| 4.4 Special warnings and precautions for use
Patients with coexisting conditions
Liver disease Hepatic impairment: the safety and efficacy of Kaletra has not been established in patients with significant underlying liver disorders. Kaletra is contraindicated in patients with severe liver impairment (see section 4.3). 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 events reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer to the relevant product information for these medicinal products.
Patients with pre-existing liver dysfunction including chronic hepatitis have an 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.
Renal disease impairment: since the renal clearance of lopinavir and ritonavir is negligible, increased plasma concentrations are not expected in patients with renal impairment. Because lopinavir and ritonavir are highly protein bound, it is unlikely that they will be significantly removed by haemodialysis or peritoneal dialysis.
4.5 Interaction with other medicinal products and other forms of interaction
Kaletra contains lopinavir and ritonavir, both of which are inhibitors of the P450 isoform CYP3A in vitro. Co-administration of Kaletra and medicinal products primarily metabolised by CYP3A may result in increased plasma concentrations of the other medicinal product, which could increase or prolong its therapeutic and adverse effects reactions. Kaletra does not inhibit CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP2B6 or CYP1A2 at clinically relevant concentrations (see section 4.3).
Fosamprenavir: co-administration of standard doses of lopinavir/ritonavir with fosamprenavir results in a significant reduction in amprenavir concentrations. Co-administration of increased doses of fosamprenavir 1400 mg twice daily with lopinavir/ritonavir 533/133 mg twice daily to protease inhibitor‑experienced patients resulted in a higher incidence of gastrointestinal adverse events and elevations in triglycerides with the combination regimen without increases in virological efficacy, when compared with standard doses of fosamprenavir/ritonavir. Therefore, concomitant administration of these medicinal products is not recommended a study has shown that co‑administration of Kaletra 400/100 mg twice daily with fosamprenavir/ritonavir 700/100 mg twice daily results in a 30 - 52% increase in lopinavir concentrations and a 58-65% decrease in amprenavir concentrations. Administration of Kaletra 533/133 mg twice daily with fosamprenavir 1400 mg twice daily (no additional ritonavir) results in similar lopinavir concentrations to Kaletra 400/100 mg alone and 26 - 42% lower amprenavir AUC and Cmin compared to fosamprenavir/ritonavir 700/100 mg alone. Appropriate doses of the combination of fosamprenavir and Kaletra with respect to safety and efficacy have not been established.
Indinavir: indinavir 600 mg twice daily in combination with Kaletra produces similar indinavir AUC, higher Cmin (by 3.5-fold) and lower Cmax relative to indinavir 800 mg three times daily alone. Furthermore, concentrations of lopinavir do not appear to be affected when both drug medicinal products, Kaletra and indinivir, are combined, based on historical comparison with Kaletra alone.
Saquinavir: saquinavir 800 mg twice daily co-administered with Kaletra produces an increase of saquinavir AUC by 9.6-fold relative to saquinavir 1200 mg three times daily given alone.
Saquinavir 800 mg twice daily co-administered with Kaletra resulted in an increase of saquinavir AUC by approximately 30% relative to saquinavir/ritonavir 1000/100 mg twice daily, and produces similar exposure to those reported after saquinavir/ritonavir 400/400 mg twice daily.
When saquinavir 1200 mg twice daily was combined with Kaletra, no further increase of concentrations was noted. Furthermore, concentrations of lopinavir do not appear to be affected when both drugs medicinal products, Kaletra and saquinavir, are combined, based on historical comparison with Kaletra alone.
Bupropion: in healthy volunteers, the AUC and Cmax of bupropion and of its active metabolite, hydroxybupropion, were decreased by about 50% when co-administered with lopinavir/ritonavir capsules 400/100 mg twice daily at steady-state. This effect may be due to induction of bupropion metabolism. Therefore, if the co‑administration of lopinavir/ritonavir with bupropion is judged unavoidable, this should be done under close clinical monitoring for bupropion efficacy, without exceeding the recommended dosage, despite the observed induction.
