Zanrit 300 mg & 100 mg Tablet

ZANRIT is indicated in combination with other antiretroviral medicines for the treatment of HIV-1 infection.

The recommended dose for adults is: One tablet, once a day taken orally, with food. The tablet should be swallowed whole.

Special populations

Concomitant therapy

Efavirenz: In treatment-nau00efve patients, it is recommended that ZANRIT be taken with efavirenz 600 mg (all once daily).

Tenofovir: When co-administered with tenofovir, it is recommended that ZANRIT be given with tenofovir 300 mg, all as a single daily dose with food (see section 4.5).

Renal impairment: In patients with renal impairment, including those with severe renal impairment who are not managed by haemodialysis, no dosage adjustment is required.

Hepatic impairment: Atazanavir in combination with ritonavir, as contained in ZANRIT, has not been studied in subjects with hepatic impairment. ZANRIT should be used with caution in patients with mild hepatic impairment. ZANRIT should not be used in patients with moderate and severe hepatic impairment (see section 4.3).

Elderly: No data are available on which to make a dose recommendation for patients above 65 years.

Method of administration: ZANRIT is to be taken orally, with food.

Missed dose: Doctors should advise patients who forget to take ZANRIT to take a dose as soon as possible and then continue with the normal dose. Patients should not take a double dose to compensate for the missed dose.

• hypersensitivity to atazanavir, ritonavir or to any of the ingredients of ZANRIT listed in section 6.1
• concomitant administration with digoxin, amiodarone, astemizole, bepridil, cisapride, dihydroergotamine, encainide, ergotamine, flecainide, pimozide, propafenone, quinidine, midazolam and triazolam (see section 4.5)
• moderate to severe liver disease (see section 4.4)
• pregnancy and lactation
• co-administration with medicines that are highly dependent on CYP3A4 for clearance, and for which elevated plasma concentrations are associated with serious and/or life-threatening events (see table 1 below and section 4.5).

Table 1 u2013 Medicines that are contraindicated with ZANRIT

Medicine Class Medicines Contraindicated Clinical Comment

• Alpha1 - adrenoreceptor antagonist Alfuzosin Potential for increased alfuzosin concentrations which can result in hypotension.
• Anti-dysrhythmics Quinidine Contraindicated due to potential for serious and/or life-threatening reactions such as cardiac dysrhythmias.
• Antifungal Voriconazole Voriconazole should not be administered to patients receiving ZANRIT.
• Antimycobacterial Rifampicin Rifampicin substantially decreases plasma concentrations of atazanavir, which may result in loss of therapeutic effect and development of resistance.
• Antipsychotics/ Neuroleptics Bionanserin May result in potential increase in frequency or intensity of known neurological or other toxicities associated with bionanserin.
• Pimozide Potential for serious and/or life-threatening reactions such as cardiac dysrhythmias.
• Calcium Channel Blockers: Bepridil Potential for serious and/or life-threatening adverse events.
• Ergot Derivatives Dihydroergotamine, Ergonovine, Ergotamine, Methylergonovine Potential for serious and/or life-threatening events such as acute ergot toxicity characterised by peripheral vasospasm and ischaemia of the extremities and other tissues.
• GI Motility Medicine Cisapride Potential for serious and/or life-threatening reactions such as cardiac dysrhythmias.
• Herbal Products St. Johnu2019s Wort (Hypericum perforatum) Co-administration may be expected to reduce plasma concentrations of atazanavir. This may result in loss of therapeutic effect and development of resistance.
• HMG Co-A Reductase Inhibitor Lovastatin, Simvastatin There may be potential for serious reactions such as myopathy including rhabdomyolysis.
• Sedative Hypnotics Orally administered Midazolam, Triazolam Potential for increased concentrations of the sedative hypnotic and increased risk of prolonged sedation or respiratory depression.
• PDE5 inhibitor Sildenafil A safe and effective dose in combination with atazanavir has not been established for sildenafil when used for the treatment of pulmonary arterial hypertension. There is increased potential for sildenafil-associated adverse events.
• Antineoplastic Irinotecan Atazanavir inhibits UGT and may interfere with the metabolism of irinotecan, resulting in increased irinotecan toxicities.
• Protease Inhibitor Indinavir Atazanavir and indinavir are associated with hyperbilirubinaemia. Co-administration of ZANRIT and indinavir is not recommended (see section 4.5).
• Proton pump inhibitors Omeprazole Co-administration may reduce plasma concentrations of atazanavir. This may result in loss of therapeutic effect and development of resistance.

