Darunavir/ Ritonavir

Registered South African indications:

• Human immunodeficiency virus (HIV) infection
  - In antiretroviral treatment experienced adult patients who are protease-inhibitor-naïve patients or after exclusion of darunavir resistance associated mutations (DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V)

Co-administration of darunavir/ ritonavir with certain non-sedating antihistamines, sedative hypnotics, anti-dysrhythmics or ergot alkaloid preparations may result in potentially serious and or life-threatening adverse events due to possible effects of ritonavir on the hepatic metabolism of these medicines

Registered South African contraindications

• Hypersensitivity to the active ingredients or any of the excipients in this combination product
• Pregnancy 
• Breastfeeding
• Severe hepatic impairment
• Coadministration with medicinal agents that are highly dependent on CYP3A for clearance and for which increased plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index), including the following: 
  - Phenobarbitone and phenytoin
  - Amiodarone, bepridil, flecainide, propafenone, quinidine, encainide and digoxin
  - Astemizole
  - Rifampicin and rifabutin
  - Blonanserin
  - Colchicine, in patients with renal or hepatic impairment
  - Dihydroergotamine, ergonovine, ergotamine and methylergonovine
  - Cisapride
  - Pimozide
  - Midazolam and triazolam
  - Ketoconazole, itraconazole and voriconazole
  - Sildenafil (when intended for the treatment of pulmonary arterial hypertension)
  - Lovastatin and simvastatin
  - Bosentan
  - Alfuzosin
  - Boceprevir and telaprevir
  - Buprenorphine/naloxone
  - Salmeterol 
  - St John's wort (Hypericum perforatum) 

Hepatic impairment/reactions

• Medicine-induced hepatitis (e.g. acute hepatitis, cytolytic hepatitis) has been linked to darunavir/ritonavir. Those with existing liver issues, such as chronic hepatitis B or C, are at a higher risk of liver function abnormalities including severe hepatic adverse events. Prior to starting darunavir/ritonavir, appropriate lab tests are advised, and regular monitoring is essential during its use
• Elevated hepatic transaminase levels (exceeding five times the upper limit of normal), clinical hepatitis, and jaundice have been observed in patients taking darunavir/ritonavir, either alone or combined with other antiretroviral drugs
• Caution is advised when giving darunavir/ritonavir to those with pre-existing liver conditions (mild to moderate liver disease), chronic hepatitis, cirrhosis, or prior liver enzyme elevations, abnormal liver enzymes, or hepatitis. Any signs of liver dysfunction while on darunavir/ritonavir, such as increased liver enzymes or symptoms like fatigue, jaundice, or nausea, may necessitate stopping or adjusting the treatment
• Closer monitoring of liver enzymes, especially during the first three months of darunavir/ritonavir treatment, is recommended
• Some cases of hepatic dysfunction, including fatalities, have been reported, especially in patients on multiple medications or those with advanced AIDS
• Darunavir/ritonavir should not be administered to patients with severe liver insufficiency (see Contraindications)

Elderly 

• Use darunavir/ritonavir cautiously in patients 65 and older due to limited data and potential health concerns common in this age group

Transmission risk

• Despite undergoing antiretroviral therapy with darunavir/ ritonavir, patients can still transmit HIV via sexual contact or blood contamination
• Patients should be informed to consistently use appropriate precautions to prevent transmission

Administration with food

• Darunavir/ ritonavir must be taken with food for effective results. Not doing so will lead to inadequate antiviral effects due to lower plasma concentrations of darunavir. The two-tablet dose of darunavir/ritonavir includes 100mg of ritonavir to enhance its effects. Adding extra ritonavir isn't advised and won't notably increase darunavir levels

Severe skin reactions

• Severe skin reactions, sometimes paired with fever or increased liver enzymes, have been reported in patients using darunavir/ritonavir. Instances of Stevens-Johnson syndrome and toxic epidermal necrolysis have been identified. If severe skin symptoms arise, including intense rashes, blisters, or other associated signs like fever, fatigue, or liver problems, stop treatment immediately. While 10.3% of darunavir/ritonavir-treated patients experienced rashes, only 0.5% had to discontinue due to it. Notably, rashes were more frequent in those on darunavir/ritonavir combined with raltegravir but were similarly attributed to the medicine across groups

