Active ingredients: Raltegravir
ISENTRESS 400 mg film-coated tablets
Isentress package inserts are available for pack sizes:- ISENTRESS 400 mg film-coated tablets
- ISENTRESS 100 mg chewable tablets
- ISENTRESS 25 mg chewable tablets
- ISENTRESS 100 mg granules for oral suspension
Why is Isentress used? What is it for?
What is Isentres
Isentress contains the active substance raltegravir. Isentress is an antiviral medicine that works against the Human Immunodeficiency Virus (HIV). This is the virus that causes Acquired Immunodeficiency Syndrome (AIDS).
How Isentress works
The virus produces an enzyme called HIV integrase. This helps the virus to multiply in the cells of his body. Isentress stops the activity of this enzyme. When used with other medicines, Isentress can reduce the amount of HIV in your blood (this is called the "viral load") and increase the number of your CD4 cells (a type of white blood cell that plays an important role in maintaining a healthy immune system to help fight infection).
Reducing the amount of HIV in your blood can improve the functioning of your immune system. This means your body can fight the infection better.
Isentress may not have these effects in all patients.
Isentress is not a cure for HIV infection.
When should Isentress be used
Isentress is used to treat HIV-infected adults, adolescents, children and infants from 4 weeks of age. Your doctor has prescribed Isentress for you to help keep your HIV infection under control.
Contraindications When Isentress should not be used
Do not take Isentress
If you are allergic to raltegravir or any of the other ingredients of this medicine.
Precautions for use What you need to know before taking Isentress
Talk to your doctor, pharmacist or nurse before taking Isentress.
Remember that Isentress is not a cure for HIV infection. This means that you can continue to get infections or other HIV-associated diseases. Continue to see your doctor regularly while you are taking this medicine.
Mental health problems
Tell your doctor if you have a history of depression or psychiatric illness.Depression, including suicidal thoughts and behaviors, has been reported in some patients taking this medicine, particularly in patients who have suffered from depression or psychiatric illness.
Bone problems
Some patients taking combination antiretroviral therapy may develop a bone disease called osteonecrosis (death of bone from lack of blood supply to the bone). Duration of combination antiretroviral therapy, corticosteroid use, alcohol consumption, severe decreased immune system activity, a higher body mass index may be, among others, some of the many risk factors for the development of this disease. Signs of osteonecrosis are stiffness, aching and pain in the joints (especially in the hip, knee and shoulder) and mobility difficulties. If you notice any of these symptoms, please contact your doctor.
Liver problems
Tell your doctor, pharmacist or nurse if you have previously had liver problems, including hepatitis B or C. Your doctor can assess the severity of your liver disease before deciding whether you can take this medicine.
Transmission of HIV to Others
HIV infection is spread through blood contact or sexual contact with a person with HIV. You can still pass on HIV while you are taking this medicine, although the risk is reduced by the effect of antiretroviral therapy. Discuss with your doctor the necessary precautions to avoid passing the infection to other people.
Infections
Tell your doctor, pharmacist or nurse immediately if you notice any symptoms of infection, such as fever and / or feeling unwell. In some patients with advanced HIV infection and who have had opportunistic infections, soon after starting anti- HIV inflammatory signs and symptoms of previous infections may arise and these symptoms are believed to be due to an improvement in the body's immune response, which allows it to fight infections that may have presented themselves without clear symptoms.
In addition to opportunistic infections, autoimmune disorders (a condition that occurs when the immune system attacks healthy body tissue) can also occur after you start taking medicines to treat HIV infection. Autoimmune disorders can occur many months after the start of treatment. If you notice any symptoms of infection or other symptoms such as muscle weakness, initial weakness in the hands and feet moving up to the trunk of the body, palpitations, tremor or hyperactivity, tell the doctor to request the necessary treatment.
Muscle problems
Contact your doctor, pharmacist or nurse immediately if you experience unexplained muscle pain, tenderness or weakness while taking this medicine.
Skin problems
Contact your doctor immediately if you develop a rash. Severe, life-threatening skin reactions and allergic reactions have been reported in some patients taking this medicine.
Children and adolescents
Isentress should not be used in infants less than 4 weeks old.
Interactions Which drugs or foods can change the effect of Isentress
Other medicines and Isentress
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines with or without a prescription.
Isentress may interact with other medicines. Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take:
- antacids. It is not recommended to take Isentress with some antacids (those containing aluminum and / or magnesium). Talk to your doctor about other antacids you can take.
