Norvir 80 mg/ml oral solutionRitonavir - Ireland[爱尔兰药品]

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Norvir 80 mg/ml oral solutionRitonavir

2014-11-23 16:14:27 来源: 作者: 【大中小】浏览:704次评论:0条

Table of Contents
1. NAME OF THE MEDICINAL PRODUCT
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
3. PHARMACEUTICAL FORM
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
4.2 Posology and method of administration
4.3 Contraindications
4.4 Special warnings and precautions for use
4.5 Interaction with other medicinal products and other forms of interaction
4.6 Pregnancy and lactation
4.7 Effects on ability to drive and use machines
4.8 Undesirable effects
4.9 Overdose
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
5.2 Pharmacokinetic properties
5.3 Preclinical safety data
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
6.2 Incompatibilities
6.3 Shelf life
6.4 Special precautions for storage
6.5 Nature and contents of container
6.6 Special precautions for disposal and other handling
7. MARKETING AUTHORISATION HOLDER
8. MARKETING AUTHORISATION NUMBER(S)
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
10. DATE OF REVISION OF THE TEXT

1. NAME OF THE MEDICINAL PRODUCT

Norvir 80 mg/ml oral solution

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of oral solution contains 80 mg of ritonavir.

Excipients:

Alcohol (43% v/v)

Polyoxyl 35 Castor Oil

Sunset Yellow (E110)

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Oral solution

The solution is a practically clear, orange solution for oral administration.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Ritonavir is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infected patients (adults and children of 2 years of age and older).

4.2 Posology and method of administration

Ritonavir should be administered by physicians who are experienced in the treatment of HIV infection.

Norvir solution is administered orally and should preferably be ingested with food.

Ritonavir dosed as a pharmacokinetic enhancer

When ritonavir is used as a pharmacokinetic enhancer with other protease inhibitors the Summary of Product Characteristics for the particular protease inhibitor must be consulted.

The following HIV-1 protease inhibitors have been approved for use with ritonavir as a pharmacokinetic enhancer at the noted doses.

Adult use:

Amprenavir 600 mg twice daily with ritonavir 100 mg twice daily

Atazanavir 300 mg once daily with ritonavir 100 mg once daily

Fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily

Lopinavirco-formulated with ritonavir (lopinavir/ritonavir) 400 mg/100 mg or 800 mg/200mg.

Saquinavir 1000 mg twice daily with ritonavir 100 mg twice daily

Tipranavir 500 mg twice daily with ritonavir 200 mg twice daily

Darunavir 600 mg twice daily with ritonavir 100 mg twice daily in antiretroviral treatment (ART) experienced patients

Darunavir 800mg once daily with ritonavir 100 mg once daily in ART-naïve patients

Paediatric use: Ritonavir is recommended for children 2 years of age and older. For further dosage recommendations, refer to the product information of other Protease Inhibitors approved for co-administration with ritonavir. Norvir is not recommended in children below 2 years of age due to lack of data on safety and efficacy.

Renal impairment: As ritonavir is primarily metabolised by the liver, ritonavir may be appropriate for use with caution as a pharmacokinetic enhancer in patients with renal insufficiency depending on the specific protease inhibitor with which it is co-administered. However, since the renal clearance of ritonavir is negligible, the decrease in the total body clearance is not expected in patients with renal impairment. For specific dosing information in patients with renal impairment, refer to the Summary of Product Characteristics (SPC) of the co-administered protease inhibitor.

Hepatic impairment: Ritonavir should not be given as a pharmacokinetic enhancer to patients with decompensated liver disease (see section 4.3). In the absence of pharmacokinetic studies in patients with stable severe hepatic impairment (Child Pugh Grade C) without decompensation, caution should be exercised when ritonavir is used as a pharmacokinetic enhancer as increased levels of the co-administered PI may occur. Specific recommendations for use of ritonavir as a pharmacokinetic enhancer in patients with hepatic impairment are dependent on the protease inhibitor with which it is co-administered. The SPC of the co-administered PI should be reviewed for specific dosing information in this patient population.

Ritonavir dosed as an antiretroviral agent

Adult use: The recommended dosage of Norvir solution is 600 mg (7.5 ml) twice daily by mouth.

