NEW ZEALAND DATA SHEET 2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Transcription

1 NEW ZEALAND DATA SHEET 1. KALETRA 100 mg/25 mg film-coated tablets KALETRA 200 mg/50 mg film-coated tablets KALETRA 80 mg/20 mg per ml oral solution 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Film-Coated Tablets 100/25 mg: Each film-coated tablet contains 100 mg of lopinavir co-formulated with 25 mg of ritonavir as a pharmacokinetic enhancer. 200/50 mg: Each film-coated tablet contains 200 mg of lopinavir co-formulated with 50 mg of ritonavir as a pharmacokinetic enhancer. Oral Solution 80/20 mg: Each 1 ml of oral solution contains 80 mg of lopinavir co-formulated with 20 mg of ritonavir as a pharmacokinetic enhancer. Excipients with Known Effect oral solution contains alcohol (42.4% v/v), high fructose maize syrup, propylene glycol (15.3% w/v) (see section 4.3), Castor oil PEG 40 hydrogenated and acesulfame potassium. For the full list of excipients, see section PHARMACEUTICAL FORM Film-Coated Tablets 100/25 mg film-coated tablets are pale yellow, debossed with the Abbott logo and KC. 200/50 mg tablets are yellow, ovaloid, film-coated tablets embossed with the Abbott logo KA. and Oral Solution oral solution is a light yellow to golden coloured liquid, supplied in 60 ml amber-coloured multipledose bottle containing 400 mg lopinavir and 100 mg ritonavir per 5 ml marked dosing syringe, equivalent to 80 mg lopinavir and 20 mg ritonavir per 1 ml of oral solution. 01 May 2017 Page 1 of 47

2 4. CLINICAL PARTICULARS 4.1 Therapeutic Indications is indicated for the treatment of HIV-1 infection, in combination with other antiretroviral agents in adults and children aged 2 years and older. This indication is based on analyses of plasma HIV RNA levels and CD4 cell counts from controlled clinical studies (see section Clinical Efficacy and Safety Results). 4.2 Dose and Method of Administration Film-Coated Tablets tablets should be swallowed whole and not chewed, broken or crushed. tablets may be taken with or without food. Adults The recommended dosage of film-coated tablets is 400/100 mg (two 200/50 mg tablets) twice daily. tablets may also be administered as 800/200 mg (four 200/50 mg tablets) once daily, in patients with less than three lopinavir-associated mutations. There are insufficient data to support the use of once daily administration of for adult patients with three or more lopinavir-associated mutations (see section Table 11 and Table 12). Concomitant Therapy: Efavirenz, Nevirapine, Amprenavir, or Nelfinavir A dose increase of lopinavir/ritonavir to 500/125 mg twice daily (such as two 200/50 mg tablets and one 100/25 mg tablet or 6.25 ml of oral solution) should be considered when used in combination with efavirenz, nevirapine, amprenavir or nelfinavir in treatment experienced patients where reduced susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence), (see section 4.5). Paediatric Population (2 years of age and above) The adult dose of tablets (400/100 mg twice daily) may be used in children 35 kg or greater. For children weighing less than 35 kg and able to swallow tablets, refer to the dosing guideline tables below. oral solution is available for children with a body weight of less than 7 kg. once daily is not recommended for any paediatric patients. The following table contains dosing guidelines for 100/25 mg tablets in children based on body weight, without efavirenz, nevirapine, nelfinavir or amprenavir. 01 May 2017 Page 2 of 47

3 Table 1: Paediatric Dosing Guidelines without Concomitant Efavirenz, Nevirapin or Amprenavir Body Weight (kg) Recommended number of 100/25 mg Tablets Twice Daily Administered Dose 7 to < /25 mg 10 to < /50 mg 25 to < /75 mg /100 mg Concomitant Therapy: Efavirenz, Nevirapine, Nelfinavir or Amprenavir The following table contains dosing guidelines for 100/25 mg tablets in children based on body weight, when used in combination with efavirenz, nevirapine, nelfinavir, or amprenavir. Table 2: Paediatric Dosing Guidelines with Concomitant Efavirenz, Nevirapin or Amprenavir Body Weight (kg) Recommended number of 100/25 Administered Dose mg Tablets Twice Daily 10 to < /50 mg 20 to < /75 mg > 30 kg to 45 kg 4 400/100 mg > 45 kg 5 500/125 mg Oral Solution Adults oral solution is available to patients who cannot take a tablet formulation. The recommended dosage of is 5 ml of oral solution (400/100 mg) twice daily taken with food. oral solution may also be administered as 10 ml once daily with food, in patients with less than three lopinavir-associated mutations. Paediatric Population (2 years of age and above) Total amounts of alcohol and propylene glycol from all medicines, including oral solution, that are to be given to infants should be taken into account in order to avoid toxicity from these excipients. The recommended dosage for children 2 years and older is 230/57.5 mg/m 2 (or 12/3 mg/kg for children < 15 kg or 10/2.5 mg/kg for children 15 kg) twice daily taken with food, up to a maximum dose of 400/100 mg (5 ml) twice daily. In subjects receiving concomitant nevirapine or efavirenz an increase in dosage to 300/75 mg/m 2 (or 13/3.25 mg/kg for children < 15 kg or 11/2.75 mg/kg for children 15 kg) twice daily taken with food, should be considered. should not be administered once daily in paediatric patients. 01 May 2017 Page 3 of 47