- rifampicin (medicine used to treat some infections such as tuberculosis), as it may decrease the levels of Isentress. Your doctor may consider increasing the dose of Isentress if you are taking rifampicin.
Warnings It is important to know that:
Pregnancy and breastfeeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.
- Isentress is not recommended in pregnancy because it has not been studied in pregnant women.
- Women with HIV should not breastfeed their babies because they can become infected with HIV through breast milk.
Ask your doctor what is the best way to feed your baby. Ask your doctor, pharmacist or nurse for advice before taking any medicine if you are pregnant or breastfeeding.
Driving and using machines
Do not use machines, drive or ride a bicycle if you feel dizzy after taking this medicine.
Isentress film-coated tablets contain lactose
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.
Dose, Method and Time of Administration How to use Isentress: Posology
You must always take this medicine exactly as your doctor, pharmacist or nurse has told you. If you are unsure, ask your doctor, pharmacist or nurse. Isentress must be used in combination with other HIV medicines.
- It is very important that you take this medicine exactly as directed.
How much to take
Adults
The recommended dose is one tablet (400 mg) by mouth twice a day.
- Do not change your dose or stop taking this medicine without first talking to your doctor, pharmacist or nurse.
Use in children and adolescents
The recommended dose of Isentress is 400 mg by mouth, twice a day for adolescents and children weighing at least 25 kg.
Isentress is also available as a chewable tablet for children weighing at least 11 kg and as granules for oral suspension for infants and children from 4 weeks of age weighing at least 3 kg and less than 20 kg.
- Do not change the 400 mg tablet to the chewable tablet or granules for oral suspension without first checking with your doctor, pharmacist or nurse.
It is recommended not to chew, crush or split the tablets as this can change the levels of the medicine in the body. This medicine can be taken with or without food or drink.
If you forget to take Isentress
- If you forget to take a dose, take it as soon as you remember it.
- However, if it is time for your next dose, skip the missed dose and go back to your usual schedule.
- Do not take a double dose to make up for a forgotten dose.
If you stop taking Isentress
It is important that you take Isentress exactly as prescribed by your doctor. Do not stop the treatment because:
- It is very important that you take all your HIV medicines as prescribed and at the correct times of the day. This will allow your medicines to work better. drug resistance ").
- When your supply of Isentress begins to dwindle, get more from your doctor or pharmacist. This is because it is very important not to be without the medicine, even for a short time. During a short break in taking the medicine, the amount of viruses in the blood may increase. This may mean that the HIV virus is developing resistance to Isentress and becoming more difficult to treat.
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.
Overdose What to do if you have taken too much Isentress
Do not take more tablets than prescribed by your doctor. If you take too many tablets contact your doctor
Side Effects What are the side effects of Isentress
Like all medicines, Isentress can cause side effects, although not everybody gets them.
Serious side effects - these are uncommon (may affect up to 1 in 100 people)
See your doctor right away if you notice any of the following:
- herpes infections including herpes zoster
- anemia including the form due to iron deficiency
- signs and symptoms of infection or inflammation
- mental disorder
- suicide intention or attempt
- stomach inflammation
- inflammation of the liver
- liver failure
- allergic skin rash
- some types of kidney problems
- taking medication in quantities higher than those recommended
See your doctor immediately if you notice any of the side effects listed above.