Sulpha allergy

• Darunavir has a sulphonamide moiety. Patients with a known sulphonamide allergy should use darunavir/ritonavir with caution

Haemodialysis or peritoneal dialysis

• As darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that they will be significantly removed by haemodialysis or peritoneal dialysis

Haemophilia patients

• Patients with haemophilia type A and B taking protease inhibitors like darunavir/ritonavir may experience increased bleeding, including spontaneous skin haematomas and hemarthrosis. Such patients should be informed about this risk
• Some patients received additional factor VIII treatments
• In many cases, protease inhibitor treatment continued or was restarted
• There's a suggested causal relationship, but the specific mechanism remains unknown

Lipodystrophy

• Patients on combination antiretroviral therapy may experience changes in body fat distribution. This can manifest as central obesity, dorso-cervical fat enlargement (often referred to as a "buffalo hump"), peripheral and facial wasting, and breast enlargement
• The cause and long-term effects of these observations remain unclear, and a direct causal link has not been confirmed
• Patients displaying signs of lipodystrophy should undergo a comprehensive cardiovascular risk assessment
• Treatment with darunavir/ritonavir in conjunction with saquinavir can lead to significant elevations in total triglyceride and cholesterol levels
• Prior to starting ritonavir therapy and periodically during treatment, triglyceride and cholesterol tests should be conducted
• Any resulting lipid abnormalities should be managed as clinically appropriate

Metabolic abnormalities

• Elevated levels of lipids and glucose have been reported in patients on this therapy

Immune Reconstitution Inflammatory Syndrome (IRIS)

• Patients may show unexpected worsening of a current opportunistic infection or reveal a previously undetected one. These infections often manifest with unusual inflammatory symptoms. Most cases of IRIS arise within the initial three months of starting ART. Patients with low CD4 counts are at a higher risk
• HIV-infected patients undergoing combination antiretroviral therapy may experience immune reconstitution syndrome
• Some frequently observed IRIS reactions to opportunistic diseases include tuberculosis, cytomegalovirus retinitis, and cryptococcal meningitis, mycobacterium avium infection, pneumocystis jiroveci (carinii) pneumonia which may necessitate further evaluation and treatment
• 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

• Though caused by multiple factors such as corticosteroid use, alcohol, severe immunosuppression, and higher body mass index, osteonecrosis is seen especially in patients with advanced HIV or long-term cART usage. If patients feel joint pain, stiffness, or movement difficulty, they should consult a doctor

Diabetes mellitus/hyperglycaemia

• There have been reports of new onset diabetes, worsening of existing diabetes, and hyperglycemia in patients taking protease inhibitors like darunavir/ritonavir post-marketing
• Some patients required either initiation or dose adjustment of insulin or oral hypoglycaemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred
• Even after stopping protease inhibitor therapy, hyperglycemia persisted in some patients

Allergic reactions

• Some patients have experienced allergic reactions such as urticaria, skin eruptions, bronchospasm, and angioedema after taking darunavir/ritonavir. Severe reactions, including anaphylaxis and Stevens-Johnson syndrome, have also been noted

Pancreatitis

• Pancreatitis has been observed in patients on darunavir/ritonavir therapy, especially those with hypertriglyceridemia. There have been fatalities
• Those with advanced HIV disease may be at increased risk of elevated blood levels of triglycerides and of pancreatitis
• Symptoms to watch for include nausea, vomiting, and abdominal pain, as well as elevated serum lipase or amylase levels
• If pancreatitis is diagnosed, darunavir/ritonavir therapy should be stopped

Opportunistic infections

• Even when taking darunavir/ritonavir, patients may still develop infections linked to HIV. They should regularly visit HIV-experienced healthcare professionals and monitor their viral load and CD4 counts