4 The following tables contain dosing guidelines for oral solution based on children weighing less than 40 kg. Table 3: Paediatric Dosing Guidelines for Oral Solution* based on Body Weight without Concomitant Efavirenz, Nevirapine or Amprenavir Body Weight Dose Volume of Oral Administered Dose (kg) (mg/kg)* Solution Twice Daily* 7 to < 15 kg 12 mg/kg twice daily 7 to 10 kg 1.25 ml 100/25 mg > 10 to < 15 kg 1.75 ml 140/35 mg 15 to 40 kg 10 mg/kg twice daily 15 to 20 kg 2.25 ml 180/45 mg > 20 to 25 kg 2.75 ml 220/55 mg > 25 to 30 kg 3.5 ml 280/70 mg > 30 to 35 kg 4.0 ml 320/80 mg > 35 to 40 kg 4.75 ml 380/95 mg > 40 kg See adult dosage recommendation * Dosing based on the lopinavir component of lopinavir/ritonavir solution (80 mg/20 mg per ml). Table 4: Paediatric Dosing Guidelines for Oral Solution based on Body Weight with Concomitant Efavirenz, Nevirapine or Amprenavir Body Weight Dose Volume of Oral Administered Dose (kg) (mg/kg)* Solution Twice Daily 7 to < 15 kg 13 mg/kg twice daily 7 to 10 kg 1.5 ml 120/30 mg > 10 to < 15 kg 2.0 ml 160/40 mg 15 to 45 kg 11 mg/kg twice daily 15 to 20 kg 2.5 ml 200/50 mg > 20 to 25 kg 3.25 ml 260/65 mg > 25 to 30 kg 4.0 ml 320/80 mg > 30 to 35 kg 4.5 ml 360/90 mg > 35 to 40 kg 5.0 ml 400/100 mg > 40 kg See adult dosage recommendation for concomitant therapy * Dosing based on the lopinavir component of lopinavir/ritonavir solution (80 mg/20 mg per ml). Use of Oral Solution with a Feeding Tube The prescribed dose of oral solution can be administered via a feeding tube. Follow the instructions for the feeding tube to administer the medicine. Products containing alcohol, like oral solution, are not recommended for use with polyurethane feeding tubes due to potential incompatibility. 4.3 Contraindications is contraindicated in patients with known hypersensitivity to lopinavir, ritonavir, or any excipients listed in section 6.1. should not be co-administered concurrently with medicines that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These medicines are listed in Table May 2017 Page 4 of 47

5 Table 5: Medicines which should not be co-administered with Therapeutic Class Alpha1-adrenoreceptor antagonist Antianginal Antiarrhythmic Antibiotics Antigout Antihistamines Antipsychotics Benzodiazepines Medicines Within Class Not to Be Co-administered Alfuzosin hydrochloride Ranolazine Dronedarone Fusidic acid Colchicine in patients with renal and/or hepatic impairment Astemizole, terfenadine Blonanserin, lurasidone, pimozide Oral midazolam, Triazolam Ergot derivatives Ergotamine, Dihydroergotamine, Ergometrine, GI motility agent Herbal product Hepatitis C direct acting antiviral HMG-CoA Reductase Inhibitors Long acting beta-adrenoreceptor agonist PDE5 inhibitor Methylergometrine Cisapride St John s Wort (Hypericum perforatum) Elbasvir/grazoprevir Lovastatin, simvastatin * see sections 4.5 for co-administration of sildenafil in patients with erectile dysfunction Salmeterol Sildenafil * only when used for the treatment of pulmonary arterial hypertension (PAH) oral solution is contraindicated in children below the age of 2 years, pregnant women, patients with hepatic and renal failure and patients treated with disulfiram or metronidazole due to the potential risk of toxicity from the excipient propylene glycol. 4.4 Special Warnings and Precautions for Use 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 adjustments of insulin or oral hypoglycaemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycaemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established. Consideration should be given to the monitoring of blood glucose. 01 May 2017 Page 5 of 47

6 Pancreatitis Pancreatitis has been observed in patients receiving therapy, including those who developed marked triglyceride elevations. In some cases, fatalities have been observed. Although a causal relationship to has not been established, marked triglyceride elevations is a risk factor for development of pancreatitis (see section Lipid Elevations). Patients with advanced HIV disease may be at increased risk of elevated triglycerides and pancreatitis, and patients with a history of pancreatitis may be at increased risk for recurrence during therapy. Hepatic Impairment is principally metabolised by the liver. Therefore, caution should be exercised when administering this medicine to patients with impaired hepatic function. has not been studied in patients with severe hepatic impairment. Pharmacokinetic data suggests increases in lopinavir plasma concentrations of approximately 30% as well as decreases in plasma protein binding in HIV and HCV co-infected patients with mild to moderate hepatic impairment (see section 5.2). Patients with underlying hepatitis B or C or marked elevations in transaminases prior to treatment may be at increased risk for developing further transaminase elevations. There have been post-marketing reports of hepatic dysfunction, including some fatalities. These have generally occurred in patients with advanced HIV disease taking multiple concomitant medications in the setting of underlying chronic hepatitis or cirrhosis. A causal relationship with therapy has not been established. Increased AST/ALT monitoring should be considered in these patients, especially during the first several months of treatment. Elevated transaminases with or without elevated bilirubin levels have been reported in HIV-1 mono-infected and uninfected patients after the initiation of in conjunction with other antiretroviral agents. In some cases, the hepatic dysfunction was serious; however, a definitive causal relationship with therapy has not been established. Resistance/Cross-Resistance Various degrees of cross-resistance among protease inhibitors have been observed. The effect of therapy on the efficacy of subsequently administered protease inhibitors is under investigation (see section Resistance). 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 more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. Neither a causal relationship nor a mechanism of action between protease inhibitor therapy and these events has been established. 01 May 2017 Page 6 of 47

