Sustiva 600 mg

1. Name drug - SUSTIVA

SUSTIVA 600 mg film-coated tablets



2. Qualitative and quantitative composition

Each film-coated tablet contains 600 mg of efavirenz.

Excipient: Every film-coated tablet contains 249.6 mg lactose monohydrate.

For a complete list of fillers, see section 6.1.



3. PHARMACEUTICALS FORM

The film-coated tablet

Dark yellow, capsule-shaped, printed with "SUSTIVA" on both sides.



4. CLINICAL PARTICULARS


SUSTIVA 600 mg

4.1 Therapeutic indications

SUSTIVA indicated in combination antiviral treatment for HIV-1-infected adults, adolescents and children 3 years and older.

SUSTIVA has not been adequately studied in patients with advanced HIV infection, namely in patients with CD4 counts <50 cells/mm3, and after the failure of protease inhibitor (PI) containing scheme. Although cross-resistance to efavirenz with PV was not documented, there are currently insufficient data on the effectiveness of the subsequent use of IP based combination therapy after failure of the scheme, containing SUSTIVA.

For more information about clinical and pharmacodynamic information, see section 5.1.




Posology 4.2 and the method of administration

Treatment should be initiated by a physician experienced in the management of HIV infection.

Along with antiretroviral therapy: SUSTIVA should be given in combination with other antiretroviral drugs (see section 4.5).

He recommended that SUSTIVA be taken on an empty stomach. Increasing concentrations of efavirenz observed after the introduction of SUSTIVA with food may lead to an increase in frequency of adverse events (see sections 4.4 and 5.2).

In order to increase the allowable nervous system undesirable consequences, bedtime dosing is recommended (see section 4.8).

Adults and adolescents over 40 kg: SUSTIVA recommended dose in combination with nucleoside analogue reverse transcriptase inhibitors (NRTIs), with or without PI (see section 4.5) is 600 mg orally once a day.

Efavirenz film-coated tablets are not suitable for children weighing less than 40 kg. Efavirenz hard capsules are available for these patients.

Dosage adjustment: if SUSTIVA was coadministered with voriconazole year voriconazole maintenance dose should be increased to 400 mg every 12 hours and SUSTIVA dose should be reduced by 50%, that is, to 300 mg once a day. When treatment with voriconazole stops, the initial dosage efavirenz should be restored (see section 4.5).

If SUSTIVA is coadministered with rifampicin, SUSTIVA dose should be increased to 800 mg / day (see section 4.5).

Renal failure: efavirenz pharmacokinetics have not been studied in patients with renal failure, but less than 1% of the efavirenz dose unchanged excretion in urine, so that the effects of deterioration of renal elimination of efavirenz should be kept to a minimum (see section 4,4).

Liver Disease: Patients with mild to moderate liver disease can be seen with their generally recommended dose of efavirenz. Patients should be carefully monitored for dose-related adverse events, particularly the nervous system, symptoms (see sections 4.3 and 4,4).


SUSTIVA 600 mg

4.3 Overdosage

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

Efavirenz should not be used in patients with severe hepatic view (Child Pugh Class C) (see section 5.2).

Efavirenz should not be administered concurrently with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, or ergot alkaloids (such as ergotamine, dihydroergotamine, ergonovine and methylergonovine), as well as competition for CYP3A4 on efavirenz could result in inhibition of metabolism and create the potential for serious and / or life-threatening undesirable consequences [eg, cardiac arrhythmias, prolonged sedation or respiratory depression] (see section 4.5).

Herbal products containing St. John's wort (Hypericum perforatum), should not be used when taking efavirenz because of the risk of reducing the concentration of plasma and reducing clinical implications efavirenz (see section 4.5).




4.4 Special warnings and precautions for use

Efavirenz should not be used as a single agent for the treatment of HIV, or added as a single agent in the absence of treatment. As with all other non-nucleoside reverse transcriptase inhibitors (NNRTIs), resistant virus quickly arises when efavirenz is administered as monotherapy. Selection of new antiretroviral agent (s) to be used in combination with efavirenz should take into account the potential for viral cross-resistance (see section 5.1).

When prescription medications concurrently with SUSTIVA, physicians should refer to the appropriate Summary Characteristics products.