Rifabutin: when rifabutin and Kaletra were co-administered for 10 days, rifabutin (parent drug substance and active 25-O-desacetyl metabolite) Cmax and AUC were increased by 3.5- and 5.7-fold, respectively. On the basis of these data, a rifabutin dose reduction of 75% (i.e. 150 mg every other day or 3 times per week) is recommended when administered with Kaletra. Further reduction may be necessary.
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 Kaletra (see section 4.8).
4.8 Undesirable effects
Adult patients
Adverse events reactions:
The following adverse reactions of moderate to severe intensity with possible or probable relationship to Kaletra 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: very common >1/10, common > 1/100, < 1/10, uncommon > 1/1000, < 1/100.
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Undesirable eEffects in cClinical sStudies in aAdult pPatients
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Infections and infestations
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Uncommon
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Otitis media, bronchitis, sinusitis, furunculosis, bacterial infections, viral infection
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Neoplasms benignh, malignant and unspecified (including cysts and polyps)
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Uncommon
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Skin benign neoplasm, cyst
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Blood and lymphatic system disorders
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Uncommon
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Anaemia, leucopenia and lymphadenopathy
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Endocrine disorders
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Uncommon
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Hypergonadism male, Cushing syndrome, hypothyroidism
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Metabolic and nutritional disorders
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Uncommon
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Avitminosis, dehydration, oedema, increased appetite, lactic acidosis, obesity, anorexia, diabetes mellitus, hyperglycaemia, hypocholesteramia
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Phsychiatric disorders
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Common
Uncommon
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Insomnia
Abnormal dreams, agitation, anxiety, confusion, depression, dyskinesia, emotional lability, decreased libido, nervousness, abnormal thinking
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Nervous system disorders
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Common
Uncommon
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Headache, parathesia
Dizziness, amnesia, ataxia, encephalopathy, facial paralysis, hypertonia, neuropathy, peripheral neuritis, somnolence, tremor, taste perversion, migraine, extrapyramidal syndrome
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Euye disorder
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Uncommon
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Abnormal vision, eye disorder
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Ear and labyrinth disorders
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Uncommon
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Tinnitus
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Cardiac disorders
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Uncommon
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Palpitation, lung oedema, myocardial infarc1
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Vascular disorders
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Uncommon
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Hypertension, thrombophlebitis, vasculitis, varicose vein, deep thrombophlebitis, vascular disorder
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Respiratory, thoracic and mediastinal disorders
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Uncommon
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Dyspnoea, rhinitis, cough increased
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Gastrointestinal disorders
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Very common
Common
Uncommon
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Diarrhoea
Nausea, vomiting, abdominal pain, abnormal stools, dyspepsia, flatulence, gastrointestinal disorder
Abdomen enlarged, constipation, dry mouth, dysphagia, entercolitis, eructation, oesophagitis, faecal incontinence, gastritis, gastroenteritis, haemorrhagic colitis, mouth ulcerations, panreatitis2, sialadenitis, stomatitis, ulcerative stomatitis, periedontitis
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Hepatobiliary disorders
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Uncommon
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Cholecystitis, hepatitis, hepatomegaly, liver fatty deposit, liver tenderness
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Skin and subcutaneous tissue disorders
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Common
Uncommon
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Rash, lipodystrophy, acne
Alopecia, dry skin, eczema, exfoliative dermatitis, maculopapular rash, nail disorder,
Pruritis, seborrhoea, skin discoloration, skin ulcer, face oedema, sweating, skin striae
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Musculoskeletal and connective tissue disorder
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Uncommon
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Arthralgia, arthosis, myalgia, back pain, joint disorder
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Renal and urinary disorders
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Uncommon
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Kidney calculus, urine abnormality, albuminuria, hypercalcinuria, hypericaemia
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Reproductive system and breast disorders
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Uncommon
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Abnormal ejaculation, breast enlargement, gynecomastia, impotence, menorrhagia
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General disorders and administration site conditions
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Common
Uncommon
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Asthemia, pain
Chest pain, chest pain substernal, chills, fever, flu syndrome, malaise, peripheral oedema, drug interaction
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Investigations
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Very common
(Grade 3or 4)
Common
(Grade 3 or 4)
Uncommon
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Increased triglycerides, increased total cholesterol, increased GGT
Increased glucose, increased amylase, increased SGOT/AST, increased SGPT/ALT, liver function tests abnormal
Decreased glucose tolerance, weight gain, weight loss, increased bilirubin, hormone level altered, lab test abnormal
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1 This event had a fatal outcome.