7 QT Interval Prolongation Post-marketing cases of QT interval prolongation and torsade de pointes have been reported although causality of could not be established. Avoid use in patients with congenital long QT syndrome, those with hypokalaemia, and with other drugs that prolong the QT interval. PR Interval Prolongation has been shown to cause modest asymptomatic prolongation of the PR interval in some patients. Rare 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 in patients receiving. should be used with caution in such patients. Lipid Elevations Treatment with has resulted in increases in the concentration of total cholesterol and triglycerides (see section Table 8 and 9). Triglyceride and cholesterol testing should be performed prior to initiating therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate. See section HMG-CoA Reductase Inhibitors for additional information on potential interactions with and HMG CoA reductase inhibitors. Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including. During the initial phase of combination antiretroviral treatment when the immune system responds, patients may develop an inflammatory response to asymptomatic or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves disease, polymyosistis, and Guillain-Barre syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment. Excipients in Oral Solution Healthcare professionals should be aware that oral solution is highly concentrated and contains alcohol (42.4% v/v) and propylene glycol (and 15.3% w/v). Each 1 ml of oral solution contains mg of alcohol and mg of propylene glycol respectively. Paediatric Population The safety and pharmacokinetic profiles of in paediatric patients below the age of six months have not been established. For paediatric use of oral solution, see section 4.2. In HIV-infected patients aged six months to 12 years, the adverse event profile seen during a clinical trial was similar to that for adult patients. The evaluation of the antiviral activity of in paediatric patients in clinical trials is ongoing (see section Clinical Efficacy and Safety Results). 01 May 2017 Page 7 of 47

8 Elderly Population Clinical studies of did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, appropriate caution should be exercised in the administration and monitoring of in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other therapies. 4.5 Interactions with Other Medicines and Other Forms of Interactions is an inhibitor of CYP3A (cytochrome P450 3A) both in-vitro and in-vivo. Co-administration of and medicines primarily metabolised by CYP3A (e.g. dihydropyridine calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressants and PDE5 inhibitors) may result in increased plasma concentrations of the other medicines that could increase or prolong their therapeutic and adverse effects. Agents that are extensively metabolised by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in AUC (greater than 3-fold) when co-administered with. Medicines that are contraindicated specifically due to the expected magnitude of interaction and potential for serious adverse events are listed in Table 5 under section 4.3. is metabolised by CYP3A. Co-administration of and medicines that induce CYP3A may decrease lopinavir plasma concentrations and reduce its therapeutic effect (see section Medicine Interactions). Although not noted with concurrent ketoconazole, co-administration of and other medicines that inhibit CYP3A may increase lopinavir plasma concentrations. has been shown to be a potent inducer of CYP2C19 activity. Interactions may exist upon coadministration of and medicines primarily metabolised by CYP2C19. Anti-HIV Agents Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Stavudine and Lamivudine No change in the pharmacokinetics of lopinavir was observed when was given alone or in combination with stavudine and lamivudine. Didanosine For tablets, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine may be co-administered with tablets without food. For oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after oral solution. Zidovudine and Abacavir induces glucuronidation, therefore has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown. 01 May 2017 Page 8 of 47

9 Tenofovir A study has shown increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving and tenofovir should be monitored for tenofovir-associated adverse events. All Increased CPK, myalgia, myositis, and rarely, rhabdomyolysis have been reported with Protease Inhibitors (PIs), particularly in combination with NRTIs. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Nevirapine No change in the pharmacokinetics of lopinavir was apparent in healthy adult subjects during nevirapine and co-administration. Results from a study in HIV-positive paediatric subjects revealed a decrease in lopinavir concentrations during nevirapine co-administration (see section Medicine Interactions Table 17 and 18). The effect of nevirapine in HIV-positive adults is expected to be similar to that in paediatric subjects, and lopinavir concentrations may be decreased. The clinical significance of the pharmacokinetic interaction is unknown. should not be administered once daily in combination with nevirapine. Efavirenz Increasing the dose of tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz 600 mg once daily resulted in similar lopinavir concentrations compared to tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz (see section 4.2). Increasing the dose of tablets to 600/150 (three (3) tablets) twice daily co-administered with efavirenz significantly increased the lopinavir plasma concentrations approximately 36% and ritonavir concentrations approximately 56% to 92% compared to tablets 400/100 mg twice daily without efavirenz (see section Medicine Interactions Table 17 and 18). NOTE: Efavirenz and nevirapine induce the activity of CYP3A and thus have the potential to decrease plasma concentrations of other protease inhibitors when used in combination with. should not be administered once daily in combination with efavirenz. Delavirdine Delavirdine has the potential to increase plasma concentrations of lopinavir. Rilpivirine Concomitant use of lopinavir/ritonavir with rilpivirine causes an increase in the plasma concentrations of rilpivirine, but no dose adjustment is required. Refer to the rilpivirine prescribing information. Etravirine Concomitant use of lopinavir/ritonavir with etravirine causes a decrease in the plasma concentrations of etravirine, but no dose adjustment is required. Refer to the etravirine prescribing information. 01 May 2017 Page 9 of 47

