Lopinavir/ Ritonavir

Registered South African indications:

• HIV infection

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Severe hepatic impairment
• Coadministration with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events:
  - Alpha1-adrenoreceptor antagonists (alfuzosin)
  - Antianginal (ranolazine)
  - Antiarrhythmics (amiodarone, dronedarone)
  - Antibiotics (fusidic acid)
  - Anticancer (neratinib, venetoclax)
  - Anti-gout (colchicine)
  - Antihistamines (astemizole, terfenadine)
  - Antipsychotics/ neuroleptics (lurasidone, pimozide, quetiapine)
  - Ergot alkaloids (dihydroergotamine, ergonovine,
  ergotamine, methylergonovine)
  - GI motility agents (cisapride)
  - Hepatitis C virus direct acting antivirals (elbasvir/ grazoprevir, ombitasvir/ paritaprevir/ ritonavir with or
  without dasabuvir)
  -  HMG Co-A reductase inhibitors (lovastatin, simvastatin)
  - Microsomal triglyceride transfer protein (MTTP) inhibitors (lomitapide)
  - Phosphodiesterase (PDE5) inhibitors (avanafil, sildenafil, vardenafil)
  - Sedatives/ hypnotics (oral midazolam, triazolam)
  - Herbal products (St. John's wort)
• Porphyria

Cautions

• Breastfeeding
• Mild to moderate hepatic impairment
• Haemophilia A and B  
• History of pancreatitis
• Marked triglyceride elevation
• Asymptomatic or residual opportunistic pathogens (risk of Immune Reconstitution Inflammatory Syndrome)
• Autoimmune disorders (such as Graves' disease and autoimmune hepatitis)
• Advanced HIV disease and/or long-term exposure to combination antiretroviral therapy
• Underlying structural heart disease
• Pre-existing conduction system abnormalities
• Asian patients (sol)
• Alcoholism (sol)
• Epilepsy (sol)
• Brain injury (sol)
• Children <14 days of age and premature neonates (sol)
• Children (sol)
• Fructose intolerance (sol)
• Low potassium diet (sol)

Forms avail. in SA and covered in this monograph: tab, sol

HIV-1 infection (additional agents required)

• Oral (tab, sol): 400/100mg, 12hrly

OR

• Oral (tab, sol): 800/200mg, dly (manufacturer recommendation, STG)
  Refer to Antiretroviral Therapy: STG, Adult 2019

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Use 800/200mg once daily dosing only if protease inhibitor-naïve (STG, 2019)

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The 800/200mg once daily dosing should be limited to those adult patients having only very few protease inhibitor (PI) associated mutations and should take into account the risk of a lesser sustainability of the virologic suppression and higher risk of diarrhoea when compared to the recommended standard twice daily dosing

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The choice of lopinavir/ ritonavir to treat protease inhibitor experienced HIV-1 infected patients should be based on individual viral resistance testing and treatment history of patients

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HIV post-exposure prophylaxis - Occupational (additional agents required) 
- In women of childbearing potential, pregnant women <6 weeks gestation or where dolutegravir is not tolerated

• Oral (tab, sol): 400/100mg, 12hrly; Treatment duration: 28 days (STG)
  Refer to Post-exposure prophylaxis: STG, Adult 2019

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PEP should be started as soon as possible after the injury - up to 72 hours after exposure and, in exceptional circumstances, up to 7 days after exposure

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Tablets are to be taken whole.Solution to be taken with food

Paed. forms avail. in SA and covered in this monograph: tab, sol

HIV-1 infection (additional agents required)

Based on STG (Paeds) recommendations:

Oral (sol)

Weight (kg)	Dose
3-4.9	1ml, 12hrly
5-9.9	1.5ml, 12hrly
10-13.9	2ml, 12hrly
14-19.9	2.5ml, 12hrly
20-24.9	3ml, 12hrly
25-29.9	3.5ml, 12hrly
30-34.9	4ml, 12hrly
≥35	5ml, 12hrly

Refer to The HIV Infected Infant/Child: STG, Paeds, 2017

Oral (tab)

• Between 14-24.9kg: 200/50mg, 12hrly
• Between 25-34.9kg: 300/75mg, 12hrly
• ≥35kg: See adult dosage
  Refer to The HIV Infected Infant/Child: STG, Paeds, 2017

Based on manufacturer's recommendations:

Between 14 days and 6 months

• Oral (sol): 16/4mg/kg, 12hrly

OR

• Oral (sol): BSA: 300/75mg/m², 12hrly

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It is not recommended for lopinavir/ ritonavir to be administered with efavirenz or nevirapine in patients <6 months

