Vunad 400 & 800 Tablets

VUNAD, in combination with low dose ritonavir (VUNAD/rtv) and with other antiretroviral medicines, is indicated for the treatment of human immunodeficiency virus (HIV) infection in antiretroviral treatment experienced adult patients who are protease-inhibitor-nau00efve patients or after exclusion of darunavir resistance associated mutations (DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V). Genotypic or phenotypic testing should guide the use of VUNAD/rtv. Ritonavir is used as a pharmacokinetic enhancer of darunavir. There is no information on the use of darunavir in combination with ritonavir in the paediatric population for the once daily dose.

Posology: VUNAD must always be given with 100 mg ritonavir as a pharmacokinetic enhancer and in combination with other antiretroviral medicines. The professional information of ritonavir including the contraindications and warnings must therefore be consulted prior to initiation of therapy with VUNAD/rtv.

Adults: Genotypic or phenotypic testing should guide the use of VUNAD/rtv. VUNAD/ritonavir 800/100 mg once daily dosing regimen is recommended in HIV protease-inhibitor-nau00efve patients and in treatment-experienced patients with demonstrated absence of DRV-RAMs. VUNAD should be given with food. The type of food does not affect the exposure to darunavir. Ritonavir (100 mg) is used as a pharmacokinetic enhancer of darunavir (see section 4.5 and 5.2).

Missed Dose(s): In case a dose of VUNAD and/or ritonavir was missed within 12 hours of the time it is usually taken, patients should be instructed to take the prescribed dose of VUNAD and ritonavir 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.

Special populations: Hepatic impairment: No dose adjustment is required in patients with mild or moderate hepatic impairment. There are no data regarding the use of VUNAD/rtv when co-administered to patients with severe hepatic impairment; therefore, specific dosage recommendations cannot be made. VUNAD/rtv should not be used in patients with severe hepatic impairment as safety and efficacy have not been demonstrated (see section 4.4). Renal impairment: No dose adjustment is required in patients with renal impairment (see section 4.4 and 5.2). Paediatric population: Children (less than 12 years of age) and adolescents (12 to 17 years of age): The safety and efficacy of the once daily dose of VUNAD/rtv in paediatric patients has not been established.

Method of administration: PN is to be administered orally.

Hypersensitivity to darunavir or to any of the excipients listed in section 6.1. The presence of a contraindication to ritonavir. Patients with severe (Child-Pugh Class C) hepatic impairment. Concomitant treatment with any of the following medicinal products given the expected decrease in plasma concentrations of VUNAD, ritonavir and cobicistat and the potential for loss of therapeutic effect (see sections 4.4 and 4.5). Applicable to VUNAD boosted with either ritonavir or cobicistat:

• The combination product lopinavir/ritonavir (see section 4.5).
• The strong CYP3A inducers rifampicin and herbal preparations containing St John's wort (Hypericum perforatum). Co-administration is expected to reduce plasma concentrations of darunavir, ritonavir and cobicistat, which could lead to loss of therapeutic effect and possible development of resistance (see sections 4.4 and 4.5).

VUNAD boosted with either ritonavir or cobicistat inhibits the elimination of active substances that are highly dependent on CYP3A for clearance, which results in increased exposure to the co-administered medicinal product. Therefore, concomitant treatment with such medicinal products for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated (applies to VUNAD boosted with either ritonavir or cobicistat). These active substances include e.g.:

• alfuzosin
• amiodarone, bepridil, dronedarone, ivabradine, quinidine, ranolazine
• astemizole, terfenadine
• colchicine when used in patients with renal and/or hepatic impairment (see section 4.5)
• ergot derivatives (e.g. dihydroergotamine, ergometrine, ergotamine, methylergonovine)
• elbasvir/grazoprevir
• cisapride
• dapoxetine
• domperidone
• naloxegol
• lurasidone, pimozide, quetiapine, sertindole (see section 4.5)
• triazolam, midazolam administered orally (for caution on parenterally administered midazolam, see section 4.5)
• sildenafil - when used for the treatment of pulmonary arterial hypertension, avanafil
• simvastatin, lovastatin and lomitapide (see section 4.5)
• dabigatran, ticagrelor (see section 4.5).

