Darunavir

Registered South African indications:

• HIV infection

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Severe hepatic impairment
• Coadministration  of rifampicin with daranavir with concomitant low dose ritonavir
• Coadministration with lopinavir/ritonavir
• Coadministration with CYP3A4 substrates

Cautions

• Pregnancy
• Breastfeeding
• Mild to moderate hepatic impairment
• Elderly
• Do not use as monotherapy
• Sulphonamide allergy
• Haemophilia _2,U2D
• Not for use in paediatric patients <3 years or <15 kg

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

International manufacturer recommendations

HIV infection (additional agents required)
- Treatment-experienced patients
- Highly pre-treated

• Oral (tab): 600mg, 12hrly, with 100mg ritonavir, 12hrly with food

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Darunavir must always be given orally with low dose ritonavir as a pharmacokinetic enhancer and in combination with other antiretroviral medicinal products

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Darunavir 75mg, 150mg, and 600mg tablets can be used to construct the twice daily 600mg regimen. The use of 75mg and 150mg tablets to achieve the recommended dose is appropriate when there is a possibility of hypersensitivity to specific colouring agents or difficulty in swallowing the 600mg tablets

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- Antiretroviral therapy-naïve
- Antiretroviral therapy-experienced with no darunavir resistance-associated mutations (DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V) and who have plasma HIV-1 RNA <100,000 copies/ml and CD4+ cell count ≥100 cells x 10⁶/L

• Oral (tab): 800mg, dly, with cobicistat 150mg, dly OR with 100mg ritonavir, dly with food

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In all other ART-experienced patients or if HIV-1 genotype testing is not available, the recommended dose regimen is 600mg, 12hrly taken with ritonavir 100mg, 12hrly taken with food

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South African manufacturer recommendations

HIV infection (additional agents required)
- HIV-1 strains resistant to more than one protease inhibitor

• Oral (tab): 600mg, 12hrly, with 100mg ritonavir, 12hrly with food

- Antiretroviral therapy-experienced patient who are protease inhibitor naive
- Treatment-experienced patients after exclusion of darunavir resistance-associated mutations (DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V)

• Oral (tab): 800mg, dly, with 100mg ritonavir, dly with food

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Darunavir must always be given with 100mg ritonavir as a pharmacokinetic enhancer and in combination with other antiretroviral medicines

Not registered for use in South Africa for children: tab (600mg, 400mg)

Paed. forms avail. in SA and covered in this monograph: tab (75mg, 150mg)

International manufacturer recommendations

HIV infection (additional agents required)
- Antiretroviral therapy-naïve

75mg, 150mg, 600mg tab

Younger than 3 years and <15kg

• Not established for use

Between 3-17 years and ≥15kg

Body weight (kg)	Dose (once daily with food)
	Darunavir	Ritonavir*
≥15kg - <30kg	600mg, dly	100mg, dly
≥30kg - <40kg	675mg, dly	100mg, dly
≥40kg	800mg, dly	100mg, dly
*Ritonavir oral solution: 80 mg/ml

- Antiretroviral therapy-experienced

Body weight (kg)	Dose (once daily with food)	Dose (twice daily with food)
≥15kg - <30kg	600mg darunavir/100mg ritonavir, dly	375mg darunavir/50mg ritonavir, 12hrly
≥30kg - <40kg	675mg darunavir/ 100mg ritonavir, dly	450mg darunavir/60mg ritonavir, 12hrly
≥40kg	800mg darunavir/100mg ritonavir, dly	600mg darunavir/100mg ritonavir, 12hrly
Max dose	800mg darunavir/100mg ritonavir/24hrs	600mg darunavir/100mg ritonavir, 12hrly
*Ritonavir oral solution: 80 mg/ml

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Darunavir twice daily taken with ritonavir taken with food is usually recommended

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A once daily dose regimen of darunavir taken with ritonavir taken with food may be used in patients with prior exposure to antiretroviral medicinal products but without darunavir resistance associated mutations (DRV-RAMs: DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V)* and who have plasma HIV-1 RNA <100,000 copies/ml and CD4+ cell count ≥100 cells x 10⁶/L

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For ART-experienced paediatric patients HIV genotypic testing is recommended. However, when HIV genotypic testing is not feasible, the darunavir/ritonavir once daily dosing regimen is recommended in HIV protease inhibitor-naïve paediatric patients and the twice daily dosing regimen is recommended in HIV protease inhibitor-experienced patients

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The use of only 75mg and 150mg tablets to achieve the recommended dose of darunavir could be appropriate when there is a possibility of hypersensitivity to specific colouring agents

