Pefrilo 40 mg, 10 mg Oral Granules

u2022 PEFRILO is indicated in combination with other antiretroviral medicines for the treatment of HIV-1 infection in adults and children 6 months and older, weighing over 6 kg.

u2022 The choice of PEFRILO to treat protease inhibitor-experienced HIV-1 infected patients should be based on individual viral resistance testing and their treatment history (see sections 4.4 and 5.1).

Posology:

• PEFRILO should be initiated by a health care provider experienced in the management of HIV infection.
• PEFRILO should be given in a twice daily (every 12 hours) dosing regimen. PEFRILO should not be administered once daily (every 24 hours) to children < 18 years of age.
• PEFRILO should not be administered to premature neonates (born one month or more before expected date of delivery).
• PEFRILO administered in combination with efavirenz, nevirapine, or nelfinavir in patients younger than 6 months of age is not recommended. Total dose of lopinavir and ritonavir oral granules in paediatric patients should not exceed the recommended adult daily dose of 400/100 mg twice daily.

The recommended dose of PEFRILO for children is as follows:

• Childu2019s weight Dose
• 6 u2013 9.9 kg 3 sachets twice daily (lopinavir 120 mg/ritonavir 30 mg twice daily)
• 10 u2013 13.9 kg 4 sachets twice daily (lopinavir 160 mg/ritonavir 40 mg twice daily)
• 14 u2013 19.9 kg 5 sachets twice daily (lopinavir 200 mg/ritonavir 50 mg twice daily)
• 20 u2013 24.9 kg 6 sachets twice daily (lopinavir 240 mg/ritonavir 60 mg twice daily)

For patients co-treated with nevirapine or efavirenz, see section 4.5.

Hepatic impairment: In HIV-infected patients with mild to moderate hepatic impairment, an approximate 30 % increase in lopinavir exposure has been observed but is not expected to be of clinical relevance (see section 5.2). No data are available in patients with severe hepatic impairment. PEFRILO must not be given to these patients (see section 4.3).

Renal impairment: No dose adjustment is necessary in patients with renal impairment.

(1) Method of administration

For oral administration. PEFRILO must be taken with a meal twice daily. PEFRILO should be sprinkled/mixed with soft food such as applesauce or porridge, or mixed with liquid such as water, as described below. PEFRILO should not be chewed or crushed.

For young children older than 6 months of age who are able to take soft foods:

1. Determine the number of sachets needed to prepare a dose.
2. Prior to mixing, tap the sachet(s) to move all the granules to the bottom of the sachet(s).
3. Completely tear or cut off the top of the sachet(s) and make sure the sachet(s) are fully open.
4. Mixing with soft food such as applesauce or porridge: Using a spoon, mix the entire contents of the PEFRILO sachet(s) with soft food (approximately 1 teaspoon of soft food for 1 sachet; 2 teaspoons for 2 sachets, etc.) in a small cup or bowl. Make sure no granules/powder are left inside the sachet(s). Give or take all of the mixture. If any granules are left in the small cup/bowl or spoon, add more soft food to the granules and mix. Then give or take the mixture along with adequate drinking water, to ensure that no granules are left behind in the mouth.
5. Mixing with liquid such as drinking water: Mix the entire contents of the PEFRILO sachet(s) with approximately 5 - 15 ml of drinking water (1 teaspoon of water for 2 sachets; 2 teaspoons of water for 3 to 8 sachets; 3 teaspoons or 1 tablespoon for 10 sachets). Make sure no granules/powder are left inside the sachet(s). Give or take all of the mixture. If any granules are left in the spoon, add more liquid (water) and mix. Then give or take the mixture.
6. Administer the medicine/food mixture within 2 hours of preparation. If not administered within 2 hours of preparation, throw away the mixture and prepare a new dose.
7. No mixture of the granules and food is to be stored for later use.
8. Repeat above steps for next dose.

u2022 Known hypersensitivity to lopinavir, ritonavir or to any of the excipients of PEFRILO (see section 6.1).