Common: The following may affect up to 1 in 10 people
- decreased appetite
- sleep disturbance; alteration of the content of dreams; nightmares; abnormal behavior; feelings of deep sadness and not being worthy
- feeling dizzy; headache
- feeling of loss of balance
- swelling; abdominal pain; diarrhea; excessive gas in the stomach or intestines; feeling sick; vomiting; indigestion; belching
- certain types of rash (more often when used in combination with darunavir)
- tiredness; unusual tiredness or weakness; fever
- increased liver enzymes in the blood; alteration of white blood cells in the blood; increased blood fat levels; increase in the level of enzymes secreted by the salivary glands or pancreas
Uncommon: the following may affect up to 1 in 100 people
- infection of the hair roots; influence; skin infection due to viruses; vomiting or diarrhea due to an infectious agent; upper respiratory tract infection; lymph node abscess
- wart
- pain in the lymph nodes; low number of white blood cells that fight infections; swollen glands in the neck, armpits and groin
- allergic reaction
- increased appetite; diabetes; increased cholesterol and lipids in the blood; high blood sugar levels; excessive thirst; severe weight loss; high levels of fat (such as cholesterol and triglycerides) in the blood; disturbed body fat
- feeling anxious; feeling confused; depressed mood; mood changes; panic attack
- memory loss; pain in the hand due to nerve compression; disturbance in attention; dizziness following rapid postural changes; altered taste; increased sleepiness; lack of energy; forgetfulness, migraine; loss of sensation; numbness or weakness in the arms and / or legs; tingling; drowsiness; tension headache tremors poor sleep quality
- visual disturbances
- ringing, hissing, whistling, ringing, or other persistent noise in the ears
- palpitations; slow heartbeats; rapid or irregular heartbeats
- hot flashes; high blood pressure
- harsh, shrill, or fatigued voice; nosebleed; nasal congestion
- pain in the upper abdomen; discomfort in the rectum; constipation; dry mouth; heartburn; painful swallowing; inflammation of the pancreas; ulcer or wound in the stomach or upper intestine; bleeding from the anus; stomach discomfort; inflammation of the gums; swollen, red, painful tongue
- accumulation of fat in the liver
- acne; abnormal hair loss or thinning; redness of the skin; abnormal distribution of body fat, which may include loss of fat from legs, arms and face, and increased fat in the abdomen; excessive sweating; night sweats; skin thickening and itching due to repeated scratching; skin lesion; dry skin
- joint pain, painful joint disease; back pain; bone / muscle pain; muscle tenderness or weakness; neck pain; pain in the arms or legs; inflammation of the tendons; decrease in the amount of minerals in the bones
- kidney stones; urination at night; kidney cyst
- erectile dysfunction; breast enlargement in men; symptoms of menopause
- chest discomfort; chills; swelling of the face; feeling nervous; general feeling of being unwell; neck mass; swelling of the hands, ankles or feet; ache
- decrease in white blood cells; decrease in blood platelets (a type of cell that promotes clotting); blood tests showing reduced kidney function; high blood sugar level; increase in muscle enzymes in the blood; presence of sugar in the urine; presence of red blood cells in the urine; weight gain; increase in waist size; decrease in blood proteins (albumin); increased blood clotting time.
Additional side effects in children and adolescents
- hyperactivity
Muscle pain, tenderness or weakness have been reported during treatment with Isentress.
In clinical trials, cancer was observed in patients receiving Isentress with a similar frequency to that seen in patients receiving other anti-HIV treatments not containing Isentress.
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system. provide more information on the safety of this medicine.
Expiry and Retention
- Keep this medicine out of the sight and reach of children.
- Do not take this medicine after the expiry date which is stated on the bottle after EXP. The expiry date refers to the last day of that month.
- This medicinal product does not require any special storage conditions.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Other Information
What Isentress contains
The active substance is raltegravir. Each film-coated tablet contains 400 mg of raltegravir (as potassium).
The other ingredients are: lactose monohydrate, microcrystalline cellulose, anhydrous dibasic calcium phosphate, hypromellose 2208, poloxamer 407, sodium stearyl fumarate and magnesium stearate. In addition, the coating contains the following excipients: polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc, red iron oxide and black iron oxide.
What Isentress looks like and contents of the pack
The film-coated tablet is oval, pink, debossed with "227" on one side. Two pack sizes are available: 1 bottle of 60 tablets and 3 bottles of 60 tablets each. D.
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
ISENTRESS 400 MG TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 400 mg of raltegravir (as potassium).
Excipient with known effects:
Each tablet contains 26.06 mg of lactose (as monohydrate).
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablet.
Pink, oval tablet, debossed with "227" on one side.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
ISENTRESS is indicated in combination with other antiretroviral medicinal products for the treatment of human immunodeficiency virus (HIV-1) infection in adults, adolescents, children and infants from 4 weeks of age (see sections 4.2, 4.4, 5.1 and 5.2).
04.2 Posology and method of administration
Treatment should be initiated by a physician experienced in the management of HIV infection.
Dosage
ISENTRESS should be used in combination with other active antiretroviral therapy (ART) (see sections 4.4 and 5.1).
Adults
The recommended dose is 400 mg (one tablet) twice a day.
Children and adolescents
In people weighing at least 25 kg, the recommended dose is 400 mg (one tablet) twice a day. In individuals unable to swallow the tablet, consider using the chewable tablet.
ISENTRESS is also available in a chewable tablet formulation for children weighing at least 11 kg and in a granule formulation for oral suspension for infants and children from 4 weeks of age weighing at least 3 kg and less than 20 kg. For more information on dosing refer to the European Summaries of Product Characteristics for chewable tablet and granulate formulations for oral suspension.