10 Protease Inhibitors (PIs) Amprenavir is expected to increase concentrations of amprenavir (amprenavir 750 mg twice daily plus produces increased AUC, similar C max, increased C min, relative to amprenavir 1200 mg twice daily). Coadministration of and amprenavir result in decreased concentrations of lopinavir (see section 4.2). should not be administered once daily in combination with amprenavir. Fosamprenavir A study has shown that co-administration of with fosamprenavir lowers amprenavir and lopinavir concentrations. Appropriate doses of the combination of fosamprenavir and with respect to safety and efficacy have not been established. should not be administered once daily in combination with fosamprenavir. Indinavir is expected to increase concentrations of indinavir (indinavir 600 mg twice daily plus produces similar AUC, decreased C max, increased C min relative to indinavir 800 mg three times daily. The dose of indinavir may need to be decreased during co-administration with 400/100 mg twice daily (see section Medicine Interactions Table 18). Nelfinavir is expected to increase concentrations of nelfinavir and increased M8 metabolite of nelfinavir (nelfinavir 1000 mg twice daily plus produces similar AUC, similar C max, increased C min relative to nelfinavir 1250 mg twice daily). Co-administration of and nelfinavir result in decreased concentrations of lopinavir (see section 4.2). should not be administered once daily in combination with nelfinavir. Ritonavir When was co-administered with an additional 100 mg ritonavir twice daily, lopinavir AUC increased 33% and C min increased 64% as compared to 400/100 mg (three (3) soft gel capsules) twice daily (see section Medicine Interactions Table 17). Saquinavir is expected to increase concentrations of saquinavir (saquinavir 800 mg twice daily plus produces increased AUC, increased C max, increased C min relative to saquinavir 1200 mg three times daily). The dose of saquinavir may need to be decreased when co-administered with 400/100 mg twice daily (see section Medicine Interactions Table 18). Tipranavir In a clinical study the dual-boosted protease inhibitor combination therapy in multiple-treatment experienced HIV-positive adults, tipranavir (500 mg twice daily) with ritonavir (200 mg twice daily), co-administered with lopinavir/ritonavir (400/100 mg twice daily), resulted in a 55% and 70% reduction in lopinavir AUC and C min respectively. The concomitant administration of lopinavir/ritonavir and tipranavir with low dose ritonavir is therefore not recommended. 01 May 2017 Page 10 of 47

11 Hepatic C direct acting antivirals Boceprevir Concomitant administration of boceprevir and lopinavir/ritonavir resulted in reduced boceprevir and lopinavir steady-state exposure. It is not recommended to co-administer lopinavir/ritonavir and boceprevir. Simeprevir Concomitant use of lopinavir/ritonavir and simeprevir may result in increased plasma concentrations of simeprevir. It is not recommended to co-administer lopinavir/ritonavir and simeprevir. Ombitasvir/paritaprevir/ritonavir and dasabuvir Concentrations of ombitasvir, paritaprevir, and ritonavir may be increased when co-administered with lopinavir/ritonavir, therefore co-administration is not recommended. Telaprevir Concomitant administration of telaprevir and lopinavir/ritonavir resulted in reduced telaprevir steady-state exposure, while the lopinavir steadystate exposure was not affected. HIV CCR5 antagonist Maraviroc Concurrent administration of maraviroc with lopinavir/ritonavir will increase plasma levels of maraviroc. The dose of maraviroc should be decreased during co-administration with lopinavir/ritonavir 400/100 mg twice daily. For further details, see complete prescribing information for maraviroc. Other Drugs Analgesics Fentanyl inhibits CYP3A4 and, as a result, is expected to increase the plasma concentrations of fentanyl. Careful monitoring of therapeutic and adverse effects (including respiratory depression) is recommended when fentanyl is concomitantly administered with. Antiarrhythmics (amiodarone, bepridil, dronedarone (see section 4.3), systemic lignocaine and quinidine) Concentrations may be increased when co-administered with. Caution is warranted and therapeutic concentration monitoring is recommended when available. Digoxin A literature report has shown that co-administration of ritonavir (300 mg every 12 hours) and digoxin resulted in significantly increased digoxin levels. Caution should be exercised when co-administering lopinavir/ritonavir with digoxin, with appropriate monitoring of serum digoxin levels. 01 May 2017 Page 11 of 47

12 Anticancer Agents (e.g. dasatinib, nilotinib, venetoclax, vincristine, vinblastine) May have their serum concentrations increased when co-administered with lopinavir/ritonavir resulting in the potential for increased adverse events usually associated with these anticancer agents. Co-administration of venetoclax and lopinavir/ritonavir could increase venetoclax exposure potentially resulting in a serious risk of tumor lysis syndrome. For venetoclax, nilotinib and dasatinib refer to their prescribing information for dosing instructions. Anticoagulant Warfarin Concentrations may be affected when co-administered with. It is recommended that INR (international normalised ratio) be monitored. Rivaroxaban Co-adminstration of rivaroxaban and lopinavir/ritonavir may increase rivaroxaban exposure which may increase the risk of bleeding. Antidepressants Trazodone Concomitant use of ritonavir and trazodone may increase concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed. If trazodone is used with a CYP3A4 inhibitor such as lopinavir/ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered. Bupropion Concurrent administration of bupropion with lopinavir/ritonavir will decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Anticonvulsants Phenobarbital, phenytoin, carbamazepine These drugs are known to induce CYP3A4 and may decrease lopinavir concentrations. In addition, coadministration of phenytoin and lopinavir/ritonavir resulted in moderate decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with lopinavir/ritonavir. should not be administered once daily in combination with carbamazepine, phenobarbital or phenytoin. Lamotrigine and valproate Co-administration of lopinavir/ritonavir and either of these medicines was associated with reduction in exposure of the anticonvulsant. Use with caution. A dose increase of the anticonvulsant may be needed when co-administered with lopinavir/ritonavir and therapeutic concentration monitoring for the anticonvulsant may be indicated, particularly during dosage adjustments. 01 May 2017 Page 12 of 47