Patients should be advised that current antiretroviral therapy, including VUNAD, does not prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be employed.

Elderly: As limited information is available on the use of VUNAD/rtv in patients aged 65 and over, caution should be exercised in the administration of VUNAD in elderly patients, reflecting the greater frequency of decreased hepatic function and of concomitant disease or other therapy (see section 5.2).

General: VUNAD must be co-administered with ritonavir and food to exert its therapeutic effect (see Section 4.2). Failure to correctly administer VUNAD with ritonavir and food will result in reduced plasma concentrations of darunavir that will be insufficient to achieve the desired antiviral effect. VUNAD should be used in combination with 100 mg of ritonavir as a pharmacokinetic enhancer (see section 5.2). Increasing the dose of ritonavir did not significantly affect darunavir concentrations and is not recommended.

Severe skin reactions: During the clinical development program, severe skin reactions, which may be accompanied with fever and/or elevations of transaminases, have been reported. Stevens-Johnson Syndrome has been reported; and during post-marketing experience toxic epidermal necrolysis has also been reported. VUNAD should be discontinued immediately if signs or symptoms of severe skin reactions develop. These can include but are not limited to severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia. Rash (all grades, regardless of causality) occurred in 10.3% of patients treated with VUNAD. The discontinuation rate due to rash in patients using VUNAD/rtv was 0.5%. Rash occurred more commonly in treatment-experienced subjects receiving regimens containing VUNAD/rtv + raltegravir compared to subjects receiving VUNAD/rtv without raltegravir or raltegravir without VUNAD/rtv. However, rash that was considered medicine related occurred at similar rates for all three groups.

Sulpha allergy: Darunavir contains a sulphonamide moiety. VUNAD should be used with caution in patients with a known sulphonamide allergy.

Patients with coexisting conditions: Hepatic impairment: VUNAD should not be used in patients with severe hepatic impairment. No dose adjustment is required in patients with mild or moderate hepatic impairment (see section 4.2 and section 5.2). Hepatotoxicity: Medicine-induced hepatitis (e.g. acute hepatitis, cytolytic hepatitis) has been reported with VUNAD/rtv. Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe hepatic adverse events. Appropriate laboratory testing should be conducted prior to initiating therapy with VUNAD/rtv and patients should be monitored during treatment. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of VUNAD/rtv treatment. Evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, liver tenderness, hepatomegaly) in patients on VUNAD/rtv should prompt consideration of interruption or discontinuation of treatment.

Renal impairment: Since the renal clearance of darunavir is limited, a decrease in the elimination of VUNAD is not expected in patients with renal impairment. As darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that they will be significantly removed by haemodialysis or peritoneal dialysis (see section 4.2 and section 5.2).

Haemophilia patients: There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthrosis in patients with haemophilia type A and B treated with PIs such as VUNAD. Haemophilia patients should therefore be made aware of the possibility of increased bleeding.

Hyperglycaemia: New onset diabetes mellitus, hyperglycaemia, or exacerbation of pre-existing diabetes mellitus has been reported in patients receiving VUNAD.

Lipodystrophy and metabolic abnormalities: Combination antiretroviral therapy has been associated with the redistribution/accumulation of body fat, including central obesity, dorso-cervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and elevated serum lipid and glucose levels in HIV patients. Clinical examination should include evaluation for physical signs of fat redistribution. Patients with evidence of lipodystrophy should have a thorough cardiovascular risk assessment.