Medicine interactions

• Darunavir/ritonavir inhibit CYP3A. Combining darunavir/ritonavir with medicines mainly metabolized by CYP3A can lead to increased plasma levels of these medicines, potentially enhancing their therapeutic effect and adverse events
• For medicines that rely heavily on CYP3A metabolism and have a limited therapeutic range (e.g., amiodarone, bepridil, systemic lidocaine, quinidine), combining with darunavir/ritonavir can increase and prolong their effects and risks
• When starting darunavir/ritonavir alongside methadone, no immediate dose adjustment is necessary. But, regular clinical monitoring is essential as methadone therapy may need later adjustment

Oestrogen-based contraceptives

• Ritonavir decreases the plasma concentrations of ethinylestradiol by increasing its metabolism. Non-hormonal contraceptive methods are recommended

Corticosteroids

• When darunavir/ritonavir and fluticasone propionate are taken together, there's a significant rise in fluticasone propionate plasma levels and a drop in serum cortisol levels
• Systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression have been reported when co-administered with inhaled or intranasally administered fluticasone propionate
• Caution is advised when combining darunavir/ritonavir with other inhaled corticosteroids that metabolize similarly to fluticasone, such as budesonide, due to potential similar effects

PDE 5 inhibitors

• Caution is advised when prescribing erectile dysfunction or pulmonary hypertension drugs like sildenafil, tadalafil, or vardenafil to those on darunavir/ritonavir
• Their concentrations are expected to increase when taken with darunavir/ritonavir, potentially leading to side effects like hypotension and prolonged erection
• Combining sildenafil with darunavir/ritonavir is strictly not advised for pulmonary arterial hypertension patients (see Contraindications)

Herbal products

• Those taking darunavir/ritonavir are advised against using products containing St John’s wort (Hypericum perforatum)
• Using them together can likely decrease ritonavir plasma concentrations, risking a loss of therapeutic effect and potential development of resistance

HMG-CoA reductase inhibitors

• Simvastatin and lovastatin are metabolized by CYP3A, so their combination with darunavir/ritonavir is contraindicated due to a heightened risk of muscle-related side effects like rhabdomyolysis
• For those on darunavir/ritonavir and needing to use atorvastatin, caution is advised and doses should be reduced, given that atorvastatin's metabolism is somewhat reliant on CYP3A4
• Even though rosuvastatin isn't dependent on CYP3A, its levels can be elevated when co-administered with darunavir/ritonavir
• If there's a need to administer an HMG-CoA reductase inhibitor with darunavir/ritonavir, pravastatin or fluvastatin is preferred

Resistance/cross-resistance

• Cross-resistance is observed among different protease inhibitors
• If darunavir/ritonavir is continually used even after a loss of viral suppression, there's an increased chance of cross-resistance to other protease inhibitors
• The complete impact of darunavir/ritonavir on the effectiveness of other concurrently or subsequently administered protease inhibitors, due to potential cross-resistance, remains uncertain

Laboratory tests

• Darunavir/ritonavir is linked with changes in several laboratory values including triglyceride, ALT, AST, GGT, CPK, and uric acid levels
• Proper laboratory tests should be conducted before starting darunavir/ritonavir and regularly during treatment, or if any symptoms arise
• For detailed information about nucleoside analogues, it's recommended that doctors refer to the full product details for each respective drug

PR interval prolongation

• Ritonavir can cause a slight asymptomatic extension of the PR interval in some patients
• There have been cases of second or third-degree atrioventricular block in patients with pre-existing heart conditions or those on medications known to prolong the PR interval (like verapamil or atazanavir) while receiving ritonavir
• Caution is advised when using darunavir/ritonavir in such patients

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

South African registered indications and dosages

Human immunodeficiency virus (HIV) infection (Additional agents required)
- In antiretroviral treatment experienced adult patients who are protease-inhibitor-naïve patients or after exclusion of darunavir resistance associated mutations (DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V)

Darunavir/ Ritonavir
400/50 (mg)

• Oral (fct): 2 tab, dly with food

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Genotypic or phenotypic testing should guide the use of darunavir/ritonavir

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Darunavir/ritonavir must always be given in combination with other antiretrovirals

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Missed dose(s)
In case a dose is missed within 12 hours of the time it is usually taken, patients should be instructed to take the prescribed dose with food as soon as possible. If this was noticed later than 12 hours after the time it is usually taken, the missed dose should not be taken and the patient should resume the usual dosing schedule

