dose adjustment recommended
• >65 years: Caution; no information available

Porphyria information

• Probably not porphyrinogenic (PNP)

Drugs in sport

• Permitted - No warnings

Central Nervous System Disorders

• Insomnia
• Sleep disorders
• Abnormal dreams
• Depression
• Headache
• Dizziness
• Somnolence
• Asthenia
• Peripheral neuropathy
• Abnormal behaviour
• Convulsions

Gastrointestinal Disorders

• Diarrhoea
• Nausea and vomiting
• Elevated amylase
• Elevated serum lipase
• Pancreatitis
• Abdominal pain
• Abdominal discomfort
• Abdominal distension
• Dyspepsia
• Flatulence
• Dry mouth

Hepatobiliary Disorders

• Increased transaminases (AST and/or ALT)
• Increased bilirubin
• Hepatitis
• Hepatic steatosis
• Severe hepatomegaly

Genitourinary Disorders

• Proximal renal tubulopathy
• Fanconi Syndrome
• Increased creatinine
• Proteinuria
• Renal failure (acute and chronic)
• Acute tubular necrosis
• Proximal renal tubulopathy
• Nephritis
• Acute interstitial nephritis
• Nephrogenic diabetes insipidus

Endocrine and Metabolic Disorders

• Increased total cholesterol (fasted)
• Increased LDL cholesterol (fasted)
• Hypophosphataemia
• Hypertriglyceridaemia
• Hyperglycaemia
• Decreased appetite
• Hypokalaemia
• Hyperlactatemia
• Lactic acidosis

Musculoskeletal Disorders

• Elevated creatine kinase
• Rhabdomyolysis
• Muscular weakness
• Bone abnormailities
• Oesteonecrosis
• Osteomalacia
• Bone pain
• Bone fractures
• Decreased bone mineral density
• Joint aches and pain
• Joint stiffness
• Difficulty in movement
• Myopathy

Skin and Subcutaneous Tissue 

• Rash
• Blisters
• Vesiculobullous rash
• Pustular rash
• Urticaria
• Skin discolouration (increased pigmentation)
• Maculopapular rash
• Pruritus
• Angioedema
• Severe skin reactions with systemic symptoms

Immune, Blood and Lymphatic System Disorders

• Allergic reaction
• Immune reconstitution inflammatory syndrome (IRIS)
• Reactivated autoimmune disorders
• Opportunistic infections
• Haematological abnormalities
• Neutropenia
• Decreased white blood cell count
• Decreased haemoglobin
• Decreased platelet count
• Anaemia
• Eosinophilia
• Fever

Sensory Disorders

• Conjunctivitis

Other

• Mitochondrial dysfunction

• CYP3A inducers
• CYP3A inhibitors
• Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
• Delavirdine
• Efavirenz
• Etravirine
• Nevirapine
• Nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs/NtRTIs)
• Didanosine
• Emtricitabine
• Tenofovir disoproxil fumarate/tenofovir alafenamide
• Rilpivirine
• Zidovudine
• Stavudine
• Abacavir sulfate
• Cytidine analogues
• Lamivudine
• Adefovir dipivoxil
• Protease inhibitors (PIs)
• Atazanavir
• Lopinavir
• Ritonavir
• Darunavir
• Fosamprenavir
• Saquinavir
• Tipranavir
• Indinavir
• Nelfinavir
• CCR5 Antagonists
• Maraviroc
• Integrase Strand Transfer Inhibitors (INSTIs)
• Raltegravir
• Agents that reduce renal function
• Agents that compete for tubular secretion
• Cidofovir
• Acyclovir
• Valaciclovir
• Ganciclovir
• Valganciclovir
• Agents that are nephrotoxic
• Aminoglycosides
• Amphotericin B
• Foscarnet
• Pentamidine
• Vancomycin
• Interleukin-2/aldesleukin
• QTc prolonging agents
• Agents with known risk of Torsade de Pointes
• Etexilate
• Antacids
• Aluminium magnesium hydroxide
• Calcium carbonate
• Anticonvulsants
• Carbamazepine
• Oxcarbazepine
• Phenobarbital
• Phenytoin
• Antimycobacterials
• Rifampin
• Rifapentine
• Rifabutin
• Azole antifungal agents
• Fluconazole
• Itraconazole
• Ketoconazole
• Posaconazole
• Voriconazole
• Systemic glucocorticoids
• Dexamethasone (more than a single-dose treatment)
• Antiviral agents
• Ledipasvir
• Sofosbuvir
• Velpatasvir
• Voxilaprevir
• Simeprevir
• Herpesvirus antiviral agents
• Famciclovir
• H-receptor antagonists
• Cimetidine
• Famotidine
• Nizatidine
• Ranitidine
• St John’s wort (Hypericum perforatum)
• Macrolides or Ketolide Antibiotics
• Clarithromycin
• Erythromycin
• Troleandomycin
• Narcotic analgesics
• Methadone
• Analgesics
• Paracetamol
• Proton pump inhibitors
• Dexlansoprazole
• Esomeprazole
• Lansoprazole
• Omeprazole
• Pantoprazole
• Rabeprazole
• Oral contraceptives
• Ethinylestradiol
• Norethinidrone
• Antiarrhythmics
• P-glycoprotein substrates
• Digoxin
• Dabigatran
• Immunosuppressants
• Tacrolimus
• Antidiabetics
• Metformin
• HMG CoA reductase inhibitors
• Atorvastatin
• PDE-5 inhibitors
• Sildenafil
• Vardenafil
• Tadalafil
• Ribavirin
• Transporter MATE-2K substrates
• Non-steroidal anti-inflammatory drugs (NSAIDs)