2 See section 4.4: pancreatitis and lipids
Paediatric patients
In children 2 years of age and older, the nature of the safety profile is similar to that seen in adults.
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Undesirable eEffects in cClinical sStudies in pPaediatric pPatients
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Infections and infestations
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Common
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Viral infection
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Nervous system disorders
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Common
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Taste perversion
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Gastrointestinal disorders
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Common
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Constipation, vomiting, pancreatitis*
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Hepatobiliary disorders
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Common
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Hepatomegaly
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Skin and subcutaneous tissue disorders
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Common
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Rash, dry skin
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General disorders and administration site conditions
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Common
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Fever
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Investigations
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Common
(Grade 3 or 4)
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Increased activated partial thromboplastin time, decreased haemoglobin, decreased platelets, increased sodium, increased potassium, increased calcium, increased bilirubin, increased SGPT/ALT, increased SGOT/AST, increased total cholesterol, increased amylase, increased uric acid, decreased sodium, decreased potassium, decreased calcium, decreased neutrophils
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5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmaco-therapeutic group: antiviral for systemic use protease inhibitor, ATC code: J05AE06
Mechanism of action: Lopinavir provides the antiviral activity of Kaletra. 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.
5.2 Pharmacokinetic properties
Metabolism: in vitro experiments with human hepatic microsomes indicate that lopinavir primarily undergoes oxidative metabolism. Lopinavir is extensively metabolised by the hepatic cytochrome P450 system, almost exclusively by isozyme CYP3A. Ritonavir is a potent CYP3A inhibitor which inhibits the metabolism of lopinavir and therefore, increases plasma levels of lopinavir. A 14C‑lopinavir study in humans showed that 89% of the plasma radioactivity after a single 400/100 mg Kaletra dose was due to parent drug active substance. At least 13 lopinavir oxidative metabolites have been identified in man. The 4-oxo and 4-hydroxymetabolite epimeric pair are the major metabolites with antiviral activity, but comprise only minute amounts of total plasma radioactivity. Ritonavir has been shown to induce metabolic enzymes, resulting in the induction of its own metabolism, and likely the induction of lopinavir metabolism. Pre-dose lopinavir concentrations decline with time during multiple dosing, stabilising after approximately 10 days to 2 weeks.
5.3 Preclinical safety data
During in vitro studies, cloned human cardiac potassium channels (HERG) were inhibited by 30% at the highest concentrations of lopinavir/ritonavir tested, corresponding to a lopinavir exposure 7-fold total and 15-fold free peak plasma levels achieved in humans at the maximum recommended therapeutic dose. In contrast, similar concentrations of lopinavir/ritonavir demonstrated no repolarisation delay in the canine cardiac Purkinje fibres. Lower concentrations of lopinavir/ritonavir did not produce significant potassium (HERG) current blockade. Tissue distribution studies conducted in the rat did not suggest significant cardiac retention of the drug active substance; 72-hour AUC in heart was approximately 50% of measured plasma AUC. Therefore, it is reasonable to expect that cardiac lopinavir levels would not be significantly higher than plasma levels.
9. Date of first authorisation/renewal of THE authorisation
Date of first authorisation: 20 March 2001
Date of last renewal: 220 March 2006
10. Date of revision of the text
August 2008
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