13 Antifungals Ketoconazole and itraconazole Either of these medicines may have serum concentrations increased by (see section Medicine Interactions Table 17 and 18). High doses of ketoconazole and itraconazole (greater than 200 mg/day) are not recommended. Voriconazole Co-administration of voriconazole with has not been studied. However, a study has shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients. Antigout Agents Concentrations of colchicine are expected to increase when co-administered with. Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and strong inhibitors of CYP3A like ritonavir (see section 4.3). Refer to the colchicine product information for prescribing information. Anti-infective Moderate increases in clarithromycin AUC are expected when co-administered with. For patients with renal or hepatic impairment dose reduction of clarithromycin should be considered. Anti-mycobacterial Rifabutin When rifabutin and were co-administered for ten days, rifabutin (parent active substance and active 25-O-desacetyl metabolite) C max and AUC were increased by 3.5- and 5.7-fold, respectively (see section Medicine Interactions Table 17 and 18). On the basis of these data, a rifabutin dose reduction of 75% (i.e. 150 mg every other day or three times per week) is recommended when administered with. Further dose reduction of rifabutin may be necessary. Rifampicin Due to large decreases in lopinavir concentrations, rifampicin should not be used in combination with standard dose. The use of rifampicin with, may lead to loss of virologic response and possible resistance to or to the class of protease inhibitors or other co-administered antiretroviral agents. In healthy volunteers, co-administration of rifampicin with 800/200 mg lopinavir/ritonavir twice daily resulted in decreases in lopinavir of up to 57%, and co-administration with lopinavir/ritonavir 400/400 mg twice daily resulted in decreases of up to 7% when compared to lopinavir/ritonavir 400/100 mg twice daily dosed in the absence of rifampicin (see section Medicine Interactions Table 17). ALT and AST 01 May 2017 Page 13 of 47

14 elevations have been noted in studies with doses of lopinavir/ritonavir greater than 400/100 mg twice daily co-administered with rifampicin and may be dependent on the sequence of dose administration. The information with regard to the co-administration of and rifampicin in the target population of TB-HIV co-infected patients is not available, and in the absence of such data, co-administration of rifampicin and should be avoided. In case no alternatives are available, should be initiated at standard doses for approximately 10 days prior to addition of rifampicin. dose should then be titrated upward. Extreme caution and close monitoring of liver enzymes and plasma drug concentrations is warranted (see section Medicine Interactions Table 17 for magnitude of interaction). Bedaquiline Co-administration of bedaquiline with strong CYP3A4 inhibitors may increase the systemic exposure of bedaquiline, which could potentially increase the risk of bedaquiline-related adverse reactions. In a healthy volunteer drug interaction study of 400 mg single dose bedaquiline and lopinavir/ritonavir 400/100 mg twice daily for 24 days, bedaquiline exposures (AUC) were increased by 22%. Bedaquiline must be used cautiously with, only if the benefit of co-administration outweighs the risk. Delamanid In a healthy volunteer drug interaction study of delamanid 100 mg twice daily and lopinavir/ritonavir 400/100 mg twice daily for 14 days, exposures of delamanid and a delamanid metabolite, DM-6705, were slightly increased. Exposure to the delamanid metabolite has been associated with QTc prolongation. Due to the risk of QTc prolongation associated with DM-6705, if co-administration of delamanid with lopinavir/ritonavir is considered necessary, frequent ECG monitoring throughout the full delamanid treatment period is recommended. Anti-parasitic Decreases in the therapeutic concentration of atovaquone are possible when co-administered with. Increases in atovaquone doses may be necessary. Anti-psychotics Caution should be exercised when lopinavir/ritonavir is co-administered with quetiapine. Due to CYP3A inhibition of lopinavir/ritonavir, concentrations of quetiapine are expected to increase, which may lead to quetiapine-related toxicities. When quetiapine is administered to patients who are receiving (lopinavir/ritonavir), refer to the quetiapine product information for prescribing information. Corticosteroids Concomitant use of lopinavir/ritonavir and inhaled, injectable, or intranasal fluticasone, budesonide, triamcinolone, or other glucocorticoids that are metabolised by CYP3A4, such as budesonide, is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects, including Cushing s syndrome and adrenal suppression. 01 May 2017 Page 14 of 47

15 Concomitant use of (lopinavir/ritonavir) and fluticasone propionate can significantly increase fluticasone propionate plasma concentrations and reduce serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported when lopinavir/ritonavir has been co-administered with inhaled or intranasally administered fluticasone propionate or budesonide, or injectable triamcinolone. Dexamethasone Dexamethasone may induce CYP3A4 and may decrease lopinavir concentrations. Fluticasone propionate Concomitant use of lopinavir/ritonavir and fluticasone or other glucocorticoids that are metabolised by CYP3A4, such as budesonide, is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects, including Cushing s syndrome and adrenal suppression. Consider alternatives to fluticasone propionate, particularly for long-term use. Dihydropyridines Calcium Channel Blockers Felodipine, nifedipine, nicardipine May have their serum concentrations increased by. Disulfiram/Metronidazole oral solution contains alcohol, which can produce disulfiram like reactions when co-administered with disulfiram or other drugs that produce this reaction, such as metronidazole. PDE5 inhibitors Co-administration of lopinavir/ritonavir with avanafil is not recommended, as it is expected to result in large increases in avanafil exposure. Particular caution should be used when prescribing sildenafil, tadalafil or vardenafil for the treatment of erectile dysfunction in patients receiving. Co-administration of with these drugs is expected to substantially increase their concentrations and may result in increased associated adverse events such as hypotension, and prolonged erection. Sildenafil Use sildenafil for the treatment of erectile dysfunction with caution at reduced doses of 25 mg every 48 hours with increased monitoring for adverse events. Concomitant use of sildenafil with is contraindicated in pulmonary arterial hypertension (PAH) patients (see section 4.3). Tadalafil Use tadalafil with caution at reduced doses of no more than 10 mg every 72 hours with increased monitoring for adverse events. When tadalafil is administered for the treatment of pulmonary arterial hypertension to patients who are receiving, refer to the tadalafil product information for prescribing information. Vardenafil Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse events. 01 May 2017 Page 15 of 47