Not established for use in children below 18 years

Pregnancy

South African recommendations

• Contraindicated 
• Darunavir/ritonavir is contraindicated in pregnancy as safety has not been established
• Studies in animals do not indicate direct harmful effects of darunavir with respect to pregnancy, embryonal/foetal development, parturition or postnatal development
• A large amount (6100 live births) of pregnant women were exposed to ritonavir during pregnancy; of these, 2800 live births were exposed during the first trimester. These data largely refer to exposures where ritonavir was used in combination therapy and not at therapeutic ritonavir doses but at lower doses as a pharmacokinetic enhancer for other protease inhibitors. These data indicate no increase in the rate of birth defects compared to rates observed in population-based birth defect surveillance systems. Animal data have shown reproductive toxicity

Breastfeeding

South African recommendations

• Contraindicated 
• Darunavir/ritonavir is contraindicated in beastfeeding as safety has not been established
• It is not known whether darunavir or ritonavir is excreted in human milk. Studies in rats have demonstrated that darunavir is excreted in milk. Because of the potential for serious adverse events in breastfeeding infants, mothers should be instructed not to breastfeed if they are receiving darunavir/ritonavir

Fertility

South African recommendations

• No information available 

South African recommendations

• No dose adjustment recommended 

South African recommendations

• Mild to moderate: Caution; no dose adjustment recommended 
  Caution should be exercised when administering darunavir/ritonavir to patients with pre-existing mild to moderate liver disease, liver enzyme abnormalities or hepatitis
• Severe: Contraindicated 
  Darunavir/ ritonavir should not be used in patients with severe hepatic impairment as safety and efficacy have not been demonstrated

South African recommendations

• Caution; no dose adjustment recommended 
  Limited information available for patients 65 years and older
  Caution should be exercised in elderly patients, reflecting the greater frequency of decreased hepatic function and of concomitant disease or other therapy

Darunavir/ Ritonavir

Central Nervous System Disorders

• Headache
• Asthenia
• Abnormal dreams

Gastrointestinal Disorders

• Diarrhoea
• Nausea and vomiting
• Abdominal pain
• Dyspepsia
• Abdominal distension
• Flatulence
• Acute pancreatitis
• Increased pancreatic enzymes
• Increased lipase
• Increased amylase 

Hepatobiliary Disorders

• Hepatitis
  - Acute hepatitis
  - Cytolytic hepatitis
• Increased alanine aminotransferase 
• Increased aspartate aminotransferase
• Increased alkaline phosphatase

Genitourinary Disorders

• Gynaecomastia

Endocrine and Metabolic Disorders

• Diabetes mellitus
  - New onset
  - Exacerbation of pre-existing diabetes mellitus
• Hypertriglyceridaemia
• Hypercholesterolaemia
• Hyperlipidaemia
• Anorexia
• Dyslipidaemia
• Lipodystrophy
  - Loss of peripheral and facial subcutaneous fat
  - Increased intra-abdominal and visceral fat
  - Breast hypertrophy
  - Dorsocervical fat accumulation (buffalo hump)
• Hyperglycaemia
• Insulin resistance
• Hyperlactataemia
• Increased low density lipoprotein

Musculoskeletal Disorders

• Myalgia
• Osteonecrosis
• Increased creatine phosphokinase (CPK)
• Myositis
• Rhabdomyolysis

Skin and Subcutaneous Tissue Disorders

• Rash 
• Allergic reactions
  - Urticaria
  - Skin eruptions
  - Bronchospasm
  - Angioedema
• Pruritus
• Angioedema
• Urticaria
• Anaphylaxis
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis
• Acute generalised exanthematous pustulosis

Immune, Blood and Lymphatic System Disorders

• Immune reconstitution inflammatory syndrome
• Inflammatory reaction to asymptomatic or residual opportunistic infections
• Hypersensitivity