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400mg tab

Younger than 3 years or <15kg

• Not established for use

Between 3-17 years and ≥40kg

• Oral (tab): 800mg, dly, with 100mg ritonavir, dly with food

OR

(>12 years)

• Oral (tab): 800mg, dly, with 150mg cobicistat, dly with food

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- Antiretroviral therapy-experienced patients with no darunavir resistance-associated mutations (DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V) and who have plasma HIV-1 RNA <100,000 copies/ml and CD4+ cell count ≥100 cells x 10⁶/L

Younger than 12 years and <40kg

• Not established for use

Older than 12 years and ≥40kg

• Oral (tab): 800mg, dly, with 100mg ritonavir, dly with food

OR

• Oral (tab): 800mg, dly, with 150mg cobicistat, dly with food

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The dose of cobicistat to be used with darunavir in children less than 12 years of age has not been established. Cobicistat should not be used in children aged 3-11 years of age weighing <40kg as the dose of cobicistat to be used in these children has not been established

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Darunavir 400mg tablets are not suitable for this patient population. Consider the 75mg and 150mg formulations

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South African manufacturer recommendations

HIV infection (additional agents required)

75mg, 150mg

- Antiretroviral treatment-experienced paediatric patients

Younger than 6 years and <20kg

• Not established for use

Between 6-18 years and ≥20kg

Body weight (kg)	Dose (twice daily with food)
	Darunavir	Ritonavir*
≥20kg - <30kg	375mg, 12hrly	50mg, 12hrly
≥30kg - <40kg	450mg, 12hrly	60mg, 12hrly
≥40kg	600mg, 12hrly	100mg, 12hrly
Max dose	600mg, 12hrly	100mg, 12hrly

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Treatment history, and when available, genotypic or phenotypic testing, should guide the use of darunavir/ritonavir

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

Pregnancy

• Caution
• As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, the animal data, as well as the clinical experience in pregnant women, should be taken into account
• There are no adequate and well-controlled studies on pregnancy outcome with darunavir in pregnant women. Studies in animals do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development
• Darunavir co-administered with low dose ritonavir should be used during pregnancy only if the potential benefit justifies the potential risk

Breastfeeding

• Caution; not recommended
• It is not known whether darunavir is excreted in human milk. Studies in rats have demonstrated that darunavir is excreted in milk and at high levels (1,000mg/kg/day) resulted in toxicity. Because of both the potential for HIV transmission and the potential for adverse reactions in breastfed infants, mothers should be instructed not to breastfeed under any circumstances if they are receiving darunavir

Fertility

• No human data on the effect of darunavir on fertility are available. There was no effect on mating or fertility with darunavir treatment in rats 

Renal Impairment

• No dose adjustment recommended

Hepatic Impairment

• Mild to moderate: Caution; no dose adjustment recommended
• Severe: Contraindicated

Elderly

• Caution; no dose adjustment recommended

Porphyria Information

• Possibly porphyrinogenic (PSP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Insomnia
• Depression
• Disorientation
• Anxiety
• Sleep disorder
• Irritability
• Abnormal dreams
• Nightmare
• Decreased libido
• Confusional state
• Altered mood
• Restlessness
• Headache
• Peripheral neuropathy
• Dizziness
• Lethargy
• Paraesthesia
• Asthenia
• Fatigue
• Hypoaesthesia
• Dysgeusia
• Disturbance in attention
• Memory impairment
• Somnolence
• Syncope
• Convulsion
• Ageusia
• Sleep phase rhythm disturbance

Cardiovascular Disorders

• Myocardial infarction
• Angina pectoris
• Prolonged electrocardiogram QT
• Tachycardia
• Acute myocardial infarction
• Sinus bradycardia
• Palpitations
• Hypertension
• Flushing
• Chest pain
• Peripheral oedema

Respiratory Disorders

• Dyspnoea
• Cough
• Epistaxis
• Throat irritation
• Rhinorrhoea

Gastrointestinal Disorders

• Diarrhoea
• Nausea and vomiting
• Abdominal pain
• Increased blood amylase 
• Dyspepsia
• Abdominal distension
• Flatulence
• Pancreatitis
• Gastritis
• Gastro-oesophageal reflux disease
• Aphthous stomatitis
• Retching
• Dry mouth
• Abdominal discomfort
• Constipation
• Increased lipase
• Eructation
• Oral dysaesthesia
• Stomatitis
• Haematemesis
• Cheilitis
• Dry lip
• Coated tongue