Gradually increasing the dose of ritonavir when initiating therapy may help to improve tolerance. Treatment should be initiated at 300 mg (3.75 ml) twice daily for a period of three days and increased by 100 mg (1.25 ml) twice daily increments up to 600 mg twice daily over a period of no longer than 14 days. Patients should not remain on 300 mg twice daily for more than 3 days.

Paediatric use (2 years of age and above): the recommended dosage of Norvir solution in children is 350 mg/m^² by mouth twice daily and should not exceed 600 mg twice daily. Norvir should be started at 250 mg/m^² and increased at 2 to 3 day intervals by 50 mg/m^² twice daily. When possible, dose should be administered using a calibrated dosing syringe.

Paediatric Dosage Guidelines

Body Surface area* (m^²)	Twice daily dose 250 mg/m^²	Twice daily dose 300 mg/m^²	Twice daily dose 350 mg/m^²
0.25	0.8 ml (62.5 mg)	0.9 ml (75 mg)	1.1 ml (87.5 mg)
0.50	1.6 ml (125 mg)	1.9 ml (150 mg)	2.2 ml (175 mg)
1.00	3.1 ml (250 mg)	3.8 ml (300 mg)	4.4 ml (350 mg)
1.25	3.9 ml (312.5 mg)	4.7 ml (375 mg)	5.5 ml (437.5 mg)
1.50	4.7 ml (375 mg)	5.6 ml (450 mg)	6.6 ml (525 mg)

* Body surface area can be calculated with the following equation

BSA (m^²)⁼√(Height (cm) X Weight (kg) / 3600)

Doses for intermediate body surface areas not included in the above table can be calculated using the following equations:

To calculate the volume to be administered (in ml) the body surface area should be multiplied by a factor of: 3.1 for a dose of 250 mg/m^²; 3.8 for one of 300 mg/m^²; and by 4.4 for 350 mg/m^².

Renal impairment: Currently, there are no data specific to this patient population and therefore specific dosage recommendations cannot be made. The renal clearance of ritonavir is negligible; therefore, a decrease in the total body clearance is not expected in patients with renal impairment. Because ritonavir is highly protein bound it is unlikely that it will be significantly removed by haemodialysis or peritoneal dialysis.

Hepatic impairment: Ritonavir is principally metabolised and eliminated by the liver. Pharmacokinetic data indicate that no dose adjustment is necessary in patients with mild to moderate hepatic impairment (see section 5.2). Ritonavir should not be given to patients with severe hepatic impairment (see section 4.3).

Elderly: Pharmacokinetic data indicated that no dose adjustment is necessary for elderly patients (see section 5.2).

The bitter taste of Norvir solution may be lessened if mixed with chocolate milk.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

When ritonavir is used as a pharmacokinetic enhancer of other PIs, consult the Summary of Product Characteristics of the co-administered protease inhibitor for contraindications.

Ritonavir should not be given as a pharmacokinetic enhancer or as an antiretroviral agent to patients with decompensated liver disease.

In vitro and in vivo studies have demonstrated that ritonavir is a potent inhibitor of CYP3A- and CYP2D6- mediated biotransformations. The following medicines are contraindicated when used with ritonavir and unless otherwise noted, the contraindication is based on the potential for ritonavir to inhibit metabolism of the co-administered medicinal product, resulting in increased exposure to the co-administered medicinal product and risk of clinically significant adverse effects.

The enzyme-modulating effect of ritonavir may be dose dependent. For some products, contraindications may be more relevant when ritonavir is used as an antiretroviral agent than when ritonavir is used as a pharmacokinetic enhancer (eg rifabutin and voriconazole):