Ritonavir

Central Nervous System Disorders

• Insomnia
• Depression
• Anxiety
• Agitation
• Confusion
• Emotional lability
• Euphoria
• Hallucinations
• Nervousness
• Personality disorder
• Abnormal thinking
• Decreased libido
• Dizziness
• Paraesthesia
  - Circumoral paraesthesia
  - Peripheral paraesthesia
• Headache
• Hyperesthaesia
• Somnolence
• Abnormal dreams
• Amnesia
• Aphasia
• Ataxia
• Convulsion
• Grand mal convulsion
• Incoordination
• Neuralgia
• Neuropathy
• Paralysis
• Parosmia
• Peripheral neuropathy
• Peripheral sensory neuropathy
• Tremor
• Syncope
• Migraine
• Asthenia
• Seizure

Cardiovascular Disorders

• Tachycardia
• Palpitation
• Hypotension
• Postural hypotension
• Peripheral vascular disorder
• Chest pain
• Substernal chest pain
• Vasodilation
• Myocardial infarction

Respiratory Disorders

• Pharyngitis
• Dyspnoea
• Increased cough
• Asthma
• Epistaxis
• Hiccup
• Hypoventilation
• Interstitial pneumonia
• Lung disorder
• Rhinitis

Gastrointestinal Disorders

• Dry mouth
• Abdominal pain
• Diarrhoea
• Nausea and vomiting
• Eructation
• Dyspepsia
• Flatulence
• Local throat irritation
• Mouth ulcer
• Enlarged abdomen
• Abnormal stools
• Bloody diarrhoea
• Cheilitis
• Colitis
• Constipation
• Dysphagia
• Oesophagitis
• Gastritis
• Gastroenteritis
• Gastrointestinal disorder
• Gastrointestinal haemorrhage
• Gingivitis
• Ileitis
• Oral moniliasis
• Pancreatitis
• Periodontal abscess
• Rectal disorder
• Tenesmus
• Increased amylase 

Hepatobiliary Disorders

• Hepatomegaly
• Cholangitis
• Hepatitis
• Liver damage
• Abnormal liver function tests
• Increased gamma-glutamyl transpeptidase (GGT)
• Increased aspartate aminotransferase (AST)
• Increased alanine aminotransferase (ALT)
• Increased total bilirubin
• Increased alkaline phosphate
• Decreased albumin

Genitourinary Disorders

• Renal failure
• Dysuria
• Glycosuria 
• Nocturia
• Haematuria
• Kidney calculus
• Renal pain
• Polyuria
• Pyelonephritis
• Urethritis
• Urinary frequency
• Urinary retention
• Impotence
• Penis disorder
• Menorrhagia
• Increased uric acid
• Increased creatinine

Endocrine and Metabolic Disorders

• Diabetes mellitus
• Anorexia
• Hyperlipaemia
• Decreased weight
• Avitaminosis
• Cachexia
• Dehydration
• Gout
• Hypercholesterolemia
• Redistribution/accumulation of body fat
• Thirst
• Altered hormone level
• Increased triglycerides
• Decreased potassium
• Increased potassium
• Increased serum magnesium
• Decreased serum magnesium
• Decreased total serum calcium
• Increased total serum calcium
• Increased glucose level
• Decreased glucose level
• Increased lactate dehydrogenase
• Increased serum chloride
• Decreased serum chloride
• Increased serum sodium
• Decreased serum sodium
• Increased inorganic phosphorus

Musculoskeletal Disorders

• Myalgia
• Back pain
• Facial pain
• Joint disorder
• Muscle cramps
• Muscle weakness
• Myositis
• Neck pain
• Neck rigidity
• Twitching
• Arthralgia
• Arthrosis
• Increased creatine phosphokinase (CPK)

Skin and Subcutaneous Tissue Disorders

• Macropapular rash
• Pruritus
• Rash
• Sweating
• Contact dermatitis
• Eczema
• Facial oedema
• Folliculitis
• Molluscum contagiosum
• Photosensitivity reaction
• Psoriasis
• Seborrhoea
• Urticaria
• Vesiculobullous rash
• Acne
• Dry skin
• Ecchymosis