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

Lipodystrophy and metabolic abnormalities: Combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia. Combination antiretroviral therapy has also been associated with the redistribution/accumulation of body fat, including central obesity, dorso-cervical fat, enlargement (u201cbuffalo humpu201d), peripheral wasting, facial wasting, breast enlargement, u201cCushingoid appearanceu201d, 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.

Lipid disorders, weight and metabolic parameters: Treatment with ritonavir as in ZANRIT therapy in combination with saquinavir has resulted in substantial increases in the concentration of total triglycerides and cholesterol. Triglyceride and cholesterol testing should be performed prior to initiating ritonavir therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate. See section 4.5 u2013 Table 2 for additional information on potential medicine interactions with ritonavir and HMG-CoA Reductase Inhibitors (hypolipidemics). An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and lifestyle. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose, reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Extra monitoring is recommended when diarrhoea occurs. The relatively high frequency of diarrhoea during treatment with ritonavir may compromise the absorption and efficacy (due to decreased compliance) of ritonavir or other concurrent medicines. Serious persistent vomiting and/or diarrhoea associated with ritonavir use might also compromise renal function. It is advisable to monitor renal function in patients with renal function impairment.

Immune Reconstitution Inflammatory Syndrome (IRIS): 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, Mycobacterium avium infection, cytomegalovirus, or Pneumocystis jiroveci (carinii) pneumonia. 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.

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 ZANRIT 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.

Allergic reactions, rash, and associated syndromes: Ritonavir: Allergic reactions including urticaria, skin eruptions, bronchospasm, and angioedema have been reported. Rare cases of anaphylaxis and Stevens-Johnson syndrome have also been reported. Atazanavir: Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first 3 weeks of initiating therapy with ZANRIT. In most patients, rash resolves within 2 weeks while continuing therapy. ZANRIT should be discontinued if severe rash develops. Cases of Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions including Drug Rash, Eosinophilia, and Systemic Symptoms (DRESS) syndrome have been reported in patients taking atazanavir.

Hepatic impairment and toxicity: Atazanavir and ritonavir are principally metabolised by the liver; caution should be exercised when administering ZANRIT to patients with hepatic impairment because both atazanavir and ritonavir concentrations may be increased, in some cases up to five times the upper limit of normal. Clinical hepatitis and jaundice have occurred (see section 4.2). Patients with underlying hepatitis B or C viral infections or marked elevations in transaminases prior to treatment may be at increased risk for developing further transaminase elevations. Hepatic transaminase elevations exceeding five times the upper limit of normal, clinical hepatitis and jaundice have occurred in patients receiving atazanavir alone or in combination with other antiretroviral medicines. Therefore, caution should be exercised when administering ZANRIT to patients with pre-existing mild liver disease, liver enzyme abnormalities or hepatitis. Increased AST/ALT monitoring should be considered in these patients during the first three months of ZANRIT treatment. There have been reports of hepatic dysfunction, including fatalities, particularly in patients taking multiple concomitant medicines and/or with advanced AIDS. ZANRIT is contraindicated in patients with severe hepatic insufficiency (see section 4.3).

Pancreatitis: Pancreatitis has been observed in patients receiving ritonavir therapy, including those who developed hypertriglyceridemia, with fatalities having been observed in some cases. Patients with advanced HIV disease may be at increased risk of elevated triglycerides and pancreatitis. Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis should occur. Patients who exhibit these signs or symptoms should be evaluated and ZANRIT therapy should be discontinued if a diagnosis of pancreatitis is made.

Diabetes mellitus/hyperglycaemia: New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycaemia have been reported during post-marketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustment of insulin or oral hypoglycaemic medicines for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In patients who discontinued protease inhibitor therapy, the hyperglycaemia persisted in some cases.

Corticosteroids: Concomitant use of ritonavir and fluticasone propionate can significantly increase fluticasone propionate plasma concentrations and reduce serum cortisol concentrations. Systemic corticosteroid effects including Cushingu2019s syndrome and adrenal suppression have been reported when ritonavir has been co-administered with inhaled or intranasally administered fluticasone propionate. Similar findings with concomitant administration of ritonavir and other inhaled corticosteroids that are metabolised similarly to fluticasone, such as budesonide, cannot be excluded. Particular caution should be used when administering ZANRIT and any of these inhaled or intranasally administered glucocorticoids (see section 4.5 u2013 Table 2).