The maximum dose of the chewable tablet is 300 mg twice a day. As the formulations are not bioequivalent, the 400 mg tablet should not be replaced with the chewable tablet or granules for oral suspension (see section 5.2). Chewable tablets and granules for oral suspension have not been studied in adolescents (12 to 18 years) or HIV-infected adults.
Senior citizens
There is limited information on the use of raltegravir in the elderly (see section 5.2). Therefore, ISENTRESS should be used with caution in this population.
Renal impairment
No dose adjustment is required in patients with renal impairment (see section 5.2).
Hepatic impairment
No dose adjustment is required in patients with mild to moderate hepatic impairment. The safety and efficacy of raltegravir have not been established in patients with severe underlying liver disorders. Therefore, ISENTRESS should be used with caution in patients with severe hepatic impairment (see sections 4.4 and 5.2).
Pediatric population
The safety and efficacy of raltegravir in infants less than 4 weeks old have not yet been established. No data are available.
Method of administration
Oral use.
ISENTRESS 400 mg tablets can be administered with or without food.
The tablets should not be chewed, crushed or divided due to the expected changes in the pharmacokinetic profile.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
04.4 Special warnings and appropriate precautions for use
Patients should be advised that current antiretroviral therapy is not curative of HIV and has not been proven to prevent transmission of HIV to other individuals through the blood. Although effective viral suppression with antiretroviral therapy has been shown to significantly reduce the risk of sexual transmission, a residual risk cannot be excluded, and precautions should be taken to prevent transmission in accordance with national guidelines.
Overall, considerable inter- and intra-individual variability was observed in the pharmacokinetics of raltegravir (see sections 4.5 and 5.2).
Raltegravir has a relatively low genetic barrier to resistance. Therefore, whenever possible, raltegravir should be administered with two other active antiretroviral medicinal products to minimize the potential for virological failure and the development of resistance (see section 5.1).
In naïIn addition to treatment, clinical trial data on the use of raltegravir are limited to use in combination with two nucleotide reverse transcriptase inhibitors (NRTIs) (emtricitabine and tenofovir disoproxil fumarate).
Depression
Depression, including suicidal thoughts and behaviors, has been reported, particularly in patients with a "history of depression or psychiatric illness. Caution should be used in patients with a" history of depression or psychiatric illness.
Hepatic impairment
The safety and efficacy of raltegravir have not been established in patients with severe underlying liver disorders. Therefore, ISENTRESS should be used with caution in patients with severe hepatic impairment (see sections 4.2 and 5.2).
Patients with pre-existing liver impairment, including those with chronic hepatitis, have a higher frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored as usual. If worsening liver disease is observed in such patients, interruption or discontinuation of treatment should be considered.
Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy have a higher risk of developing serious and life-threatening hepatic adverse reactions.
Osteonecrosis
Although the etiology is thought to be multifactorial (including corticosteroid use, alcohol intake, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported, especially in patients with advanced HIV disease and / or long-term exposure to combination antiretroviral therapy Patients should be advised to seek medical attention if they develop joint pain and pain, joint stiffness or mobility difficulties.
Immune Reactivation Syndrome
In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first weeks or months of initiation of combination antiretroviral therapy (CART). Relevant examples of this are cytomegalovirus retinitis, generalized and / or focal mycobacterial infections and pneumonia Pneumocystis jiroveci (formerly known as Pneumocystis carinii). Any inflammatory symptoms should be evaluated and, if necessary, treatment instituted.
The occurrence of autoimmune disorders (such as Graves' disease) has also been reported in the context of immune reactivation; however, the recorded time to onset is more variable and these events can occur even many months after the start of treatment.
Antacids
Co-administration of ISENTRESS with aluminum and magnesium containing antacids resulted in decreased plasma levels of raltegravir. Co-administration of ISENTRESS with aluminum and / or magnesium-containing antacids is not recommended (see section 4.5).
Rifampicin
Use caution when administering ISENTRESS concomitantly with potent inducers of uridine diphospho-glucuronosyl transferase (UGT) 1A1 (e.g. rifampicin). Rifampicin reduces plasma levels of raltegravir; the impact on the efficacy of raltegravir is unknown. However, if concomitant administration with rifampicin cannot be avoided, doubling the dose of ISENTRESS in adults may be considered. There are no data to guide concomitant administration of ISENTRESS with rifampicin in patients below 18 years of age (see section 4.5).
Myopathy and rhabdomyolysis
Myopathy and rhabdomyolysis have been reported. Use with caution in patients who have had myopathy or rhabdomyolysis in the past or have any predisposing conditions including other medicinal products associated with these conditions (see section 4.8).