Immune, Blood and Lymphatic System Disorders

• Haemorrhage
• Thrombocytopenia
• Anaemia
• Leukopenia
• Lymphadenopathy
• Lymphocytosis
• Oedema
• Peripheral oedema
• Allergic reactions
• Fever
• Chills
• Flu syndrome
• Hypothermia
• Decreased white blood cell (WBC) count
• Increased WBC count
• Decreased red blood cell (RBC) count
• Decreased haematocrit
• Decreased haemoglobin
• Decreased neutrophil count
• Increased neutrophil count
• Increased eosinophil count
• Decreased platelet count
• Increased prothrombin time
• Increased activated partial thromboplastin time

Sensory Disorders

• Taste perversion
• Taste loss
• Abnormal vision
• Amblyopia/blurred vision
• Blepharitis
• Diplopia
• Eye pain
• Iritis
• Photophobia
• Uveitis
• Visual field defect
• Ear pain
• Hearing impairment
• Increased cerumen
• Tinnitus
• Vertigo
• Abnormal gait
• Abnormal electro-oculogram
• Abnormal electroretinogram

Metabolism and Nutrition Disorders

• Dehydration, usually associated with gastrointestinal symptoms, and sometimes resulting in hypotension, syncope or renal insufficiency
• Syncope
• Orthostatic hypotension
• Renal insufficiency

Reproductive System and Breast Disorders

• Menorrhagia

Laboratory Determinations

• Increased gamma-glutamyl transpeptidase (GGT) (>300 IU/L)
• Increased aspartate aminotransferase (AST) (>180 IU/L) and alanine aminotransferase (ALT) (>215 IU/L)
• Increased total bilirubin (>3.6mg/dL)
• Increased alkaline phosphate (>550 IU/L)
• Decreased albumin

Other clinical chemistry tests

• Increased creatine phosphokinase (CPK) (>1000 IU/L)
• Increased triglycerides (>1500mg/dL)
• Increased amylase (>2 x upper limit of normal range)
• Increased uric acid (>12mg/dL)
• Decreased potassium (>3mEq/L)
• Increased potassium (>6mEq/L)
• Increased serum magnesium (>2 .9mEq/L)
• Decreased serum magnesium (<1.0mEq/L)
• Decreased total serum calcium (<6.9mEq/L)
• Increased total serum calcium (>12.6mEq/L)
• Increased glucose level (>250mg/dL)
• Decreased glucose level (<40mg/dL)
• Increased lactate dehydrogenase (>1170 IU/L)
• Increased serum chloride (>122mEq/L)
• Decreased serum chloride (<84mEq/L)
• Increased serum sodium (>157mEq/L)
• Decreased serum sodium (<123mEq/L)
• Increased creatinine (>3.6mg/dL)
• Increased inorganic phosphorus (>7.0mg/dL)

Haematology

• Decreased white blood cell (WBC) count (<2.5 x 10⁹/L)
• Increased WBC count (>25 x 10⁹ /L)
• Decreased red blood cell (RBC) count (<3.0 x 10¹²/L)
• Decreased haematocrit (<30%)
• Decreased haemoglobin (<8g/dL)
• Decreased neutrophil count (<0.5 x 10⁹/L)
• Increased neutrophil count (>20 x 10⁹/L)
• Increased eosinophil count (>1.0 x 10⁹/L)
• Decreased platelet count (<20 x 10⁹/L)
• Increased prothrombin time (> 1.5 x ULN)
• Increased activated partial thromboplastin time (>2.3 x ULN)