Patients should be informed that the current antiretroviral therapy, including efavirenz, has been proven to prevent the risk of HIV transmission through other sexual contact or blood contamination. Appropriate precautions should continue.

If any antiretroviral medicinal product in combination treatment interrupted because of the suspicion of intolerance, serious attention should be given to the simultaneous cessation of all anti-retroviral drugs. In antiretroviral drugs should be restarted at the same time to address intolerance symptoms. Intermittent monotherapy and the progressive restoration of antiretrovirals is not recommended because of the increasing capacity for the selection of resistant virus.

Rash: mild to moderate rash was reported in the clinical studies with efavirenz and normally permitted, in a continuous therapy. Relevant antihistamines, and / or corticosteroids may increase the allowable speed up the settlement and rash. Severe rash associated with blistering, moist desquamation or ulcers has been reported in fewer than 1% of patients with efavirenz. The incidence of erythema multiforme and Stevens-Johnson syndrome was about 0.1%. Efavirenz should be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement, or fever.

If therapy with efavirenz terminated, attention should be paid to interrupt therapy with other anti-retroviral drugs, to avoid the development of resistance to the effects of the virus (see section 4.8).

Rash was reported in 26 out of 57 children (46%) treated with efavirenz for 48 weeks and was severe in three patients. Prophylaxis with the antihistamines before the start of therapy with efavirenz in children can be considered.

Patients who discontinued treatment with the other NNRTIs because of the rash may be at a higher risk of rash in the treatment of efavirenz.

Psychiatric symptoms: psychiatric adverse experiences were reported in patients treated with efavirenz. Patients with a prior history of mental disorders, appear to be at greater risk of serious psychiatric adverse experiences. In particular, severe depression was greater in those with a history of depression. There were also post-marketing reports of severe depression, death from suicide, delusions and psychosis type of behaviour. Patients should be informed that if they are experiencing symptoms such as severe depression, psychosis or suicidal ideation, they should consult a doctor immediately assess the likelihood that symptoms may be associated with the use of efavirenz, and if so, to determine whether the risks outweigh the benefits of continuing therapy (see section 4.8).

Nervous system symptoms: Symptoms, including, but not limited to, dizziness, insomnia, drowsiness, and abnormal concentration violation dreaming frequently reported undesirable effects in patients receiving efavirenz 600 mg / day in the clinical studies (see section 4.8). Nervous system symptoms usually begin during the first one or two days of treatment, and generally resolve after the first 2 - 4 weeks. Patients should be informed that if they do occur, these common symptoms that can improve with continued therapy, and did not predict subsequent onset of any of the less frequent symptoms of mental disorders.

Confiscation: convulsions were rarely in patients receiving efavirenz, generally in the presence of known history of seizures. Patients who receive both anticonvulsant drugs primarily metabolized in the liver, such as phenytoin, carbamazepine and phenobarbital, may require periodic monitoring of plasma levels. In drug interaction studies, carbamazepine plasma concentrations decreased when carbamazepine was together with efavirenz (see section 4.5). Attention should be taken in any patient with a history of seizures.

Influence of food: the administration of SUSTIVA with food can increase the effects of efavirenz (see section 5.2), and may lead to an increase in the frequency of undesirable consequences. He recommended that SUSTIVA be taken on an empty stomach, preferably at bedtime.

Resumption of immune syndrome: in HIV-infected patients with severe immune deficiency at the time of the establishment of combination antiretroviral therapy (CART), an inflammatory reaction to the asymptomatic or residual opportunistic pathogens could arise and cause serious clinical conditions, or exacerbation of symptoms. Typically, these reactions have been observed in the first few weeks or months after the start of CART. Examples cytomegalovirus retinitis, generalized and / or focal mycobacterial infections, as well as Pneumocystis carinii pneumonia. Any inflammatory symptoms should be assessed and established treatment, if necessary.
SUSTIVA 600 mg
Lipodystrophy and metabolic abnormalities: combination antiretroviral therapy was associated with the redistribution of fat (lipodystrophy) in HIV patients. The long-term consequences of these events are currently unknown. Knowledge of the mechanism is incomplete. A connection between the visceral and lipomatosis PX and lipoatrophy and NRTIs was hypothesised. A higher risk was associated with lipodystrophy individual factors, such as old age, and drug-related factors such as longer duration of antiretroviral therapy and related metabolic disorders. Clinical analysis should include an assessment for physical signs of fat redistribution. Consideration should be given to the post of measuring serum lipids and glucose in the blood. Lipid disorders should be managed as clinically appropriate (see section 4.8).