PDE5 Inhibitors: Caution should be used when prescribing sildenafil, tadalafil or vardenafil for the treatment of erectile dysfunction or pulmonary hypertension in patients receiving ZANRIT. Co-administration of ZANRIT with these medicines is expected to increase their concentrations and may result in increased associated adverse events, such as hypotension and prolonged erection. Concomitant use of sildenafil with ZANRIT is contraindicated in pulmonary arterial hypertension patients (see Section 4.3).

Herbal Products: Patients on ZANRIT should not use products containing St. Johnu2019s Wort (Hypericum perforatum) because co-administration may be expected to reduce plasma concentrations of ritonavir. This may result in loss of therapeutic effect and development of resistance (see IRIS and section 4.3).

HMG-CoA Reductase Inhibitors: The HMG-CoA reductase inhibitors simvastatin and lovastatin are highly dependent on CYP3A for metabolism, thus concomitant use of ZANRIT with simvastatin or lovastatin is contraindicated due to an increased risk of myopathy including rhabdomyolysis. Caution must be exercised, and reduced doses should be considered if ZANRIT is used concurrently with atorvastatin, which is metabolised to a lesser extent by CYP3A4. While rosuvastatin elimination is not dependent on CYP3A, an elevation of rosuvastatin exposure has been reported with ritonavir co-administration. If treatment with an HMG-CoA reductase inhibitor is indicated, pravastatin or fluvastatin is recommended (see section 4.5 u2013 Table 2).

Resistance/Cross - Resistance: Varying degrees of cross-resistance among protease inhibitors have been observed. Continued administration of ZANRIT therapy following loss of viral suppression may increase the likelihood of cross-resistance to other protease inhibitors. The potential for HIV cross-resistance between protease inhibitors has not been fully explored. Therefore, it is unknown what effect ZANRIT therapy will have on the activity of concordantly or subsequently administered protease inhibitors.

Hyperbilirubinemia: Reversible elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyl transferase (UGT) have occurred in patients receiving atazanavir. Hepatic transaminase elevations that occur with elevated bilirubin in patients receiving ZANRIT should be evaluated for alternative aetiologies. No long-term safety data are available for patients experiencing persistent elevations in bilirubin >5 times the upper limit of normal (ULN). Alternative antiretroviral therapy to ZANRIT may be considered if jaundice or scleral icterus associated with bilirubin elevations presents cosmetic concerns for patients. Dose reduction of ZANRIT is not recommended since long-term efficacy of reduced doses has not been established.

Laboratory Tests: Ritonavir as in ZANRIT has been associated with alterations in triglycerides, ALT, AST, GGT, CPK and uric acid. Appropriate laboratory testing should be performed prior to initiating ZANRIT therapy and at periodic intervals or if any clinical signs or symptoms occur during therapy.

For comprehensive information concerning laboratory test alterations associated with nucleoside analogues, the healthcare professional should refer to the complete product information for each of these medicines.

Adult patients: The most frequently reported laboratory abnormality in patients receiving regimens containing atazanavir and one or more NRTIs was elevated total bilirubin (87 % Grade 1, 2, 3 or 4). Grade 3 or 4 elevation of total bilirubin was noted in 36 % (20 % Grade 3, 6 % Grade 4, reported predominantly as elevated indirect bilirubin). Other marked clinical laboratory abnormalities (Grade 3 or 4) reported in u2265 2 % of patients receiving regimens containing atazanavir and one or more NRTIs included: elevated amylase (12 %), elevated creatine kinase (CK) (8 %), elevated ALT/SGPT (6 %), low neutrophils (6 %), elevated AST/SGOT (4 %) and elevated lipase (3 %).

The selection of antiretroviral therapy must be guided principally by antiviral efficacy. Consultation with standard guidelines for management of dyslipidaemia is recommended.

Haemophilia: There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthrosis, in patients with haemophilia type A and B treated with protease inhibitors. In some patients, additional factor VIII was given. In most reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship has been postulated, although mechanism of action has not been established.