Others

• Pain
• Accidental injury

• Medicines primarily metabolised by CYP3A
• Anticonvulsants
• Phenobarbitone
• Phenytoin
• Antidysrhythmics
• Amiodarone
• Bepridil
• Flecainide
• Lidocaine (systemic)
• Propafenone
• Quinidine
• Encainide
• Digoxin
• Antihistamines
• Astemizole
• Antimycobacterials
• Rifampicin
• Rifabutin
• Blonanserin
• Bosentan
• PDE-5 inhibitor
• Sildenafil indicated for pulmonary artery hypertension (PAH)
• Sildenafil indicated for erectile dysfunction
• Tadalafil
• Vardenafil
• Colchicine
• Alfuzosin
• Ergot derivatives
• Ergot alkaloids
• Dihydroergotamine
• Ergonovine
• Ergotamine
• Methylergonovine
• Gastrointestinal motility agents
• Cisapride
• Hepatitis C virus (HCV) direct-acting antivirals
• NS3-4A protease inhibitors
• Boceprevir
• Telaprevir
• HMG CoA reductase inhibitors
• Lovastatin
• Simvastatin
• Atorvastatin
• Pravastatin
• Rosuvastatin
• Pimozide
• Sedative/hypnotics
• Midazolam
• Triazolam
• Antifungals
• Ketoconazole
• Itraconazole
• Voriconazole
• Buprenorphine/ naloxone
• Salmeterol
• Oestrogen-based contraceptives
• Oral contraceptive
• Patch contraceptive
• Implants
• Ethinylestradiol and norethindrone
• Fluticasone (inhaled or intranasal)
• Inhaled budesonide
• Efavirenz
• Other HIV protease inhibitors  
• Lopinavir/ritonavir
• Saquinavir
• Indinavir
• Ritonavir
• CCR5 (Cysteine-Cysteine Chemokine Receptor 5) antagonist
• Maraviroc
• Anticoagulants
• Warfarin
• Carbamazepine
• Antimalarials
• Artemether/lumefantrine
• Calcium channel blockers
• Felodipine
• Nifedipine
• Nicardipine
• Clarithromycin (in patients with renal impairment)
• Clarithromycin (doses >1g)
• Dexamethasone (systemic)
• Immunosuppressants
• Ciclosporin
• Tacrolimus
• Sirolimus
• Medicines that prolong PR interval
• Verapamil
• Atazanavir
• Methadone
• Estrogen (Oestrogen) based contraceptives
• Selective serotonin reuptake inhibitors (SSRIs)
• Sertraline
• Paroxetine
• Disopyramide mexiletine
• Nefazodone
• Fluoxetine
• Desipramine
• Theophylline
• Trazadone
• Alprazolam
• Amprenavir
• Bupropion
• Buspirone
• Didanosine
• Fusidic acid
• Nelfinavir
• Vincristine
• Vinblastine
• Alfentanil
• Amitriptyline
• Amlodipine
• Bromocriptine
• Clomipramine
• Cyclophosphamide
• CYP3A inhibitors
• CYP3A substrates
• CYP450 inducers
• Diltiazem
• Erythromycin
• Everolimus
• Fentanyl
• Ifosfamide
• Imipramine
• Isradipine
• Loratadine
• Maprotiline
• Miconazole
• Nimodipine
• Nisoldipine
• Nitrendipine
• Nortriptyline
• Quinine
• Sulfamethoxazole/trimethoprim
• Tamoxifen
• Trimipramine

Other interactions

• St John’s wort (Hypericum perforatum)
• Tobacco

• Hepatic function 
• Lipid profile
• Blood glucose
• Viral load
• CD4 counts
• Genotypic and/or phenotypic testing
• Creatine phosphokinase (CPK)
• Uric acid

Specific cases may require

• International normalized ratio (INR) with coadministered warfarin 
• Cardiovascular risk assessment
• Serum lipase
• Serum amylase

Drug levels

• Therapeutic drug monitoring or drug concentrations
  - Carbamazepine
  - Immunosuppressants (ciclosporin, tacrolimus, sirolimus)

Additional observations

• Physical signs of fat redistribution
• New or worsening liver dysfunction
  - Clinically significant elevation of liver enzymes
  - Symptoms such as fatigue, anorexia, nausea, jaundice, liver tenderness, hepatomegaly
• Clinical monitoring with coadministered medicinal agents
  - Buprenorphine
  - Methadone
  - Calcium channel blockers
  - Pravastatin
  - Rosuvastatin
  - Selective serotonin reuptake inhibitors (SSRIs)
  - Indinavir
• Opportunistic infections

Darunavir
Darunavir is an inhibitor 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. Darunavir tightly binds to the HIV-1 protease. 

Ritonavir 
Ritonavir is used in this combination as pharmacokinetic enhancer, as it is an inhibitor of CYP3A, thereby increasing the plasma concentrations of darunavir. 

 

COMBINATION PREPARATIONS

Darunavir/ Ritonavir
Film coated tablet 400mg/50mg

• Zadurna (Mylan) originator