Osteonecrosis: Though considered a multifactorial etiology (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis were reported particularly in patients with advanced HIV disease and / or long-term effect of combination antiretroviral therapy (CART ). Patients should be advised to seek medical advice if they are experiencing pain and joint pain, joint stiffness, or difficulty in movement.


Special population:

Liver disease: because of the extensive mediated by the cytochrome P450 metabolism of efavirenz and limited clinical experience in patients with chronic liver disease, caution must be exercised in administering efavirenz for patients with mild to moderate liver disease. Patients should be carefully monitored for dose-related adverse events, particularly the nervous system symptoms. Laboratory tests should be carried out to assess their liver disease on a periodic basis (see section 4.2).

Safety and efficacy has not been established efavirenz in patients with serious underlying liver disorders. Efavirenz is contraindicated in patients with severe hepatic of view (see section 4.3). In patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at increased risk of severe and potentially fatal liver adverse events. Patients with pre-existing liver dysfunction, including chronic active hepatitis are more frequent liver function abnormalities during combination antiretroviral therapy and should be monitored in accordance with normal practice. If there is evidence of worsening liver disease or persistent elevations of serum transaminases more than 5 times the upper limit of normal range, to continue therapy with efavirenz should be weighed against the potential risks of significant liver toxicity. In such patients, treatment interruption or termination should be considered (see section 4.8).

In patients with other medications associated with liver toxicity, monitoring of liver enzymes are also recommended. In the case of associated antiviral therapy against hepatitis B or C, please refer to the relevant information about the products of those drugs.

Renal failure: efavirenz pharmacokinetics have not been studied in patients with renal failure, but less than 1% of the efavirenz dose unchanged excretion in urine, so that the effects of deterioration of renal elimination of efavirenz should be kept to a minimum (see section 4,2). There is no experience in patients with severe renal failure and recommended close monitoring of security in this group.

Older people: the insufficient number of elderly patients who have been tested in clinical studies to determine whether they respond differently than younger patients.

Children: efavirenz have not been evaluated in children under 3 years old, or who weigh less than 13 kg. Therefore, efavirenz should not be given to children under 3 years old.

Lactose: This drug contains 250 mg lactose, in each-600 mg daily dose. This number is not likely to cause the symptoms of lactose intolerance.

Patients with rare hereditary problems galactose intolerance, Sami lactase deficiency or glucose-galactose malabsorption should not take this drug. Individuals with these conditions can take efavirenz oral solution, which is free of lactose.




4.5 Interactions with other drugs and other forms of interaction

Efavirenz is an inducer of CYP3A4 inhibitor and including some CYP isozymes CYP3A4 (see section 5.2). Other compounds, which are substrates of CYP3A4, possibly decreased plasma concentrations in joint jurisdiction with efavirenz. Efavirenz exposure can be changed when given the medicines and foods (for example, grapefruit juice), which affect CYP3A4 activity.

Efavirenz should not be administered concurrently with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, or ergot alkaloids (such as ergotamine, dihydroergotamine, ergonovine and methylergonovine), as the oppression of their metabolism may lead to a serious, life-threatening events (see . section 4.3).


Along antiretroviral drugs:

Protease inhibitors:

Amprenavir: while efavirenz was shown a reduction Cmax, AUC and Cmin in amprenavir about 40% in adults, when combined with ritonavir amprenavir, to offset the effect of efavirenz pharmacokinetics ritonavir booster effect. Therefore, if efavirenz is given in combination with amprenavir (600 mg twice daily) and ritonavir (100 or 200 mg twice daily), no dosage adjustment is necessary. For joint management efavirenz with low doses of ritonavir in combination with a protease inhibitor, see the section below on ritonavir.
SUSTIVA 600 mg
Moreover, if efavirenz is given in combination with amprenavir and nelfinavir, no dosage adjustment necessary for any of the drugs. Treatment with efavirenz in combination with saquinavir and amprenavir is not recommended because the impact of both PV is expected to be significantly reduced. No dosage recommendations can be made available for co-management with other IP amprenavir and efavirenz in children and patients with renal impairment. Such combinations should be avoided in patients with hepatic impairment.