PR Interval prolongation: ZANRIT has the potential to prolong the PR interval of the electrocardiogram in some patients. Reports of second-or third-degree atrioventricular block in patients with underlying structural heart disease and pre-existing conduction system abnormalities or in patients receiving medicines known to prolong the PR interval (such as verapamil or atazanavir) have been reported. ZANRIT should be used with caution in patients with pre-existing conduction system disease. Caution should be used when co-administering ZANRIT with medicines known to induce PR interval prolongation.

Cholelithiasis: Cholelithiasis has been reported in patients receiving atazanavir (see section 4.8). Some patients required hospitalization for additional management and some had complications. If signs or symptoms of cholelithiasis occur, temporary interruption or discontinuation of treatment may be considered.

Nephrolithiasis: Cases of nephrolithiasis have been reported during post-marketing surveillance in HIV-infected patients receiving ZANRIT therapy. If signs or symptoms of nephrolithiasis occur, temporary interruption or discontinuation of therapy may be considered.

Renal disease: Since the renal clearance of ritonavir is negligible, the decrease in the total body clearance is not expected in patients with renal impairment (see also section 4.2). Renal failure, renal impairment, elevated creatinine, hypophosphataemia and proximal tubulopathy (including Fanconi syndrome) have been reported with the use of tenofovir disoproxil fumarate in clinical practice (see section 4.8). Chronic kidney disease in HIV-infected patients treated with atazanavir, with or without ritonavir, has been reported during post-marketing surveillance. A large prospective observational study has shown an association between an increased incidence of chronic kidney disease and cumulative exposure to atazanavir/ritonavir-containing regimen in HIV-infected patients with an initially normal eGFR. This association was observed independently of exposure to tenofovir disoproxil. Regular monitoring of the renal function of patients should be maintained throughout the treatment duration (see section 4.8).

Elderly: Safety and efficacy have not been established in the elderly.

ZANRIT contains lactose: ZANRIT contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Medicines which increase CYP3A activity (e.g. phenobarbital, carbamazepine, dexamethasone, phenytoin, rifampicin and rifabutin) would be expected to increase the clearance of ZANRIT resulting in decreased ritonavir plasma concentrations.

ZANRIT has a high affinity for several cytochrome P450 (CYP) isoforms with the following ranked order: CYP34A> CYP206> CYP2C9> CYP2C19 >> CYP2A6, CYP1A2, CYP2E1.

There is some evidence that ZANRIT may increase the activity of glucuronosyl glucuronyl transferase; and therefore, loss of therapeutic effects from directly glucuronidated medicines during ZANRIT therapy may signify the need for dosage adjustments of these medicines. In addition to the medicines listed in the section 4.3, Table 1 summarises some commonly prescribed medicines, separated by the type of metabolism and expected magnitude of interaction when co-administered with ZANRIT. Careful monitoring of therapeutic and adverse effects is recommended when these medicines are concomitantly administered with ritonavir, as contained in ZANRIT. Dosage reductions may be required for those medicines extensively metabolised by CYP3A.

There have been reports of cardiac and neurologic events when ritonavir, as contained in ZANRIT, has been co-administered with disopyramide, mexiletine, nefazodone or fluoxetine. The possibility of medicine interaction cannot be excluded.

Table 2 Potential Effects on Medicines co-administered with ritonavir contained in ZANRIT

Contra-Indicated Medicines Large1 u2191AUC2 (CYP3A) Moderate1 u2191AUC2 (CYP2D6) Moderate1 u2191 Or u2193AUC2 (CYP2C9/19) Possible u2193AUC2 (Unknown CYP)

Analgesics, Narcotics Alfentanil, Fentanyl, Hydrocodone, Oxycodone, Propoxyphene, Tramadol

Levamet hadyl (LAAM), Codeine, Hydromorphone, Pethidine, Methadone*, Morphine

Analgesics, Non-steroidal Diclofenac, Flurbiprofen, Ibuprofen, Indomethacin, Piroxicam, Nabumetone, Sulindac, Ketoprofen, Ketorolac, Naproxen

Antidysrhythmic Amiodarone, Encainide, Flecainide, Propafenone, Quinidine, Lidocaine, Disopyramide, Mexiletine, Tocainide

Anti-asthmatic Theophylline*

Antibiotic, Macrolide Erythromycin, Clarithromycin*

Antibiotic, Steroidal Fusidic acid

Anticonvulsant Carbamazepine, Clonazepam, Phenobarbital, Valproate, Ethosuximide

Antidepressant tricyclic Amitriptyline, Clomipramine, Desipramine*, Imipramine, Maprotiline, Nortriptyline, Trimipramine, Doxepin*