Severe skin and hypersensitivity reactions
Serious, life-threatening and fatal skin reactions have been reported in patients receiving ISENTRESS, in most cases concomitantly with other medicinal products associated with these reactions. These include cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. Hypersensitivity reactions characterized by rash, systemic symptoms, and sometimes organ dysfunction, including liver failure, have also been reported. Immediately discontinue therapy with ISENTRESS and other suspected agents if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but are not limited to, severe skin rash or rash accompanied by fever, general malaise, fatigue, muscle or joint pain, blisters, oral lesions, conjunctivitis, face edema, hepatitis, eosinophilia, angioedema). The clinical status, including hepatic aminotransferase, should be monitored and appropriate therapy instituted. Delay in stopping treatment with ISENTRESS or other suspect agents after the onset of a severe rash may result in a life-threatening reaction.
Rash
Rash occurred more commonly in treatment-experienced patients receiving regimens containing ISENTRESS and darunavir than in patients receiving ISENTRESS without darunavir or darunavir without ISENTRESS (see section 4.8).
Lactose
ISENTRESS film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
04.5 Interactions with other medicinal products and other forms of interaction
Education in vitro indicate that raltegravir is not a substrate of cytochrome P450 (CYP) enzymes, does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A enzymes, does not induce CYP3A4, and does not inhibit P-based transport. from these data, raltegravir is not expected to alter the pharmacokinetics of medicinal products that are substrates of these enzymes or P-glycoprotein.
Based on studies in vitro And in vivo, raltegravir is eliminated primarily via the UGT1A1-mediated glucuronidation pathway.
Although the studies in vitro indicate that raltegravir is not an inhibitor of UDP glucuronosyltransferase (UGT) 1A1 and 2B7, a clinical study has suggested that partial inhibition of UGT1A1 could occur in vivo based on the observed effects on bilirubin glucuronidation. However, in drug interactions the magnitude of this effect would not seem to be of clinical relevance.
Considerable inter- and intra-individual variability in raltegravir pharmacokinetics was observed. The following drug interaction information is based on geometric mean values; the effect in the individual patient cannot be predicted with accuracy.
Effect of raltegravir on the pharmacokinetics of other medicinal products
In interaction studies, raltegravir had no clinically relevant effects on the pharmacokinetics of etravirine, maraviroc, tenofovir, hormonal contraceptives, methadone, midazolam or boceprevir.
In some studies, co-administration of ISENTRESS with darunavir resulted in a modest decrease in darunavir plasma concentrations; the mechanism of this effect is unknown. However, the effect of raltegravir on darunavir plasma concentrations does not appear to be clinically significant.
Effect of other agents on raltegravir pharmacokinetics
As raltegravir is primarily metabolised via UGT1A1, caution should be used when ISENTRESS is co-administered with potent inducers of UGT1A1 (e.g. rifampicin). Rifampicin reduces plasma levels of raltegravir; the impact on the efficacy of raltegravir is unknown. However, if concomitant administration with rifampicin cannot be avoided, a doubling of the dose of ISENTRESS may be considered in adults. There are no data to guide concomitant administration of ISENTRESS with rifampicin in patients less than 18 years of age (see section 4.4). The impact of other potent inducers of drug metabolizing enzymes, such as phenytoin and phenobarbital, on UGT1A1 is unknown. Less potent inducers (eg efavirenz, nevirapine , etravirine, rifabutin, glucocorticoids, St. John's wort, pioglitazone) can be used with the recommended dose of ISENTRESS.
Co-administration of ISENTRESS with other medicinal products known to be potent inhibitors of UGT1A1 (e.g. atazanavir) may increase the plasma levels of raltegravir. Less potent UGT1A1 inhibitors (e.g. indinavir, saquinavir) may also increase the plasma levels of raltegravir, but to a lesser extent than atazanavir. Additionally, tenofovir may increase the plasma levels of raltegravir, however the mechanism by which this effect occurs is not known (see Table 1). In clinical studies, a substantial proportion of patients were taking atazanavir and / or tenofovir, both agents that cause increases in plasma levels of raltegravir, within the optimized background regimens. The safety profile in patients taking atazanavir and / or tenofovir was generally similar to the safety profile of patients who did not receive these agents, therefore no dose adjustment is required.