16 Herbal Products Patients on should not use products containing St John s Wort concomitantly, since this combination may be expected to result in reduced plasma concentrations of protease inhibitors. This effect may be due to an induction of CYP3A4 and may result in the loss of therapeutic effect and development of resistance to lopinavir or to the therapeutic class of protease inhibitors (see section 4.3). HMG-CoA Reductase Inhibitors HMG-CoA reductase inhibitors, which are highly dependent on CYP3A4 metabolism, such as lovastatin and simvastatin, are expected to have markedly increased plasma concentrations when co-administered with. Since increased concentrations of HMG-CoA reductase inhibitors may cause myopathy, including rhabdomyolysis, the combination of these drugs with is contraindicated (see section 4.3). Atorvastatin is less dependent on CYP3A for metabolism. When atorvastatin was given concurrently with, a mean 4.7-fold and 5.9-fold increase in atorvastatin C max and AUC, respectively, was observed. When used with, the lowest possible doses of atorvastatin should be administered. In a pharmacokinetic study, co-administration of rosuvastatin and in healthy volunteers was associated with an approximately two and five fold increase in rosuvastatin steady state AUC (0 to 24) and C max, respectively. Consideration should be given, both to the benefit of lipid lowering by the use of rosuvastatin in patients receiving, and the potential risks of this increased exposure to rosuvastatin when initiating and up titrating rosuvastatin treatment. Results from a drug interaction study with and pravastatin reveal no clinically significant interaction (see section Medicine Interactions Table 17 and 18). The metabolism of pravastatin and fluvastatin is not dependent on CYP3A4, and interactions are not expected with. If treatment with a HMG-CoA reductase inhibitor is indicated, pravastatin or fluvastatin is recommended. Immunosuppressants Concentrations of these drugs (e.g. cyclosporin, tacrolimus and sirolimus (rapamycin)) may be increased when co-administered with. More frequent therapeutic concentration monitoring is recommended until blood levels of these products have stabilised. Methadone was demonstrated to lower plasma concentrations of methadone. Monitoring plasma concentrations of methadone is recommended (see section Medicine Interactions Table 18). Oral Contraceptives or Patch Contraceptives Since levels of ethinyloestradiol may be decreased, alternative or additional contraceptive measures are to be used when oestrogen-based oral contraceptives or patch contraceptives and are co-administered (see section Medicine Interactions Table 18). 01 May 2017 Page 16 of 47

17 Vasodilating Agents Bosentan Co-administration of bosentan and increased steady-state bosentan maximum concentrations (C max ) and area-under-the-curve (AUC). Refer to the bosentan product information for prescribing information. Clinically Significant Drug Interactions Are Not Expected A drug interaction study has revealed no clinically significant interaction with administered once or twice daily, and omeprazole or ranitidine (see section Medicine Interactions Table 17). Clinical studies showed no clinically significant interaction between lopinavir/ritonavir and raltegravir. Based on known metabolic profiles, clinically significant drug interactions are not expected between and desipramine (CYP2D6 probe), fluvastatin, dapsone, trimethoprim/sulfamethoxazole, azithromycin, or fluconazole in patients with normal renal and hepatic function. 4.6 Fertility, Pregnancy and Lactation Fertility Lopinavir in combination with ritonavir at a 2:1 ratio produced no effects on fertility in male and female rats at levels up to 100/50 mg/kg/day. Based on AUC measurements, the exposures in rats at the high doses were approximately 0.6-fold for lopinavir and 0.8-fold for ritonavir of the exposures in humans at the recommended therapeutic dose (400/100 mg twice daily). Pregnancy (Category B3) No treatment-related malformations were observed when lopinavir in combination with ritonavir was administered to pregnant rats or rabbits. Embryonic and foetal development toxicities (early resorption, decreased foetal viability, decreased foetal body weight, increased incidence of skeletal variations and skeletal ossification delays) occurred in rats at a maternally toxic dosage (100/50 mg/kg/day). Based on AUC measurements, the drug exposures in rats at 100/50 mg/kg/day were approximately 0.6-fold for lopinavir and 1.6-fold for ritonavir for males and females that of the exposures in humans at the recommended therapeutic dose (400/100 mg twice daily). In a peri- and post-natal study in rats, a developmental toxicity (a decrease in survival of pups between birth and post-natal day 21) occurred at 40/20 mg/kg/day and greater. No embryonic and foetal developmental toxicity was observed in rabbits at a maternally toxic dosage (80/40 mg/kg/day). Based on AUC measurements, the drug exposures in rabbits at 80/40 mg/kg/day were approximately 0.6- fold for lopinavir and 1.0-fold for ritonavir that of the exposures in humans at the recommended therapeutic dose (400/100 mg twice daily). There are, however, no adequate and wellcontrolled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, should be used during pregnancy only if the potential benefit justifies the potential risks to the foetus. 01 May 2017 Page 17 of 47