Antidepressant SSRIs and non-tricyclics Nefazodone, Sertraline, Bupropion, Fluoxetine, Paroxetine, Trazodone*, Venlafaxine, Fluvoxamine

Antidiarrhoeal Diphenoxylate, Loperamide

Anti-emetics Prokinetics Cisapride, Dronabinol, Ondansetron, Prochlorperazine*, Promethazine, Metoclopramide

Antifungal Agents Itraconazole, Ketoconazole*, Micronazole

Antihistamines Loratadine

Antihypertensive Losartan, Doxazosin*, Prazosin*, Terazosin*

Antimycobacterial Rifabutin*, Ethionamide, Rifampicin

Antiparasitics Quinine, Proguanil, Albendazole, Chloroquine, Metronidazole, Primaquine, Pyrimethamine, Trimetrexate, Atovaquone

Antiulcer Agents Lansoprazole, Omeprazole

Beta-blockers Calcium channel blockers Bepridil, Amlodipine, Diltiazem, Felodipine, Isradipine, Nicardipine, Nifedipine, Nimodipine, Nisoldipine, Nitrendipine, Verapamil, Metoprolol, Penbutolol, Pindolol, Timolol, Propranolol, Betaxolol

Cancer chemotherapeutic Tamoxifen, Etoposide, Paclitaxel, Vinblastine, Vincristine, Cyclophosphamide*, Ifosfamide, Daunorubicin*, Doxorubicin*

Ergot alkaloids and derivatives Dihydroergotamine, Bromocriptine, Ergonovine*, Methylergonovine*, Methysergide*

Haemorrheologic agent Pentoxifylline

HIV Antivirals Indinavir*, Saquinavir*

Hypoglycaemics Glimepiride, Glipizide, Glyburide, Tolbutamide

Hypolipidaemics Atorvastatin, Lovastatin, Simvastatin, Gemfibrozil, Clofibrate

Immunosuppressants Ciclosporin, Tacrolimus, Sirolimus (rapamycin)

Neuroleptics Pimozide, Chlorpromazine, Haloperidol, Perphenazine, Risperidone, Thioridazine, Clozapine

Sedatives/Hypnotics Midazolam, Triazolam, Buspirone, Clorazepate, Diazepam, Estazolam, Flurazepam, Zolpidem, Lorazepam, Oxazepam, Propofol, Temazepam

Steroids Dexamethasone, Fluticasone*, Prednisone, Ethinyl Oestradiol*

Stimulants Dexfenfluramine, Methamphetamine, Methylphenidate

1 Large = > 3X; Moderate = 1.5 - 3X 2 AUC = area under the plasma concentration-time curve, a measure of substance exposure. 3 An increase in the AUC of cyclophosphamide and ifosfamide, both activated by CYP, may correspond to a decrease in the AUC of the active metabolite(s) and a possible decrease in efficacy of these medicines. 11 A possible increase in concentration is more likely when combined with ritonavir * Clinical medicine interaction study has been performed

Pregnancy: ZANRIT is contraindicated in pregnancy, as safety has not been established.

Breastfeeding: ZANRIT is contraindicated during breastfeeding (see section 4.3). Transfer of one or both active ingredients into breastmilk in concentrations that may harm the baby cannot be excluded. It is recommended that HIV infected women do not breast-feed their infants in order to avoid transmission of HIV.

ZANRIT may influence the ability to drive and use machines. Patients should not drive and use machines until they know how treatment with ZANRIT affects them, as nervous system side effects such as dizziness, somnolence, disorientation, blurred vision and syncope have been reported in patients taking atazanavir/ritonavir.

a). Summary of the safety profile: The most frequent reported clinical adverse events, other than asthenia, among patients receiving ritonavir were gastrointestinal and neurological disturbances including nausea, diarrhoea, vomiting, anorexia, abdominal pain, taste perversion and circumoral and peripheral paraesthesias. The more frequent adverse events of any severity with at least a possible relationship to regimens containing atazanavir and one or more NRTIs were nausea (20 %), jaundice (13 %), and diarrhoea (10 %). Among patients receiving atazanavir 300 mg with ritonavir 100 mg, (as in ZANRIT) the frequency of jaundice was 19 %. Jaundice was reported within a few days to a few months after the initiation of treatment and resulted in discontinuation of treatment in < 1 % of patients. Lipodystrophy, of moderate intensity or greater, was reported in regimens containing atazanavir and one or more NRTIs, as at least possibly related to the regimen, in 5 % of patients.

