Ritonavir

Registered South African indications:

• Enhancer of antiretroviral protease inhibitors

Warning: Co-administration of ritonavir with certain non-sedating antihistamines, sedative hypnotics, anti-dysrhythmics, or ergot alkaloid preparations may result in potentially serious and/or life-threatening adverse events due to possible effects of ritonavir on the hepatic metabolism of these medicines.

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients 
• Severe hepatic impairment
• Porphyria
• When ritonavir is used as a pharmacokinetic enhancer of other protease inhibitors, consult the monograph of the co-administered protease inhibitor for contraindications
• Antituberculosis regimens containing rifampicin

Cautions 

• Breastfeeding
• Mild to moderate hepatic impairment
• Haemophilia
• Diabetes mellitus
• Pancreatitis
• Chronic hepatitis B or C 
• Advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy 
• Underlying structural heart disease
• Pre-existing cardiac conduction system abnormalities
• Co-administration of medicinal products known to prolong the PR interval

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

Protease inhibitor enhancer

• Oral (cap, tab, sol): 100-200mg, 12-24hrly; in combination with other agents

---

Not to be used as monotherapy

To always be used in combination with another protease inhibitor

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

Protease inhibitor enhancer

• Oral (cap, sol): Initial: 250mg/m², 12hrly; increase every 2-3 days by 50mg/m² to maintenance: 400mg/m², 12hrly, in combination with other agents; Max: 1200mg/m²/24hrs

---

Not to be used as monotherapy

To always be used in combination with another protease inhibitor

Pregnancy 

• Safe; no evidence of risk
• A large amount (6100 live births) of pregnant women were exposed to ritonavir during pregnancy; of these, 2800 live births were exposed during the first trimester. These data largely refer to exposures where ritonavir was used in combination therapy and not at therapeutic ritonavir doses but at lower doses as a pharmacokinetic enhancer for other PIs
• These data indicate no increase in the rate of birth defects compared to rates observed in population-based birth defect surveillance systems. Animal data have shown reproductive toxicity. Ritonavir can be used during pregnancy if clinically needed
• Ritonavir adversely interacts with oral contraceptives (OCs). Therefore, an alternative, effective and safe method of contraception should be used during treatment

Breastfeeding 

• Caution
• Limited published data reports that ritonavir is present in human milk
• There is no information on the effects of ritonavir on the breastfed infant or the effects of the drug on milk production
• 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

Renal Impairment 

• No dose adjustment recommended 

Hepatic Impairment 

• Mild to moderate (Child-Pugh class A and B): Caution; no dose adjustment recommended 
• Severe (Child-Pugh class C): Contraindicated

Elderly

• No dose adjustment recommended 

Porphyria Information

• Porphyrinogenic (P)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Dysgeusia
• Oral and peripheral paraesthesia
• Headache
• Dizziness
• Peripheral neuropathy
• Insomnia
• Anxiety
• Confusion
• Disturbance in attention
• Syncope
• Seizure

Cardiovascular Disorders

• Myocardial infarction
• Hypertension
• Hypotension 
• Peripheral coldness

Respiratory Disorders

• Pharyngitis
• Oropharyngeal pain
• Cough

Gastrointestinal Disorders

• Abdominal pain 
• Nausea and vomiting
• Diarrhoea
• Dyspepsia
• Anorexia
• Flatulence
• Mouth ulcer
• Gastrointestinal haemorrhage
• Gastroesophageal reflux disease
• Pancreatitis

Hepatobiliary Disorders

• Hepatitis
• Increased blood bilirubin

Genitourinary Disorders

• Increased urination
• Renal impairment
• Acute renal failure
• Menorrhagia

Endocrine and Metabolic Disorders

• Hypercholesterolaemia
• Hypertriglyceridaemia
• Oedema and peripheral oedema
• Dehydration
• Diabetes mellitus
• Hyperglycaemia
• Increased amylase
• Decreased free and total thyroxine
• Increased glucose
• Increased magnesium
• Increased alkaline phosphatase
• Weight loss

Musculoskeletal Disorders

• Gout 
• Arthralgia 
• Back pain
• Myositis
• Rhabdomyolysis
• Myalgia
• Myopathy

Skin and Subcutaneous Tissue Disorders

• Pruritus
• Rash 
• Acne 
• Stevens Johnson syndrome
• Toxic epidermal necrolysis