u2022 PEFRILO must not be administered to patients with severe hepatic impairment.

u2022 PEFRILO must not be administered concurrently with medicines with a narrow therapeutic window that are substrates of the isoenzyme CYP3A4, such as alfuzosin, amiodarone, dronedarone, bepridil, quinidine, propafenone, verapamil, lurasidone, pimozide, quetiapine, astemizole, terfenadine, cisapride, elbasvir/grazoprevir, ombitasvir/paritaprevir/ritonavir (with or without dasabuvir), oral midazolam, triazolam, clorazepate, diazepam, flurazepam, ergot derivatives, fusidic acid, venetoclax, colchicine, simvastatin and lovastatin, avanafil, sildenafil and vardenafil (non-exhaustive list). Inhibition of CYP3A4 by ritonavir could increase plasma concentrations of these medicines, potentially causing serious or life-threatening reactions (see also sections 4.4 and 4.5).

u2022 Herbal preparations containing St Johnu2019s wort (Hypericum perforatum) must not be used while taking lopinavir and ritonavir due to the risk of decreased plasma concentrations and reduced clinical effects of lopinavir and ritonavir (see section 4.5).

Patients with coexisting conditions

Hepatic impairment: PEFRILO is contraindicated in patients with severe liver impairment. Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions. For concomitant antiviral therapy for hepatitis B or C, refer to the relevant medicine information for these medicines. Patients with liver dysfunction including chronic hepatitis have increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment should be considered. Laboratory tests should be conducted before starting treatment with lopinavir and ritonavir and during treatment.

Renal impairment: Since the renal clearance of lopinavir and ritonavir is negligible, increased plasma concentrations are not expected in patients with renal impairment. Lopinavir and ritonavir are highly protein bound, therefore it is unlikely that they will be significantly removed by haemodialysis or peritoneal dialysis.

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. A causal relationship is likely but a biological explanation has not been elucidated. Patients with haemophilia should therefore be warned of the possibility of increased bleeding.

Specific adverse reactions

Lipid elevations: Treatment with lopinavir and ritonavir has resulted in increases, sometimes marked, in the concentration of total cholesterol and triglycerides. Triglyceride and cholesterol should be measured before starting PEFRILO and periodically during therapy. Particular caution should be paid to patients with high values at baseline and with history of lipid disorders. Lipid disorders should be managed as clinically appropriate.

Pancreatitis: Cases of pancreatitis have been reported in patients receiving lopinavir and ritonavir. Most of these patients have had a history of pancreatitis or concurrent therapy with other medicines associated with pancreatitis. Marked triglyceride elevation is a risk factor for development of pancreatitis. Patients with advanced HIV disease may be at risk of elevated triglycerides and pancreatitis. Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormal laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis occur. Patients who exhibit these signs or symptoms should be evaluated and PEFRILO therapy should be suspended if pancreatitis is diagnosed (see section 4.8).

Hyperglycaemia: New onset diabetes mellitus, hyperglycaemia or exacerbation of diabetes mellitus has been reported in patients receiving protease inhibitors. In some of these cases hyperglycaemia was severe and also associated with ketoacidosis. Many patients had confounding medical conditions. A causal relation between ritonavir-boosted lopinavir and these events has not been established.

Weight and metabolic parameters: 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 life-style. 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.

Immune Reactivation Syndrome: In HIV-infected patients with severe immune deficiency, typically in the first few weeks or months after initiation of combination antiretroviral treatment, an inflammatory reaction to asymptomatic or residual opportunistic pathogens (e.g. CMV retinitis, mycobacterial infections, Pneumocystis pneumonia) may arise and cause serious clinical conditions or aggravation of symptoms. Treatment should be instituted when necessary. Autoimmune disorders (such as Gravesu2019 disease) have also been reported in the setting of immune reactivation; however, the reported time to onset is more variable and 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. So far, this disorder has been reported mainly in adults. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

PR interval prolongation: Lopinavir/ritonavir has been shown to cause modest asymptomatic prolongation of the PR interval in some healthy adult subjects. Second- or third-degree atroventricular block has been reported in patients taking lopinavir/ritonavir who have underlying structural heart disease and conduction abnormalities or who are taking medicines that prolong the PR interval (such as verapamil or atazanavir). PEFRILO should be used with caution in such patients (see sections 4.8, 5.1 and 5.3).