Concomitant administration of ISENTRESS with antacids containing divalent metal cations may reduce the absorption of raltegravir by chelation, resulting in decreased plasma levels of raltegravir. Intake of an antacid containing aluminum and magnesium within 6 hours of ISENTRESS administration decreased in plasma levels of raltegravir significantly. Therefore, concomitant administration of ISENTRESS with aluminum and / or magnesium-containing antacids is not recommended. Co-administration of ISENTRESS with a calcium carbonate-containing antacid reduced plasma levels of raltegravir; however, this interaction is not considered clinically significant. Therefore, when ISENTRESS is co-administered with calcium carbonate-containing antacids, no dose adjustment is required.
Concomitant administration of ISENTRESS with other agents that increase gastric pH (e.g. omeprazole and famotidine) may increase the absorption rate of raltegravir and result in increased plasma levels of raltegravir (see Table 1). In the phase III studies the safety profiles in the subgroup of patients taking proton pump inhibitors or H2 antagonists were comparable to those not taking these antacids. Therefore no dose adjustment is required with the use of proton pump inhibitors or H2 antagonists.
All interaction studies were performed in adults.
Table 1
Pharmacokinetic interaction data
04.6 Pregnancy and breastfeeding
Pregnancy
There are no adequate data on the use of raltegravir in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. ISENTRESS should not be used during pregnancy.
Pregnancy registry with antiretrovirals
In order to monitor the maternal-fetal outcomes of patients who were inadvertently treated with ISENTRESS during pregnancy, a pregnancy registry of patients on antiretroviral therapy was established. Physicians are advised to register patients in this registry.
As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women and consequently to reduce the risk of vertical transmission of HIV to the newborn, animal data should be considered as well as the clinical experience in pregnant women in order to characterize the safety for the fetus.
Feeding time
It is unknown whether raltegravir is excreted in human milk. However, Raltegravir is excreted in the milk of lactating rats. In rats, at the maternal dose of 600 mg / kg / day, the mean concentrations of the active substance in milk were approximately 3 times higher than those in maternal plasma. Breastfeeding is not recommended during ISENTRESS treatment. As a general rule, it is recommended that HIV-infected mothers do not breastfeed their babies in order to avoid HIV transmission.
Fertility
No effect on fertility was seen in male and female rats at doses up to 600 mg / kg / day which resulted in exposure 3 times the exposure at the recommended human dose.
04.7 Effects on ability to drive and use machines
Dizziness has been reported in some patients during treatment with regimens including ISENTRESS. Dizziness may affect the ability of some patients to drive and use machines (see section 4.8).
04.8 Undesirable effects
Summary of the safety profile
The safety profile of ISENTRESS was based on pooled safety data from two Phase III clinical studies in treatment-experienced adult patients and one Phase III clinical study in adult patients naïve to the treatment. The most frequently reported adverse reactions during treatment were headache and nausea which occurred with a frequency of 5% or more. The most frequently reported serious adverse reaction was immune reconstitution syndrome.
In treatment-experienced patients, the two randomized clinical trials used the recommended dose of 400 mg twice daily in combination with optimized background therapy (OBT) in 462 patients, compared with 237 patients taking placebo in combination with the OBT. During double-blind treatment, the total follow-up was 708 patient-years in the group receiving ISENTRESS 400 mg twice daily and 244 patient-years in the placebo group.
In treatment-naïve patients, the multicentre, randomized, double-blind, active-controlled clinical trial used the recommended dose of 400 mg twice daily in combination with a fixed dose of emtricitabine 200 mg (+) tenofovir 245 mg in 281 patients, compared with 282 patients taking efavirenz (EFV) 600 mg (at bedtime) in combination with emtricitabine (+) tenofovir. During double-blind treatment, the total follow-up was 1,104 patient-years in the group receiving ISENTRESS 400 mg twice daily, and 1,036 patient-years in the group receiving efavirenz 600 mg at bedtime.
In the pooled analysis of treatment-experienced patients, the rates of discontinuation due to adverse reactions were 3.9% in patients receiving ISENTRESS + OBT and 4.6% in patients receiving placebo + OBT . Discontinuation rates in treatment-naïve patients due to adverse reactions were 5.0% in patients receiving ISENTRESS + emtricitabine (+) tenofovir and 10.0% in patients receiving efavirenz + emtricitabine (+ ) tenofovir.
Table of adverse reactions
Adverse reactions considered by investigators to be causally related to ISENTRESS (alone or in association with other ART) are listed below by system organ class. Frequencies are defined as common (≥ 1/100,
Description of selected adverse reactions
Cases of cancer have been reported in treatment-experienced and treatment-naïve patients who initiated ISENTRESS in combination with other antiretroviral agents. The types and incidences of the specific malignancies were those expected in the severe immunodeficiency population. The risk of developing cancer in these studies was similar in both the ISENTRESS and comparison groups.