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Between 6 months and 18 years

Without efavirenz or nevirapine

Oral (sol)

• Between 7-15kg: 12/3mg/kg, 12hrly  
• Between 15-40kg: 10/2.5mg/kg, 12hrly
• ≥40kg: See adult dosage

OR

• BSA: 230/57.5mg/m², 12hrly

Oral (tab)

•  ≥40kg or BSA >1.4 m²: 400/100mg, 12hrly

With efavirenz or nevirapine

• Oral (sol): BSA: 300/75mg/m², 12hrly; Max: 533/133mg, 12hrly

Older than 2 years

Oral (tab)

BSA (m2)	Dose
≥0.5 to <0.8	200/50mg, 12hrly
≥0.8 to <1.2	300/75mg, 12hrly
≥1.2 to <1.4	400/100mg, 12hrly
≥1.4	500/125mg, 12hrly

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The dose should be administered using a calibrated 2ml or 5ml oral dosing syringe best corresponding to the volume prescribed

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Do not administer to neonates before a postmenstrual age of 42 weeks and a postnatal age of >14 days has been attained

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Lopinavir/ ritonavir oral solution is highly concentrated with alcohol and propylene glycol. Total amounts of alcohol and propylene glycol should be taken into account to avoid toxicity from these excipients

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If administered with rifampicin, boosting with ritonavir is necessary

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See additional prescribing points

Consult HIV/infectious disease specialists prior to any decisions related to ARV regimen termination/switch

Pregnancy 

• Safe
• As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, the animal data, as well as the clinical experience in pregnant women, should be taken into account in order to characterise the safety for the foetus. Lopinavir/ritonavir has been evaluated in over 3000 women during pregnancy, including over 1000 during the first trimester
• In post-marketing surveillance through the Antiretroviral Pregnancy Registry, established since January 1989, an increased risk of birth defects exposures with lopinavir/ ritonavir has not been reported among over 1000 women exposed during the first trimester. The prevalence of birth defects after any trimester exposure to lopinavir is comparable to the prevalence observed in the general population. No pattern of birth defects suggestive of a common aetiology was seen. Studies in animals have shown reproductive toxicity. Based on the data mentioned, the malformative risk is unlikely in humans. Lopinavir can be used during pregnancy if clinically needed
• Once-daily administration of lopinavir/ ritonavir is not recommended for pregnant women due to the lack of pharmacokinetic and clinical data

Breastfeeding 

• Caution
• Studies in rats revealed that lopinavir is excreted in milk. It is not known whether lopinavir/ ritonavir is excreted in human milk
• South African HIV guidelines strongly recommend exclusive breastfeeding for the first 6 months, after which the nutritional needs of the child will require the introduction of complementary foods, while breastfeeding continues
• As a general rule, it is recommended that mothers with HIV do not breastfeed their babies under any circumstances in order to avoid transmission of HIV

Fertility

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

Renal Impairment 

• No dose adjustment recommended

Hepatic Impairment 

• Mild to moderate: Caution; no dose adjustment recommended
• Severe: Contraindicated

Elderly

• No dose adjustment recommended

Porphyria Information

• Lopinavir: Probably porphyrinogenic (PRP)
• Ritonavir: Porphyrinogenic (P)
  The common side effects from ritonavir administration, abdominal pains, nausea, diarrhoea, vomiting and back pains may be confused with an acute porphyric attack and may potentially be porphyrinogenic if leading to a decrease in carbohydrate intake

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Anxiety
• Abnormal dreams
• Decreased libido  
• Headache (including migraine)
• Neuropathy (including peripheral neuropathy)
• Dizziness
• Insomnia
• Cerebrovascular accident
• Seizures
• Dysgeusia
• Ageusia
• Tremor
• Fatigue

Cardiovascular Disorders 

• Atherosclerosis
• Myocardial infarction
• Atrioventricular block
• Tricuspid valve incompetence
• Hypertension
• Deep vein thrombosis

Respiratory Disorders 

• Upper respiratory tract infection
• Lower respiratory tract infection

Gastrointestinal Disorders

• Diarrhoea
• Nausea and vomiting
• Pancreatitis
• Gastrooesophageal reflux disease
• Gastroenteritis
• Colitis
• Abdominal pain (upper and lower)
• Abdominal distension
• Dyspepsia
• Haemorrhoids
• Flatulence
• Gastrointestinal haemorrhage    
• Gastrointestinal ulcer
• Duodenitis
• Gastritis
• Rectal haemorrhage
• Stomatitis
• Oral ulcers
• Faecal incontinence
• Constipation
• Dry mouth