18 Lactation It is not known whether lopinavir is secreted in human milk. Because of the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed when they are receiving. Studies in rats showed that lopinavir is secreted in milk. In a peri- and post-natal study in rats, there was decreased survival of pups between birth and post-natal day 21 when dams were dosed at 40/20 mg/kg/day lopinavir/ritonavir and greater. Plasma drug levels were not measured in this study. 4.7 Effects on Ability to Drive and Use Machines No studies on the effects on the ability to drive and use machines have been performed. Patients should be informed that nausea has been reported during treatment with (see section 4.8). oral solution contains approximately 42% v/v alcohol. 4.8 Undesirable Effects Adults Treatment-Emergent Adverse Events has been studied in over 2154 HIV-1 infected patients as combination therapy in Phase I/II and Phase III clinical trials. The most common adverse event associated with therapy was diarrhoea, which was generally of mild to moderate severity. Rates of discontinuation of randomised therapy due to adverse events, including death, were 5.8% in -treated and 4.9% in nelfinavir-treated patients in Study 863. Treatment-Emergent clinical adverse events of moderate or severe intensity in greater than or equal to 2% of patients treated with combination therapy including for up to 48 weeks (Studies 863, 418 and 730) and for up to 360 weeks (Study 720) are presented in Table 6, (antiretroviral -naïve patients) and for up to 48 weeks (Study 888 and 802), 84 weeks (Study 957) and 144 weeks (Study 765) in Table 7 (antiretroviral experienced patients). For other information regarding observed or potentially serious adverse events, please see section 4.4. Table 6: Percentage of Patients with Selected Treatment-Emergent 1 Adverse Events of Moderate or Severe Intensity Reported in 2% of Adult Antiretroviral-Naïve Patients Gastrointestinal disorders LPV/r 400/100 mg twice daily + d4t + 3TC (N=326) Study 863 (48 Weeks) Nelfinavir 750 mg three times daily + d4t + 3TC (N=327) LPV/r Capsules 800/200 mg once daily + TDF + FTC (N=115) Study 418 (48 Weeks) LPV/r Capsules 400/100 mg twice daily + TDF + FTC (N=75) Study 720 (360 Weeks) LPV/r twice daily 2 + d4t + 3TC (N=100) LPV/r 800/200 mg once daily + TDF + FTC (N=333) Study 730 (48 Weeks) LPV/r 400/100 mg twice daily + TDF + FTC (N=331) Abdominal distension 0.3% 0.6% 0.9% 0.0% 4.0% 0.3% 0.3% Abdominal pain 4.0% 3.1% 2.6% 2.7% 11.0% 0.6% 0.9% 01 May 2017 Page 18 of 47

19 Table 6: Percentage of Patients with Selected Treatment-Emergent 1 Adverse Events of Moderate or Severe Intensity Reported in 2% of Adult Antiretroviral-Naïve Patients LPV/r 400/100 mg twice daily + d4t + 3TC (N=326) Study 863 (48 Weeks) Nelfinavir 750 mg three times daily + d4t + 3TC (N=327) LPV/r Capsules 800/200 mg once daily + TDF + FTC (N=115) Study 418 (48 Weeks) LPV/r Capsules 400/100 mg twice daily + TDF + FTC (N=75) Study 720 (360 Weeks) LPV/r twice daily 2 + d4t + 3TC (N=100) LPV/r 800/200 mg once daily + TDF + FTC (N=333) Study 730 (48 Weeks) LPV/r 400/100 mg twice daily + TDF + FTC (N=331) Abnormal faeces 0.0% 0.3% 0.0% 0.0% 8.0% 0.0% 0.0% Diarrhoea 15.6% 17.1% 15.7% 5.3% 28.0% 16.5% 15.1% Dyspepsia 2.1% 0.3% 0.0% 1.3% 6.0% 0.0% 0.0% Flatulence 1.5% 1.2% 1.7% 1.3% 4.0% 0.9% 0.6% Nausea 6.7% 4.6% 8.7% 8.0% 16.0% 7.2% 5.4% Vomiting 2.5% 2.4% 3.5% 4.0% 6.0% 3.3% 3.9% General disorders and administration site conditions Asthenia 4.0% 3.4% 0.0% 0.0% 9.0% 0.3% 0.3% Pain 0.6% 0.0% 0.0% 0.0% 3.0% 0.0% 0.0% Nervous system disorders Headache 2.5% 1.8% 2.6% 2.7% 6.0% 1.5% 0.6% Parasthesia 0.9% 0.9% 0.0% 0.0% 2.0% 0.0% 0.0% Psychiatric disorders Insomnia 1.5% 1.2% 0.0% 0.0% 3.0% 1.2% 0.0% Libido decreased 0.3% 0.3% 0.0% 1.3% 2.0% 0.0% 0.3% Depression 0.6% 1.5% 1.0% 0.0% 0.0% 0.0% 0.0% Vascular disorders Vasodilatation 0.0% 0.0% 0.0% 0.0% 3.0% 0.0% 0.0% Skin and subcutaneous disorders Rash 0.6% 1.5% 0.9% 0.0% 5.0% 0.3% 0.6% Musculoskeletal and connective tissue disorder Myalgia 0.6% 0.9% 0.0% 0.0% 2.0% 0.0% 0.0% Infections and infestations Bronchitis 0.0% 0.0% 0.0% 0.0% 2.0% 0.0% 0.3% Endocrine disorders Hypogonadism male 0.0% 0.0% 0.0% 0.0% 2.1% 0.0% 0.0% Metabolism and nutrition disorders Anorexia 0.9% 0.3% 0.9% 1.3% 2.0% 0.3% 0.9% Investigations Weight Decreased 0.6% 0.3% 0.0% 0.0% 2.0% 0.0% 0.3% 01 May 2017 Page 19 of 47