Chronic kidney disease in HIV-infected patients treated with atazanavir, with or without ritonavir, has been reported during post marketing surveillance. A large prospective observational study has shown an association between an increased incidence of chronic kidney disease and cumulative exposure to atazanavir/ritonavir-containing regimen (as in ZANRIT) in HIV-infected patients with an initially normal eGFR. This association was observed independently of exposure to tenofovir disoproxil. Regular monitoring of the renal function of patients should be maintained throughout the treatment duration (see section 4.4).

The following adverse reactions of moderate intensity or greater with at least a possible relationship to regimens containing atazanavir and one or more NRTIs have been reported:

b). Tabulated summary of adverse reactions Atazanavir alone and in combination i.e. as in ZANRIT:

System Organ Class Frequency Side effects

Immune system disorders Less frequent Hypersensitivity, allergic reaction

Metabolism and nutrition disorders Less frequent Frequency unknown Anorexia, increased appetite, decreased weight, weight gain Hyperglycaemia, diabetes mellitus

Psychiatric disorders Less frequent Anxiety, depression, sleep disorder, insomnia, abnormal dreams, disorientation, confusion

Nervous system disorders Frequent Less frequent Headache, dizziness Peripheral neurologic symptoms, amnesia, somnolence, dysgeusia, syncope, abnormal gait

Eye disorders Frequent Ocular icterus

Cardiac disorders Less frequent Frequency unknown Oedema, palpitations, QTc prolongation, Torsades de Pointes Second-degree AV block*, third-degree AV block*

Vascular disorders Less frequent Hypertension, syncope

Respiratory, thoracic, and mediastinal disorders Less frequent Dyspnoea

Gastrointestinal disorders Frequent Less frequent Abdominal pain, diarrhoea, dyspepsia, nausea, vomiting Dry mouth, flatulence, gastritis, pancreatitis, stomatitis aphthous, abdominal distension

Hepato-biliary disorders Frequent Less frequent Jaundice Hepatitis, hepatosplenomegaly, cholelithiasis, cholestasis, cholecystitis

Skin and subcutaneous tissue disorders Frequent Less frequent Rash Alopecia, pruritus, urticaria, DRESS (medicine rash with eosinophilia and systemic symptoms) syndrome, angioedema, vasodilation, vesiculobullous rash, eczema, Stevens-Johnson syndrome, eruptions

Musculoskeletal, connective tissue and bone disorders Less frequent Arthralgia, muscle atrophy, myalgia, myopathy

Renal and urinary disorders Less frequent Haematuria, pollakiuria, proteinuria, nephrolithiasis, interstitial nephritis, kidney pain, chronic kidney disease

Reproductive system and breast disorders Less frequent Gynaecomastia

General disorders and administrative site conditions Frequent Less frequent Fatigue, lipodystrophy syndrome Chest pain, pyrexia, malaise, gait disturbance, asthenia

c). Tabulated summary of adverse reactions - Ritonavir System Organ Class Frequency Side effects

Infections and Infestations Frequent Pharyngitis

Blood and lymphatic system disorders Frequent Less frequent Frequency unknown Decreased white blood count, decreased haemoglobin, decreased neutrophils, increased eosinophils Anaemia, ecchymosis, leukopenia, lymphadenopathy, lymphocytosis, increased neutrophils, increased white blood counts, increased prothrombin time Thrombocytopaenia

Immune system disorders Frequent Less frequent Allergic reactions including urticaria, face oedema Anaphylaxis, Stevens-Johnson syndrome

Endocrine disorders Less frequent Diabetes mellitus

Metabolism and nutrition disorders Frequent Less frequent Frequency unknown Anorexia, hyperlipaemia, weight loss Hyperglycaemia, diabetes mellitus, avitaminosis, cachexia, dehydration*, oedema, glycosuria, gout, hypercholesterolaemia, peripheral oedema, redistribution/accumulation of body fat (see section 4.4) Hypertriglyceridaemia, hyperuricaemia