Hepatobiliary Disorders 

• Hepatitis
• Increased hepatic enzymes (aspartate aminotransferase, alanine aminotransferase and gamma-glutamyl transferase)
• Hepatic steatosis
• Hepatomegaly
• Cholangitis
• Hyperbilirubinemia
• Jaundice

Genitourinary Disorders

• Decreased creatinine clearance
• Nephritis
• Haematuria
• Nephrolithiasis
• Erectile dysfunction
• Menstrual disorders
• Amenorrhoea
• Menorrhagia

Endocrine and Metabolic Disorders

• Hypogonadism
• Blood glucose disorders
• Diabetes mellitus
• Hypertriglyceridaemia
• Hypercholesterolemia
• Decreased weight  
• Decreased appetite
• Increased weight
• Increased appetite

Musculoskeletal Disorders 

• Myalgia
• Musculoskeletal pain  
• Arthralgia
• Back pain
• Muscle disorders (such as weakness and spasms)
• Rhabdomyolysis
• Osteonecrosis
• Increased creatine phosphokinase
• Myositis

Skin and Subcutaneous Tissue Disorders

• Rash
• Maculopapular rash
• Dermatitis
• Eczema
• Seborrheic dermatitis
• Night sweats
• Pruritus
• Alopecia
• Capillaritis
• Vasculitis
• Stevens-Johnson syndrome
• Erythema multiforme
• Skin infections
• Cellulitis
• Folliculitis  
• Furuncle

Immune, Blood and Lymphatic System Disorders 

• Anaemia
• Leucopenia
• Neutropenia
• Lymphadenopathy
• Hypersensitivity
  - Urticaria
  - Angioedema
• Immune reconstitution inflammatory syndrome

Sensory Disorders 

• Visual impairment
• Tinnitus
• Vertigo

• CYP3A inhibitors
• CYP3A substrates
• CYP2C9 substrates
• CYP2C19 substrates
• Agents metabolised by glucuronidation
• Nucleoside/Nucleotide reverse transcriptase inhibitors (NRTIs)
• Abacavir
• Zidovudine
• Tenofovir disoproxil fumarate
• Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
• Efavirenz
• Nevirapine
• Rilpivirine
• Stavudine
• Lamivudine
• Raltegravir
• Saquinavir
• Acid reducing agents
• Omeprazole
• Ranitidine
• Etravirine
• HIV CCR5 – antagonist
• Maraviroc
• Integrase inhibitor
• Protease inhibitors
• Fosamprenavir/ ritonavir
• Fosamprenavir
• Indinavir
• Tipranavir/ ritonavir
• Alpha1 adrenoreceptor antagonist
• Alfuzosin
• Analgesics
• Fentanyl
• Antianginal
• Ranolazine
• Antiarrhythmics
• Amiodarone
• Dronedarone
• Digoxin
• Bepridil
• Systemic lidocaine
• Quinidine
• Antibiotics
• Clarithromycin
• Anticancer agents and kinase inhibitors
• Abemaciclib
• Apalutamide  
• Afatinib
• Ceritinib
• Tyrosine kinase inhibitors
• Dasatinib
• Nilotinib
• Vincristine
• Vinblastine
• Encorafenib
• Fostamatinib
• Ibrutinib
• Neratinib
• Venetoclax
• Anticoagulants
• Warfarin
• Rivaroxaban
• Vorapaxar
• Anticonvulsants
• Phenytoin
• Carbamazepine
• Phenobarbital
• Lamotrigine
• Valproate
• Antidepressants
• Anxiolytics
• Trazodone
• Antifungals
• Ketoconazole
• Itraconazole
• Voriconazole
• Anti-gout agents
• Colchicine
• Antihistamines
• Astemizole
• Terfenadine
• Anti-infectives
• Fusidic acid
• Antimycobacterials
• Bedaquiline
• Delamanid
• Rifabutin
• Rifampicin
• Antipsychotics
• Lurasidone
• Pimozide
• Quetiapine
• Benzodiazepines
• Sedatives/ hypnotics
• Midazolam (oral)
• Triazolam
• Beta2-adrenoceptor agonist (long acting)
• Salmeterol
• Calcium channel blockers
• Felodipine
• Nifedipine
• Nicardipine
• Corticosteroids
• Dexamethasone
• Fluticasone propionate
• Budesonide
• Triamcinolone
• Phosphodiesterase (PDE5) inhibitors
• Avanafil
• Tadalafil
• Sildenafil
• Vardenafil
• Ergot alkaloids
• Dihydroergotamine
• Ergonovine
• Ergotamine
• Methylergonovine
• GI motility agents
• Cisapride
• HCV direct acting antivirals
• Elbasvir/ grazoprevir
• Glecaprevir/ pibrentasvir
• Ombitasvir/ paritaprevir/ ritonavir
• Dasabuvir
• Sofosbuvir/ velpatasvir/ voxilaprevir
• HCV protease inhibitors
• Simeprevir
• St John's wort (Hypericum perforatum)
• Immunosuppressants
• Cyclosporin
• Sirolimus (rapamycin)
• Tacrolimus
• Lipid lowering agents
• Lovastatin
• Simvastatin
• Lipid-modifying agents
• Microsomal triglyceride transfer protein (MTTP) inhibitors
• Lomitapide
• Atorvastatin
• Rosuvastatin
• Fluvastatin
• Pravastatin
• Opioids
• Buprenorphine
• Methadone
• Oral contraceptives
• Ethinyl oestradiol
• Smoking cessation aids
• Bupropion
• Thyroid hormone replacement therapy
• Levothyroxine
• Vasodilating agents
• Bosentan
• Riociguat
• Agents known to prolong the PR interval
• Verapamil
• Atazanavir
• Agents known to prolong the QT interval
• Erythromycin
• Chlorpheniramine