Immune, Blood and Lymphatic System Disorders

• Decreased white blood cells
• Decreased haemoglobin
• Decreased neutrophils
• Increased eosinophils
• Thrombocytopenia
• Increased neutrophils
• Hypersensitivity
• Anaphylaxis

Others

• Fatigue 
• Asthenia
• Flushing
• Fever

• Bosentan
• St. John's wort
• Amprenavir  
• Indinavir
• Nelfinavir
• Tipranavir
• Didanosine
• Delavirdine
• Efavirenz
• Raltegravir
• Zidovudine
• Alfuzosin  
• Amphetamine
• Pethidine
• Piroxicam
• Propoxyphene
• Fentanyl
• Methadone
• Morphine
• Amiodarone
• Bepridil
• Dronedarone
• Encainide
• Flecainide
• Propafenone
• Quinidine
• Digoxin
• Theophylline
• Afatinib
• Ceritinib
• Dasatinib
• Nilotinib
• Vincristine
• Vinblastine
• Rivaroxaban
• Vorapaxar
• Warfarin
• Carbamazepine
• Divalproex
• Lamotrigine
• Phenytoin
• Amitriptyline
• Fluoxetine
• Imipramine
• Nortriptyline
• Paroxetine
• Sertraline
• Desipramine
• Trazodone
• Colchicine
• Astemizole
• Terfenadine
• Fexofenadine
• Loratadine
• Fusidic Acid
• Rifabutin
• Rifampicin
• Voriconazole
• Atovaquone
• Bedaquiline
• Clarithromycin
• Delamanid
• Erythromycin
• Itraconazole
• Ketoconazole
• Clozapine
• Pimozide
• Haloperidol
• Risperidone
• Thioridazine
• Quetiapine
• Salmeterol
• Amlodipine
• Diltiazem
• Nifedipine
• Bosentan
• Riociguat
• Dihydroergotamine
• Ergonovine
• Ergotamine
• Methylergonovine
• Cisapride
• Simeprevir
• Atorvastatin
• Fluvastatin
• Lovastatin
• Pravastatin
• Rosuvastatin
• Simvastatin
• Ethinyl estradiol
• Cyclosporine
• Tacrolimus
• Everolimus
• Avanafil
• Sildenafil
• Tadalafil
• Vardenafil
• Clorazepate
• Diazepam
• Estazolam
• Flurazepam
• Oral and parenteral midazolam
• Triazolam
• Pethidine
• Alprazolam
• Buspirone
• Zolpidem
• Bupropion
• Fluticasone propionate nasal spray
• Dexamethasone
• Prednisolone
• Disopyramide
• Mexiletine
• Nefazodone

• Hepatic function 
• Renal function 
• Lipid profile
• Blood glucose 

Ritonavir solution 80mg/ml - EML (Primary) 

Ritonavir 100mg tablet / 100mg capsule  - Non-EML 

Ritonavir dosed as a pharmacokinetic enhancer

The pharmacokinetic enhancement by ritonavir is based on ritonavir's activity as a potent inhibitor of CYP3A- mediated metabolism. The degree of enhancement is related to the metabolic pathway of the co-administered protease inhibitor and the impact of the co-administered protease inhibitor on the metabolism of ritonavir. Maximal inhibition of metabolism of the co-administered protease inhibitor is generally achieved with ritonavir doses of 100mg daily to 200mg twice daily, and is dependent on the co-administered protease inhibitor.

Ritonavir dosed as an antiretroviral agent

Ritonavir is an orally active peptidomimetic inhibitor of the HIV-1 and HIV-2 aspartyl proteases. Inhibition of HIV protease renders the enzyme incapable of processing the gag-pol polyprotein precursor which leads to the production of HIV particles with immature morphology that are unable to initiate new rounds of infection. Ritonavir has selective affinity for the HIV protease and has little inhibitory activity against human aspartyl proteases.

Tablet 100mg

• Rinavo (Mylan)
• Norvir (AbbVie) originator

Capsule 100mg

• Norvir Sec (AbbVie) originator (Discontinued: 06/03/2020)

Solution (per ml) 80mg

• Norvir (AbbVie) originator

COMBINATION PREPARATIONS

Ritonavir/ Lopinavir

Solution (per ml) 20mg/80mg

• Kaletra Solution (AbbVie) orginator

Capsule 20mg/133.3mg

• Kaletra (AbbVie) orginator (Discontinued: 06/03/2020)

Tablet 25mg/100mg

• Aluvia (AbbVie) orginator

Tablet 50mg/200mg

• Aluvia (AbbVie) orginator