• Renal function
• Serum phosphorus
• Physical signs of fat redistribution
• Blood lipids
• Body weight
• Viral load
• CD4 count

Specific cases may require

• Hepatic function
• Venous lactate
• Serum bicarbonate
• Cardiovascular risk assessment
• Urine glucose
• Urine protein
• Bone mineral density (BMD)

Recommendations for use

• Use is recommended as initial therapy in adult patients (≥35 kg) with no antiretroviral treatment history and HIV-1 RNA ≤100,000 copies/mL at the start of therapy  
• Additionally, use is recommended in patients virologically suppressed (HIV-1 RNA <50 copies/mL) that are on a stable antiretroviral regimen for at least 6 months with no treatment failure
• Use has not been evaluated in patients with previous virologic failure to any other antiretroviral therapy. There is not
  sufficient data to justify the use in patients with prior non-nucleoside reverse transcriptase inhibitor (NNRTI) failure

Early virologic failure and development of resistance 

• Early virological failure and high rates of resistance substitutions have been reported
• Use is recommended in patients with no known mutations associated with resistance to the NNRTI class, including tenofovir, emtricitabine or rilpivirine
• Triple nucleoside-only regimen should be carefully monitored and considered for treatment modification
• Genotypic resistance testing and/or historical resistance data should guide the use of antiretroviral therapy

HIV and hepatitis co-infection

• Medical practitioners should refer to current HIV treatment guidelines for the optimal management of HIV patients co-infected with hepatitis B virus (HBV)
• Use is not indicated for the treatment of chronic HBV infection as the safety and efficacy of tenofovir disoproxil fumarate/ emtricitabine/ rilpivirine have not been established in patients with HIV
• Testing for HBV prior to or when initiating therapy is recommended with assessing serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients.  In patients with chronic kidney disease, also assess serum phosphorus
• Discontinuation of therapy in patients co-infected with HBV, advanced liver disease or cirrhosis may be associated with severe, acute exacerbations of hepatitis, liver decompensation and liver failure

Missed dose

• If a patient misses a dose within 12 hours of the time it is usually taken, the tablet should be taken with food as soon as possible and resume the normal dosing schedule
• If a patient misses a dose by more than 12 hours, the patient should not take the missed dose and simply resume the usual dosing schedule
• If a patient vomits within 4 hours of taking the tablet, another tablet should be taken with food
• If a patient vomits more than 4 hours after taking the tablet, they do not need to take another dose until the next regularly scheduled dose

HIV transmission

• While effective viral suppression has been proven to substantially reduce the risk of HIV transmission, a residual risk of transmission through blood, other bodily secretions or sexual contact cannot be excluded
• Individuals should be warned that full compliance with treatment is essential to the efficacy in preventing HIV transmission
• Precautions to prevent transmission, including preventative measures, such as barrier contraception (condoms), should be taken in accordance with national guidelines

Tenofovir Disoproxil Fumarate

Tenofovir disoproxil fumarate, a Nucleoside Reverse Transcriptase Inhibitor (NRTI), is an acyclic nucleoside phosphonate diester analogue of adenosine monophosphate. Tenofovir disoproxil fumarate requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 RT by competing with the natural substrate deoxyadenosine 5’-triphosphate and, after incorporation into DNA, by DNA chain termination.  Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β and mitochondrial DNA polymerase γ.

Emtricitabine

Emtricitabine, a Nucleoside Reverse Transcriptase Inhibitor (NRTI), is a synthetic nucleoside analogue of cytidine, phosphorylated by cellular enzymes to form emtricitabine 5’-triphosphate. Emtricitabine 5’-triphosphate inhibits the activity of the HIV-1 reverse transcriptase (RT) by competing with the natural substrate deoxycytidine 5’-triphosphate and by being incorporated into nascent viral DNA which results in chain termination.  Emtricitabine 5’-triphosphate is a weak inhibitor of mammalian DNA polymerases α, β, ε and mitochondrial DNA polymerase γ.

Rilpivirine 

Rilpivirine, a second-generation Non-nucleoside Reverse Transcriptase Inhibitor (NNRTI), is a diarylpyrimidine NNRTI of HIV-1. Rilpivirine activity is mediated by non-competitive inhibition of HIV-1 reverse transcriptase (RT). Rilpivirine does not inhibit the human cellular DNA polymerases α, β and γ.

The triple combination of emtricitabine, rilpivirine, and tenofovir demonstrate synergistic antiviral activity.

COMBINATION PREPARATIONS

Tenofovir disoproxil fumarate/ Emtricitabine/ Rilpivirine 

Tablet 300mg/200mg/27.5mg

• Erestz (Mylan) originator