Immune Reconstitution Inflammatory Syndrome: Immune reconstitution inflammatory syndrome (IRIS) is an immunopathological response resulting from the rapid restoration of pathogen-specific immune responses to pre-existing antigens combined with immune dysregulation, which occurs shortly after starting combination Anti-Retroviral Therapy (cART). Typically, such reaction presents by paradoxical deterioration of opportunistic infections being treated or with unmasking of an asymptomatic opportunistic disease, often with an atypical inflammatory presentation. IRIS usually develops within the first three months of initiation of ART and occurs more commonly in patients with low CD4 counts. Common examples of IRIS reactions to opportunistic diseases are tuberculosis, cytomegalovirus retinitis, and cryptococcal meningitis. Appropriate treatment of the opportunistic disease should be instituted or continued, and ART continued. Inflammatory manifestations generally subside after a few weeks. Severe cases may respond to glucocorticoids, but there is only limited evidence for this in patients with tuberculosis IRIS. 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: Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported, particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (cART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Opportunistic infections: Patients receiving VUNAD should be advised that they may continue to develop opportunistic infections and other complications of HIV infection, and therefore they should remain under close observation by healthcare professionals experienced in the treatment of patients with associated HIV disease. Regular monitoring of viral load and CD4 counts needs to be done.

VUNAD and ritonavir are both inhibitors of CYP3A. Co-administration of VUNAD/rtv with medicines primarily metabolised by CYP3A may result in increased plasma concentrations of such medicines, which could increase or prolong their therapeutic effect and adverse events (see section 4.3 and section 4.5).

For medicines that are highly dependent on the metabolism by CYP3A and that have a narrow therapeutic index, such as amiodarone, bepridil, (systemic) lidocaine and quinidine, plasma concentrations of such medicines could increase when combined with VUNAD/rtv. This can lead to prolongation or increase of their therapeutic effect and adverse events (see section 4.5).

HMG-CoA Reductase Inhibitors: Concomitant use of VUNAD/rtv with simvastatin, pravastatin or lovastatin is not recommended due to an increased risk of myopathy, including rhabdomyolysis, as a consequence of increased plasma concentrations of simvastatin, pravastatin or lovastatin.

Methadone: No adjustment of methadone dosage is required when initiating co-administration of VUNAD/rtv. However, clinical monitoring is recommended as maintenance therapy may need to be adjusted (see section 4.5).

Oestrogen-based contraceptives: Plasma concentrations of ethinylestradiol are decreased by induction of its metabolism by ritonavir and alternative methods of non-hormonal contraception are recommended (see section 4.5).

PDE-5-Inhibitors: If concomitant use of VUNAD/rtv with sildenafil, vardenafil, or tadalafil is indicated, reduced doses of the PDE-5 inhibitors are recommended (see section 4.3 and section 4.5).

Paediatric population: VUNAD is not recommended for use in paediatric patients below 3 years of age or less than 15 kg body weight (see sections 4.2 and 5.3).

Pregnancy: Safety and efficacy have not been demonstrated. In animal studies the exposure was lower than in human exposure and no conclusions were possible.

Breastfeeding: It is not known whether darunavir 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 nursing infants, mothers should be instructed not to breastfeed if they are receiving VUNAD.

Fertility: No human data on the effect of darunavir on fertility are available.

VUNAD in combination with cobicistat or ritonavir has no or negligible influence on the ability to drive and use machines. However, dizziness has been reported in some patients during treatment with regimens containing VUNAD co-administered with cobicistat or low dose ritonavir and should be borne in mind when considering a patient's ability to drive or operate machinery (see section 4.8).

Summary of the safety profile: Side effects are tabulated in order of frequent, less frequent and frequency unknown.

Tabulated summary of adverse reactions:

Organ system/ disorder

• Frequent
• Less frequent
• Frequency unknown

Infections and infestations

• ---
• Herpes simplex
• ---

Blood and lymphatic system disorders

• ---
• Thrombocytopenia, neutropenia, anaemia, leukopenia, increased eosinophil count
• ---

Immune system disorders

• ---
• immune reconstitution inflammatory syndrome, (drug) hypersensitivity
• ---

Endocrine disorders

• ---
• hypothyroidism, increased blood thyroid stimulating hormone
• ---

Metabolism and nutrition disorders

• hypertriglyceridaemia, hypercholesterolaemia
• Diabetes mellitus, gout, anorexia, dyslipidaemia, lipodystrophy, decreased appetite, decreased weight
• ---

hyperlipidaemia, hyperglycaemia, increased weight, insulin resistance, decreased high density lipoprotein, increased appetite, polydipsia, increased blood lactate dehydrogenase