Grade 2-4 changes in creatine kinase laboratory values have been observed in subjects treated with ISENTRESS. Myopathy and rhabdomyolysis have been reported. Use with caution in patients who have had myopathy or rhabdomyolysis in the past or have any predisposing conditions including other medicinal products associated with these conditions (see section 4.4).
Cases of osteonecrosis have been reported mainly in patients with generally known risk factors, advanced HIV disease or long-term exposure to combined antiretroviral therapy (CART). The frequency is unknown (see section 4.4).
In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease) have also been reported: however, the recorded time to onset is more variable and these events can occur even many months after initiation of treatment (see section 4.4).
At least one severe case has occurred for each of the following clinical adverse reactions: genital herpes, anemia, immune reconstitution syndrome, depression, mental disorder, suicide attempt, gastritis, hepatitis, renal failure, accidental overdose.
In clinical trials in treatment-experienced patients, rash, regardless of causality, was observed more commonly with ISENTRESS and darunavir-containing regimens than with ISENTRESS-containing regimens without darunavir or darunavir without ISENTRESS. drug-related investigator occurred with similar incidence rates. The exposure-adjusted incidence rates of rash (from all causalities) were 10.9, 4.2, and 3.8 per 100 patient-years (PYR), respectively; and for drug-related rash were 2.4, 1.1, and 2.3 per 100 patient-years, respectively. The rashes observed in clinical trials were mild to moderate in severity and did not cause disease. discontinuation of therapy (see section 4.4).
Patients co-infected with hepatitis B and / or hepatitis C virus
In phase III studies, treatment-experienced patients (N = 114/699 or 16%; HBV = 6%, HCV = 9%, HBV + HCV = 1%) and treatment-naïve patients (N = 34/563 or 6%; HBV = 4%, HCV = 2%, HBV + HCV = 0.2%) with active chronic (but not acute) co-infection of hepatitis B and / or hepatitis C were included in the enrollment, provided that baseline values of liver function tests did not exceed the upper limit of normal by more than 5 times. In general, the safety profile of ISENTRESS in patients co-infected with hepatitis B and / or hepatitis C viruses was similar to that of patients without hepatitis B and / or hepatitis C virus co-infection, although the frequency of AST and ALT abnormalities was relatively higher in the hepatitis B and / or hepatitis virus co-infected subgroup C in both treatment groups. At 96 weeks, in treatment-experienced patients with grade 2 or greater laboratory changes of AST, ALT, or bil Total irubin, indicative of a worsening from baseline, occurred in 29%, 34% and 13% of co-infected subjects treated with ISENTRESS, respectively, compared to 11%, 10% and 9% of all other treated subjects with ISENTRESS. At 240 weeks in treatment-naïve patients, Grade 2 or greater laboratory changes in AST, ALT, or total bilirubin, indicative of grade worsening from baseline, occurred in 22%, 44% and 17% of patients, respectively. co-infected subjects treated with ISENTRESS compared to 13%, 13% and 5% of all other subjects treated with ISENTRESS.
The following adverse reactions were identified through post-marketing surveillance but were not reported as drug related in Phase III randomized controlled clinical trials (Protocols 018, 019 and 021): thrombocytopenia, suicidal ideation, suicidal behavior (particularly in patients with a pre-existing history of psychiatric illness), liver failure, Stevens Johnson syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), rhabdomyolysis.
Pediatric population
Children and adolescents from 2 to 18 years of age
In IMPAACT P1066 raltegravir in combination with other antiretroviral agents has been studied in 126 HIV-1 infected children and adolescents 2 to 18 years of age with antiretroviral treatment experience (see sections 5.1 and 5.2). Of the 126 patients, 96 received the recommended dose of ISENTRESS.
In these 96 children and adolescents, the frequency, type and severity of drug-related adverse reactions up to week 48 were comparable to those seen in adults.
One patient had psychomotor hyperactivity, abnormal behavior and insomnia, drug-related grade 3 clinical adverse reactions; one patient had a severe grade 2 drug-related allergic rash.
One patient had drug-related laboratory abnormalities, grade 4 AST and grade 3 ALT, which were considered severe.
Infants and children from 4 weeks to less than 2 years of age
In IMPAACT P1066 raltegravir in combination with other antiretrovirals was also studied in 26 HIV-1 infected infants and children aged at least 4 weeks and less than 2 years of age (see sections 5.1 and 5.2).
In these 26 infants and children, the frequency, type and severity of drug-related adverse reactions up to week 48 were comparable to those seen in adults.