Warnings on specific interactions with other medicines

PEFRILO contains ritonavir, which is a very potent inhibitor of the P450 isoform CYP3A. PEFRILO is likely to increase plasma concentrations of medicines that are primarily metabolised by CYP3A. These increases of plasma concentrations of co-administered medicines could increase or prolong their therapeutic effect and adverse events (see sections 4.3 and 4.5).

Bedaquiline and delamanid: Strong CYP3A4 inhibitors such as protease inhibitors may increase bedaquiline exposure which could potentially increase the risk of bedaquiline-related adverse reactions. Therefore, combination of bedaquiline with lopinavir/ritonavir should be avoided. However, if the benefit outweighs the risk, co-administration of bedaquiline with lopinavir/ritonavir must be done with caution. More frequent electrocardiogram monitoring and monitoring of transaminases is recommended (see section 4.5 and refer to the bedaquiline SmPC).

Co-administration of delamanid with a strong inhibitor of CYP3A (as lopinavir/ritonavir) may increase exposure to delamanid metabolite, which has been associated with QTc prolongation. Therefore, if co-administration of delamanid with lopinavir/ritonavir is considered necessary, very frequent ECG monitoring throughout the full delamanid treatment period is recommended (see section 4.5 and refer to the delamanid professional information).

Rifampicin: Co-administration of PEFRILO with rifampicin is not recommended. Rifampicin in combination with PEFRILO causes large decreases in lopinavir concentrations which may in turn significantly decrease the therapeutic effect of lopinavir. Adequate exposure to lopinavir/ritonavir may be achieved with a higher dose of PEFRILO but this is associated with a higher risk of liver and gastrointestinal toxicity.

HMG-CoA reductase inhibitors: Simvastatin and lovastatin are highly dependent on CYP3A for metabolism; thus concomitant use of PEFRILO and simvastatin or lovastatin is not recommended due to an increased risk of myopathy including rhabdomyolysis. Caution must also be exercised and reduced doses should be considered if PEFRILO is used concurrently with rosuvastatin or with atorvastatin, which are metabolised to a lesser extent by CYP3A4. If treatment with a HMG-CoA reductase inhibitor is indicated, pravastatin or fluvastatin is recommended (see section 4.5).

PDE5 inhibitors: Particular caution should be used when prescribing sildenafil or tadalafil for the treatment of erectile dysfunction in patients receiving PEFRILO. Co-administration of PEFRILO with these medicines is expected to substantially increase their concentrations and may result in associated adverse events such as hypotension, syncope, visual changes and prolonged erection (see section 4.5). Concomitant use of avanafil or vardenafil and lopinavir/ritonavir is contraindicated (see section 4.3). Concomitant use of sildenafil prescribed for the treatment of pulmonary arterial hypertension with PEFRILO is contraindicated (see section 4.3).

QT-interval prolonging medicines: Particular caution must be used when prescribing PEFRILO and medicines that prolong QT interval such as: chlorpheniramine, quinidine, erythromycin, clarithromycin. PEFRILO could increase concentrations of the co-administered medicines and this may increase their associated cardiac adverse events (see also section 4.3 and 4.5). Cardiac events have been reported with lopinavir/ritonavir in preclinical studies: therefore, potential cardiac effects of PEFRILO cannot be currently ruled out (see sections 4.8 and 5.3).

Sedative medicines: PEFRILO should not be used concomitantly with strongly sedative medicines metabolised by CYP3A, as this may result in excessive effects. Such medicines include fentanyl, meperidine, propoxyphene, diazepam, alprazolam, triazolam and midazolam. Morphine and oxazepam are not metabolised by CYP3A; however, due to induction of glucuronidation, an increased dose of these medicines may be necessary when co-treating with PEFRILO.