Hepatobiliary Disorders

• Increased alanine aminotransferase
• Hepatitis
• Cytolytic hepatitis
• Hepatic steatosis
• Hepatomegaly
• Increased transaminase
• Increased aspartate aminotransferase
• Increased blood bilirubin
• Increased blood alkaline phosphatase
• Increased gamma-glutamyltransferase

Genitourinary Disorders

• Acute renal failure
• Renal failure
• Nephrolithiasis
• Increased blood creatinine
• Proteinuria
• Bilirubinuria
• Dysuria
• Nocturia
• Pollakiuria
• Decreased creatinine renal clearance
• Erectile dysfunction 
• Gynaecomastia

Endocrine and Metabolic Disorders

• Hypothyroidism
• Increased blood thyroid stimulating hormone
• Diabetes mellitus
• Hypertriglyceridaemia
• Hypercholesterolaemia
• Hyperlipidaemia
• Gout
• Anorexia
• Decreased appetite
• Decreased weight
• Increased weight
• Hyperglycaemia
• Insulin resistance
• Decreased high density lipoprotein
• Increased appetite
• Polydipsia
• Increased blood lactate dehydrogenase

Musculoskeletal Disorders

• Myalgia
• Osteonecrosis
• Muscle spasms
• Muscular weakness
• Arthralgia
• Pain in extremity
• Osteoporosis
• Increased blood creatine phosphokinase
• Musculoskeletal stiffness
• Arthritis
• Joint stiffness

Skin and Subcutaneous Tissue Disorders

• Rash 
• Pruritus
• Angioedema
• Generalised rash
• Allergic dermatitis
• Urticaria
• Eczema
• Erythema
• Hyperhidrosis
• Night sweats
• Alopecia
• Acne
• Dry skin
• Nail pigmentation
• Drug Reaction with Eosinophila and Systemic Symptoms (DRESS) 
• Stevens-Johnson syndrome
• Erythema multiforme
• Dermatitis
• Seborrhoeic dermatitis
• Skin lesion
• Xeroderma
• Toxic epidermal necrolysis
• Acute generalised exanthematous pustulosis

Immune, Blood and Lymphatic System Disorders

• Herpes simplex
• Thrombocytopenia
• Neutropenia
• Anaemia
• Leukopenia
• Increased eosinophil count
• Immune reconstitution inflammatory syndrome
• Hypersensitivity

Sensory Disorders

• Conjunctival hyperaemia
• Dry eye
• Visual disturbance
• Vertigo

Others

• Pyrexia
• Pain
• Chills
• Abnormal feeling
• Xerosis

• Elvitegravir
• Tenofovir
• Efavirenz
• Etravirine
• Indinavir
• Saquinavir
• Lopinavir/ritonavir
• Maraviroc
• Alfentanil
• Antidysrhythmics
• Digoxin
• Clarithromycin
• Dexamethasone
• Anticoagulants
• Phenobarbital
• Phenytoin
• Carbamazepine
• Antidepressants
• Antifungals  
• Colchicine
• Rifampicin
• Rifapentine
• Rifabutin
• Antineoplastics 
• Ticagrelor
• Antipsychotics 
• Neuroleptics  
• Beta blockers 
• Calcium channel blockers 
• Fluticasone
• Budesonide
• Dexamethasone
• Prednisone
• Bosnian
• Telaprevir
• Boceprevir
• Simeprevir
• St John's wort
• HMG Co-A Reductase inhibitors  
• Immunosuppressants
• Salmeterol
• Methadone
• Buprenorphine  
• Oestrogen-based contraceptives
• Phosphodiesterase Type 5 PDE-5 inhibitors
• Protein pump inhibitors
• Sedatives/hypnotics

• Hepatic function
• Blood glucose
• Lipid profile

Tablet 400mg - EML (Tertiary)

Tablet 75mg, 150mg, 600mg - Non-EML

Darunavir is an HIV protease inhibitor. It prevents HIV replication by binding to the enzyme's active site, thereby preventing the dimerization and the catalytic activity of the HIV-1 protease. It selectively inhibits the cleavage of HIV encoded Gag-Pol polyproteins in virus infected cells, thereby preventing the formation of mature infectious virus particles.

Tablet 75mg

• Prezista (Janssen Pharmaceutica) originator

Tablet 150mg

• Prezista (Janssen Pharmaceutica) originator

Tablet 400mg

• Prezista (Janssen Pharmacetica) originator

Tablet 600mg

• Prezista (Janssen Pharmaceutica) originator