Psychiatric disorders Frequent Less frequent Anxiety, agitation, confusion, depression, emotional lability, euphoria, hallucinations, decreased libido, nervousness, personality disorder, abnormal thinking

Nervous system disorders Frequent Frequency unknown Circumoral paraesthesia, headache, peripheral paraesthesia, taste perversion, dizziness, hyperaesthesia, paraesthesia, somnolence Seizure, syncope, abnormal dreams, amnesia, aphasia, ataxia, convulsion, grand mal convulsion, inco-ordination, neuralgia, neuropathy, paralysis, parosmia, peripheral neuropathy, peripheral sensory neuropathy, taste loss, tremor, visual field defect

Eye disorders Less frequent Abnormal vision, amblyopia/blurred vision, blepharitis, diplopia, eye pain, iritis, photophobia, uveitis

Ear and labyrinth disorders Less frequent Ear pain, hearing impairment, increased cerumen, tinnitus, vertigo

Cardiac disorders Less frequent Frequency unknown Palpitations, syncope Tachycardia, myocardial infarction

Vascular disorders Frequent Less frequent Vasodilation Haemorrhage, hypotension including orthostatic hypotension, migraine, peripheral vascular disorder, postural hypotension

Respiratory, thoracic and mediastinal disorders Frequent Less frequent Increased cough, pharyngitis Asthma, dyspnoea, epistaxis, hiccup, hypoventilation, interstitial pneumonia, lung disorder and rhinitis

Gastrointestinal disorders Frequent Less frequent Abdominal pain, diarrhoea, nausea, vomiting, dry mouth, dyspepsia, eructation, flatulence, local throat irritation, mouth ulcer, anorexia 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, thirst

Hepato-biliary disorders Frequent Cholangitis, hepatitis (including increased AST, ALT GGT), hepatomegaly, liver damage, blood bilirubin increased (including jaundice)

Skin and subcutaneous tissue disorders Frequent Less frequent Maculopapular rash, pruritus, rash, sweating, lipodystrophy, Stevens Johnson syndrome, Toxic epidermal necrolysis (TEN), acne, contact dermatitis, dry skin, eczema, facial oedema, folliculitis, molluscum contagiosum, photosensitivity reaction, psoriasis, urticaria, vesiculobullous rash

Musculoskeletal, connective tissue and bone disorders Frequent Less frequent Myalgia Arthralgia, arthrosis, back pain, facial pain, joint disorder, muscle cramps, muscle weakness, myositis

Renal and urinary disorders Less frequent Frequency unknown Dysuria, haematuria, kidney calculus, kidney failure, kidney pain, nocturia, polyuria, pyelonephritis, urethritis, urinary frequency, urinary retention Acute renal failure

Reproductive system and breast disorders Less frequent Frequency unknown Impotence, penis disorder Menorrhagia

General disorders and administrative site conditions Frequent Less frequent Asthenia, fever, pain, weight loss Abnormal gait, chest pain, chills, flu syndrome, malaise, substernal chest pain

Investigations Frequent Less frequent Abnormal liver function tests Abnormal electro-oculogram, abnormal electroretinogram, altered hormone level

Injury and poisoning Less frequent Accidental injury, hypothermia

Surgical and medical procedures Frequent Vasodilation

d). Description of selected adverse reactions: In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4).

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via the online service for adverse drug reaction reporting by following the link: https://www.sahpra.org.za/document/adverse-drug-reactions-and-quality-problem-reporting-form/ or https://www.sahpra.org.za/Publications/Index/8. An email can be sent directly to the company, [email protected] to ensure safety of the product.

In overdose with ZANRIT side effects of both atazanavir and ritonavir can be precipitated and/or be of increased severity.

Signs and symptoms: Atazanavir: Human experience of acute overdose with atazanavir is limited. At high doses that lead to high medicine exposure, the side effects of atazanavir may be precipitated and/or be of increased severity. Jaundice, predominantly due to indirect (unconjugated) hyperbilirubinaemia (without associated liver function test changes) or PR interval prolongations, may be observed.

Ritonavir: Human experience of acute overdose with ritonavir is limited. Paraesthesias and renal failure with eosinophilia have been reported with ZANRIT overdose.

Management of overdose: There is no specific antidote for overdose with ZANRIT. Treatment of overdose with ZANRIT should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. It is proposed that management of overdose could also entail and administration of activated charcoal. Since ZANRIT is extensively metabolised by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the medicine.