• CD4 count
• Viral load
• Electrolytes
• Hepatic function
• Lipids profile

None routine. Specific cases may require

• Genotypic or phenotypic testing
• Blood glucose
• Weight
• ECG
• Serum lipase or amylase

Ritonavir (r) boosting

• Use only as booster for lopinavir/ ritonavir when rifampicin 12 hourly (0.75 x lopinavir dose, 12hrly) is used

Ritonavir
80 (mg/ml)

Oral (sol)

• Between 3-4.9kg: 1ml, 12hrly
• Between 5-13.9kg: 1.5ml, 12hrly
• Between 14-19.9kg: 2ml, 12hrly
• Between 20-24.9kg: 2.5ml, 12hrly
• Between 25-34.9kg: 3ml, 12hrly
• >35kg: 4ml, 12hrly

Risk of transmission

• Lopinavir/ ritonavir is not a cure for HIV or AIDS. While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines. People taking lopinavir/ ritonavir may still develop infections or other illnesses associated with HIV disease and AIDS

Risk of toxicity related to the alcohol and propylene glycol contained in lopinavir/ ritonavir solution

• Healthcare professionals should be aware that lopinavir/ ritonavir oral solution is highly concentrated and contains 42.4% alcohol (v/v) and 15.3% propylene glycol (w/v). Each 1 ml of oral solution contains 356.3 mg of alcohol and 152.7 mg of propylene glycol
• Total amounts of alcohol and propylene glycol from all medicines that are to be given to infants should be taken into account in order to avoid toxicity from these excipients. Infants should be monitored closely for toxicity, including: hyperosmolality, with or without lactic acidosis, renal toxicity, central nervous system (CNS) depression (including stupor, coma, and apnea), seizures, hypotonia, cardiac arrhythmias and ECG changes, and haemolysis. Postmarketing life threatening cases of cardiac toxicity (including complete atrioventricular (AV) block, bradycardia, and cardiomyopathy), lactic acidosis, acute renal failure, CNS depression and respiratory complications leading to death have been reported, predominantly in preterm neonates
• Because lopinavir/ ritonavir solution contains alcohol, it is not recommended for use with polyurethane feeding tubes due to potential incompatibility

Storage of oral solution

• Lopinavir/ ritonavir solution should be stored in a refrigerator at 2°C - 8°C
• When in use, if kept outside of the refrigerator, do not store above 25°C and discard any unused contents after 42 days (6 weeks)

Lopinavir
Lopinavir is an inhibitor of the HIV-1 and HIV-2 proteases. Inhibition of HIV protease prevents cleavage of the gag-pol polyprotein resulting in the production of immature, non-infectious virus.

Ritonavir
Ritonavir inhibits the CYP3A mediated metabolism of lopinavir, thereby increasing its plasma levels.

COMBINATION PREPARATIONS

Lopinavir/ Ritonavir

Tablet 100mg/25mg

• Aluvia (AbbVie) originator

Tablet 200mg/50mg

• Aluvia (AbbVie) originator

Solution (per ml) 80mg/20mg

• Kaletra (AbbVie) originator