Hormonal contraceptives: In case of co-administration of PEFRILO with contraceptives containing ethinylestradiol, irrespective of the formulation (e.g. oral or patch), additional barrier or non-hormonal methods of contraception are to be used. The decreased systemic exposure to the oestrogen component may not only reduce contraceptive efficacy but also alter the uterine bleeding profile.

Glucocorticoids: Concomitant use of PEFRILO and fluticasone or other glucocorticoids that are metabolised by CYP3A4 such as budesonide and fluticasone, is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects, including Cushingu2019s syndrome and adrenal suppression (see section 4.5).

Colchicine: Life-threatening and fatal interactions have been reported in patients treated with colchicine and strong inhibitors of CYP3A like ritonavir. Concomitant administration with colchicine is contraindicated in patients with renal and/or hepatic impairment (see sections 4.3 and 4.5).

Tadalafil: Co-administration of PEFRILO with tadalafil, indicated for the treatment of pulmonary arterial hypertension, is not recommended. (See section 4.5).

Pregnancy

The safety of PEFRILO in pregnant women has not been established, as there are no adequate and well-controlled studies in pregnant women. The use of PEFRILO during pregnancy is not recommended.

Breastfeeding

HIV-infected mothers should not breastfeed their infants to avoid risking postnatal transmission of HIV. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving PEFRILO. It is not known whether lopinavir is secreted in human milk.

Fertility

Animal studies have shown no effects on fertility. No human data on the effect of lopinavir/ritonavir on fertility are available.

No studies on the effects on the ability to drive and use machines have been performed. Nevertheless, the clinical status of the patient and adverse reactions of PEFRILO should be borne in mind when considering the patientu2019s ability to drive or operate machinery.

a) Summary of adverse effects

The most frequent adverse reaction associated with lopinavir therapy is diarrhoea, nausea and vomiting, usually at the start of treatment. Also, dyslipidaemia, including hypertriglyceridaemia and hypercholesterolaemia are frequent, and may require treatment or discontinuation of medicine. Pancreatitis has been reported in patients receiving ritonavir-boosted lopinavir. Furthermore, increases in the PR interval (frequency unknown) have been reported during therapy with ritonavir-boosted lopinavir (see section 4.4).

b) Tabulated summary of adverse reactions

The following adverse reactions of moderate to severe intensity with possible or probable relationship to lopinavir/ritonavir have been reported. The adverse reactions are displayed by system organ class. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Events shown with a frequency u2018Not knownu2019 were identified during post-marketing surveillance.

Undesirable effects in clinical and post-marketing studies in adults and paediatric patients

c) Description of selected adverse reactions

Cushingu2019s syndrome has been reported in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate; this could also occur with other corticosteroids metabolised via the P450 3A pathway e.g. budesonide (see section 4.4 and 4.5).

Increased creatine phosphokinase (CPK), myalgia, myositis, and rarely, rhabdomyolysis have been reported with protease inhibitors, particularly in combination with nucleoside reverse transcriptase inhibitors. Combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia (see section 4.4).

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 Gravesu2019 disease) have also been reported; however, the reported time to onset is more variable and can occur many months after initiation of treatment (see section 4.4).

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown (see section 4.4).

d) Paediatric populations

In children 2 years of age and older, the nature of the safety profile is similar to that seen in adults.

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. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions & Quality Problem Reporting Formu201d, found online under SAHPRAu2019s publications: https://sahpra.org.za/wp-ontent/uploads/2020/01/6.04_ARF1_v5.1_27Jan2020.pdf

There is no specific antidote for overdose with PEFRILO. Treatment of overdose with PEFRILO is general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. If indicated, unabsorbed active substance may be eliminated by emesis. Activated charcoal may also be used to aid removal of unabsorbed active substance. Since lopinavir and ritonavir are highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.