Medicinal Product Class	Medicinal Products within Class	Rationale
Concomitant medicinal product levels increased or decreased
α₁-Adrenoreceptor Antagonist	Alfuzosin	Increased plasma concentrations of alfuzosin which may lead to severe hypotension (see section 4.5).
Analgesics	Pethidine, piroxicam, propoxyphne	Increased plasma concentrations of norpethidine, piroxicam and propoxyphene. Thereby, increasing the risk of serious respiratory depression or haematologic abnormalities, or other serious adverse effects from these agents.
Antiarrthymics	Amiodarone, bepridil, encainide, flecanide, propafenone, quinidine	Increased plasma concentrations of amiodarone, bepridil, encainide, flecanide, propafenone, quinidine. Thereby, increasing the risk of arrhythmias or other serious adverse reactions from these agents.
Antibiotic	Fusidic Acid	Increased plasma concentrations of fusidic acid and ritonavir.
Antifungal	Voriconazole	Concomitant use of ritonavir (400 mg twice daily and more) and voriconazole is contraindicated due to a reduction in voriconazole plasma concentrations and possible loss of effect (see section 4.5)
Antihistamines	Astemizole, terfenadine	Increased plasma concentrations of astemizole and terfenadine. Thereby, increasing the risk of serious arrhythmias from these agents.
Antimycobacterial	Rifabutin	Concomitant use of ritonavir dosed as an antiretroviral agent (600 mg twice daily) and rifabutin due to an increase of rifabutin serum concentrations and risk of adverse events including uveitis (see section 4.4). Recommendations regarding use of ritonavir dosed as a pharmacokinetic enhancer with rifabutin are noted in section 4.5
Antipsychotics/ Neuroleptics	Clozapine, pimozide	Increased plasma concentrations of clozapine and pimozide. Thereby, increasing the risk of serious haematologic abnormalities, or other serious adverse effects from these agents.
Ergot Derivatives	Dihydroergotamine, ergonovine, ergotamine, methylergonovine	Increased plasma concentrations of ergot derivatives leading to acute ergot toxicity, including vasospasm and ischaemia.
GI motility agent	Cisapride	Increased plasma concentrations of cisapride. Thereby, increasing the risk of serious arrhythmias from this agent.
HMG Co-A Reductase Inhibitor	Lovastatin, simvastatin	Increased plasma concentrations of lovastatin and simvastatin; thereby, increasing the risk of myopathy including rhabdomyolysis (see section 4.5).
PDE5 inhibitor	Sildenafil	Contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) only. Increased plasma concentrations of sildenafil. Thereby, increasing the potential for sildenafil-associated adverse events (which include hypotension and syncope). See section 4.4 and section 4.5 for coadministration of sildenafil in patients with erectile dysfunction.
Sedatives/hypnotics	Clorazepate, diazepam, estazolam, flurazepam, oral midazolam and triazolam	Increased plasma concentrations of clorazepate, diazepam, estazolam, flurazepam, oral midazolam and triazolam. Thereby, increasing the risk of extreme sedation and respiratory depression from these agents. (For caution on parenterally administered midazolam, see section 4.5).
Ritonavir medicinal product level decreased
Herbal Preparation	St. John's Wort	Herbal preparations containing St John's wort (Hypericum perforatum) due to the risk of decreased plasma concentrations and reduced clinical effects of ritonavir (see section 4.5).

4.4 Special warnings and precautions for use

Ritonavir is not a cure for HIV-1 infection or AIDS. Patients receiving ritonavir or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV-1 infection.

Patients should be advised that current antiretroviral therapy has not been proven to prevent the risk of transmission of HIV to others through blood or sexual contact. Appropriate precautions should continue to be used.

When ritonavir is used as a pharmacokinetic enhancer with other PIs, full details on the warnings and precautions relevant to that particular PI should be considered, therefore the Summary of Product Characteristics for the particular PI must be consulted.

Ritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer

Patients with chronic diarrhoea or malabsorption: Extra monitoring is recommended when diarrhoea occurs. The relatively high frequency of diarrhoea during treatment with ritonavir may compromise the absorption and efficacy (due to decreased compliance) of ritonavir or other concurrent medicinal products. Serious persistent vomiting and/or diarrhoea associated with ritonavir use might also compromise renal function. It is advisable to monitor renal function in patients with renal function impairment.

Haemophilia: there have been reports of increased bleeding, including spontaneous skin haematomas and haemarthroses, in haemophiliac patients type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than a half of the reported cases, treatment with protease inhibitors was continued or reintroduced if treatment had been discontinued. A causal relationship has been evoked, although the mechanism of action has not been elucidated. Haemophiliac patients should therefore be made aware of the possibility of increased bleeding.

Diabetes mellitus and hyperglycaemia: New onset diabetes mellitus