Psychiatric disorders

• insomnia
• depression, disorientation, anxiety, sleep disorder, abnormal dreams, nightmare, decreased libido, confusional state, altered mood, restlessness
• ---

Nervous system disorders

• headache, peripheral neuropathy, dizziness
• lethargy, paraesthesia, hypo-aesthesia, dysgeusia, disturbance in attention, memory impairment, somnolence, syncope, convulsion, ageusia, sleep phase rhythm disturbance
• ---

Eye disorders

• ---
• conjunctival hyperaemia, dry eye, visual disturbance
• ---

Ear and labyrinth disorders

• ---
• vertigo
• ---

Cardiac disorders

• ---
• myocardial infarction, angina pectoris, prolonged electrocardiogram QT, tachycardia, acute myocardial infarction, sinus bradycardia, palpitations
• ---

Vascular disorders

• ---
• hypertension, flushing
• ---

Respiratory, thoracic and mediastinal disorders

• ---
• dyspnoea, cough, epistaxis, throat irritation, rhinorrhoea
• ---

Gastrointestinal disorders

• Diarrhoea, vomiting, nausea, abdominal pain, increased blood amylase
• Dyspepsia, flatulence, pancreatitis, gastritis, gastro-oesophageal reflux disease, aphthous stomatitis, retching
• ---

abdominal distension, flatulence, dry mouth, abdominal discomfort, constipation, increased lipase, eructation, oral dysaesthesia, stomatitis, haemat-emesis, cheilitis, dry lip, coated tongue

Hepatobiliary disorders

• increased alanine aminotransferase
• hepatitis, cytolytic hepatitis, hepatic steatosis, hepatomegaly, increased trans-aminase, increased aspartate amino-transferase, increased blood bilirubin, increased blood alkaline phosphatase, increased gamma-glutamyl transferase
• ---

Skin and subcutaneous tissue disorders

• rash (including macular, maculopapular, papular, erythematous and pruritic rash)
• angioedema, generalised rash, allergic dermatitis, urticaria, eczema, erythema, hyperhidrosis, night sweats, alopecia, acne, dry skin, nail pigmentation, DRESS, Stevens-Johnson syndrome, erythema multiforme, dermatitis, seborrhoeic dermatitis, skin lesion, xeroderma, pruritus
• toxic epidermal necrolysis, acute generalised exanthematous pustulosis

Musculoskeletal and connective tissue disorders

• ---
• myalgia, osteonecrosis, muscle spasms, muscular weakness, arthralgia, pain in extremity, osteoporosis, increased blood creatine phosphor kinase, musculoskeletal stiffness, arthritis, joint stiffness
• ---

Renal and urinary disorders

• ---
• acute renal failure, renal failure, nephrolithiasis, increased blood creatinine, proteinuria, bilirubinuria, dysuria, nocturia, pollakiuria, decreased creatinine renal clearance
• ---

Reproductive system and breast disorders

• ---
• erectile dysfunction, gynaecomastia
• ---

General disorders and administration site conditions

• pyrexia, chest pain, peripheral oedema, malaise, feeling hot, irritability, pain, chills, abnormal feeling, xerosis, asthenia, fatigue
• ---

Description of selected adverse reactions: Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients, including loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump). Combination antiretroviral therapy has also been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia. In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy, an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Increased CPK, myalgia, myositis and rarely, rhabdomyolysis have been reported with the use of protease inhibitors, particularly in combination with NRTIs. Patients co-infected with hepatitis B and/or hepatitis C virus: In patients co-infected with hepatitis B or C virus receiving VUNAD/rtv, the incidence of adverse events and clinical chemistry abnormalities were not higher than in patients receiving VUNAD/rtv who were not co-infected, except for increased hepatic enzymes (see section 4.4). The pharmacokinetic exposure in co-infected patients was comparable to that in patients without co-infection.

Human experience of acute overdose with VUNAD/rtv is limited. There is no specific antidote for overdose with VUNAD. Treatment of overdose with VUNAD consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. If indicated, elimination of unabsorbed active substance is to be achieved by emesis. Administration of activated charcoal may also be used to aid in removal of unabsorbed active substance. Since darunavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.