20 Table 6: Percentage of Patients with Selected Treatment-Emergent 1 Adverse Events of Moderate or Severe Intensity Reported in 2% of Adult Antiretroviral-Naïve Patients LPV/r 400/100 mg twice daily + d4t + 3TC (N=326) Study 863 (48 Weeks) Reproductive system and breast disorders 1 2 Nelfinavir 750 mg three times daily + d4t + 3TC (N=327) LPV/r Capsules 800/200 mg once daily + TDF + FTC (N=115) Study 418 (48 Weeks) LPV/r Capsules 400/100 mg twice daily + TDF + FTC (N=75) Study 720 (360 Weeks) LPV/r twice daily 2 + d4t + 3TC (N=100) LPV/r 800/200 mg once daily + TDF + FTC (N=333) Study 730 (48 Weeks) Amenorrhoea 0.0% 0.0% 4.5% 0.0% 0.0% 0.0% 0.0% Includes adverse events of possible or probable relationship to study treatment. LPV/r 400/100 mg twice daily + TDF + FTC (N=331) Includes adverse event data from dose group I (200/100mg twice daily [N = 16] and 400/100 mg twice daily only [N=16]) and dose group II (400/100 mg twice daily [N=35] and 400/200 mg twice daily [N=33]). Within dosing groups, moderate to severe nausea of probable/possible relationship to lopinavir/ritonavir occurred at a higher rate in the 400/200 mg dose arm compared to the 400/100 mg dose arm in group II. Definitions: d4t = Stavudine; 3TC = Lamivudine; TDF = Tenofovir; FTC = Emtricitabine Table 7: Percentage of Patients with Selected Treatment-Emergent 1 Adverse Events of Moderate or Severe Intensity Reported in 2% of Adult antiretroviral-experienced Patients Gastrointestinal disorders 400/100 mg twice daily + NVP + NRTIs (N=148) Study 888 (48 Weeks) (%) Investigatorselected protease inhibitor(s) + NVP + NRTIs (N=140) Study and Study ( Weeks) (%) twice daily + NNRTI + NRTIs (N= 127) 800/200 mg once daily + NRTIs (N=300) Study 802 (48 Weeks) 400/100 mg twice daily +NRTIs (N=299) Abdominal pain 2.0% 2.1% 3.9% 2.0% 0.3% Abdominal pain upper N/A N/A N/A 0.7% 2.0% Abnormal faeces 0.0% 0.0% 2.4% 0.0% 0.0% Diarrhoea 7.4% 9.3% 22.8% 14.0% 11.0% Dysphagia 2.0% 0.7% 0.0% 0.0% 0.0% Flatulence 0.7% 2.1% 1.6% 1.0% 1.0% Nausea 6.8% 16.4% 4.7% 2.7% 7.4% Vomiting 4.1% 12.1% 1.6% 2.0% 2.7% General disorders and administration site conditions Asthenia 2.7% 6.4% 9.4% 0.3% 0.3% Chills 2.0% 0.0% 0.0% 0.0% 0.0% Pyrexia 2.0% 1.4% 1.6% 0.0% 0.3% Pain 0.0% 0.0% 3.9% 0.0% 0.0% 01 May 2017 Page 20 of 47

21 Table 7: Percentage of Patients with Selected Treatment-Emergent 1 Adverse Events of Moderate or Severe Intensity Reported in 2% of Adult antiretroviral-experienced Patients Nervous system disorders 400/100 mg twice daily + NVP + NRTIs (N=148) Study 888 (48 Weeks) (%) Investigatorselected protease inhibitor(s) + NVP + NRTIs (N=140) Study and Study ( Weeks) (%) twice daily + NNRTI + NRTIs (N= 127) 800/200 mg once daily + NRTIs (N=300) Study 802 (48 Weeks) 400/100 mg twice daily +NRTIs (N=299) Headache 2.0% 2.9% 2.4% 0.3% 0.0% Paresthesia 0.0% 1.4% 2.4% 0.0% 0.0% Vascular disorders Hypertension 0.0% 0.0% 2.4% 0.0% 0.0% Metabolism and nutrition disorders Anorexia 0.7% 2.9% 0.0% 0.0% 0.7% Investigations Weight decreased 0.0% 1.4% 3.1% 0.3% 0.3% Skin and subcutaneous disorders Rash 2.0% 1.4% 2.4% 0.0% 0.0% Psychiatric disorders Insomnia 0.0% 2.1% 2.4% 0.0% 0.3% Depression 0.7% 2.1% 3.1% 0.3% 0.0% 1 Includes adverse events of possible or probable relationship to study treatment. 2 Includes adverse event data from patients receiving 400/100 mg twice daily (N=29) or 533/133 mg twice daily (N=28) for 84 weeks. Patients received in combination with NRTIs and efavirenz. 3 Includes adverse event data from patients receiving 400/100 mg twice daily (N=36) or 400/200 mg twice daily (N=34) for 144 weeks. Patients received in combination with NRTIs and nevirapine. Definitions: NVP = Nevirapine; NRTI = Nucleoside Reverse Transcriptase Inhibitors; NNRTI = Nonnucleoside Reverse Transcriptase Inhibitors Treatment-emergent adverse events occurring in less than 2% of adult patients receiving in all phase II/III clinical trials and considered at least possibly related or of unknown relationship to treatment with and of at least moderate intensity are listed below by system organ class. Infections and infestations: Bacterial infection, bronchopneumonia, cellulitis, influenza, folliculitis, furunculosis, gastroenteritis, otitis media, perineal abscess, pharyngitis, rhinitis, sialadenitis, sinusitis and viral infection. Neoplasms benign, malignant and unspecified: Benign neoplasm of skin, lipoma and neoplasm. Blood and lymphatic system disorders: Anaemia, leukopenia, lymphadenopathy, neutropenia and splenomegaly. Immune system disorders: Drug hypersensitivity, hypersensitivity, and immune reconstitution syndrome. Endocrine disorders: Cushing s syndrome and hypothyroidism. 01 May 2017 Page 21 of 47