One patient developed a severe grade 3 drug-related allergic rash, which led to treatment discontinuation.
Reporting of suspected adverse reactions
The reporting of suspected adverse reactions that occur after the authorization of the medicinal product is important, as it allows continuous monitoring of the benefit / risk ratio of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Italian Medicines Agency. , website: http://www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
No specific information is available on the treatment of an overdose of ISENTRESS.
In the event of an overdose, it is reasonable to use common supportive measures, eg. remove unabsorbed material from the gastrointestinal tract, monitor the patient clinically (including an ECG trace), and institute supportive care if necessary. It should be noted that raltegravir occurs as a potassium salt for clinical use. The dialyzability of raltegravir is not known.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: antivirals for systemic use, other antivirals, ATC code: J05AX08.
Mechanism of action
Raltegravir is an inhibitor of the activity of strand transfer integrase active against the human immunodeficiency virus (HIV-1). Raltegravir inhibits the catalytic activity of integrase, an HIV encoded enzyme required for viral replication. Inhibition of integrase prevents covalent insertion, or integration, of the HIV genome into the host cell genome. of HIV that fail to integrate cannot induce the production of new infectious viral particles, therefore the inhibition of integration prevents the spread of viral infection.
Antiviral activity in vitro
Raltegravir at concentrations of 31 ± 20 nM resulted in a 95% inhibition (IC95) of HIV-1 replication (compared to a virus-infected, untreated culture) in cultures of human T lymphoid cells infected with a cell line H9IIIB variant of adapted HIV-1. In addition, raltegravir inhibited viral replication in cultured mitogen-activated human peripheral blood mononuclear cells infected with several primary clinical isolates of HIV-1 that included isolates from 5 non-subtypes. B and isolates resistant to reverse transcriptase inhibitors and protease inhibitors. In a single cycle test of infection, raltegravir inhibited the infection of 23 HIV isolates representing 5 non-B subtypes and 5 circulating recombinant forms with a variable IC50 5 to 12 nM.
Resistence
Most viruses isolated from patients unresponsive to raltegravir had a high degree of resistance to raltegravir, referring to the appearance of two or more mutations. Most had a key mutation at amino acid 155 (N155 modified to H), amino acid 148 (Q148 modified to H, K or R) or amino acid 143 (Y143 modified to H, C or R), together with one or more additional integrase mutations (eg L74M, E92Q, T97A, E138A / K, G140A / S, V151I, G163R, S230R). Key mutations reduce viral susceptibility to raltegravir and the addition of other mutations results in a further reduction in raltegravir susceptibility. Factors that reduced the likelihood of developing resistance included lower baseline viral load and use of other active antiretroviral agents. . Mutations that confer resistance to raltegravir generally also confer resistance to the activity inhibitor strand transfer mutations in amino acid 143 confer greater resistance to raltegravir than elvitegravir and the E92Q mutation confers greater resistance to elvitegravir than raltegravir. Viruses that have a mutation at amino acid 148, along with one or more mutations that result in resistance to raltegravir, may also have clinically significant resistance to dolutegravir.
Clinical experience
Evidence for the efficacy of ISENTRESS was based on data analysis from two 96-week, randomized, double-blind, placebo-controlled clinical trials (BENCHMRK 1 and BENCHMRK 2, Protocols 018 and 019) in adult patients infected with HIV-1 antiretroviral treatment experience and data analysis from a 240-week, randomized, double-blind, active-controlled study (STARTMRK, Protocol 021) in HIV-1 infected adult patients naïve to antiretroviral treatment.
Effectiveness
Treatment-experienced adult patients
The safety and antiretroviral activity of ISENTRESS 400 mg twice daily vs placebo in combination with optimized background therapy (OBT) was evaluated with BENCHMRK 1 and BENCHMRK 2 (multicentre, randomized, double-blind, placebo-controlled studies). , in HIV-infected patients, aged 16 years or older, with documented resistance to at least one drug from each of the 3 antiretroviral therapy classes (NRTIs, NNRTIs, PIs). Prior to randomization, OBT was set by the researcher on the basis of the history of previous treatments performed by the patient, as well as on the baseline genotypic and phenotypic viral resistance tests.
Patient demographics (gender, age and race) and baseline characteristics were comparable between the two groups receiving ISENTRESS 400 mg twice daily and placebo. Patients had previous exposure to a median of 12 antiretroviral treatments for a median duration of 10 years. A median number of 4 ART was used in the OBT.
Results of the analysis at 48 weeks and at 96 weeks
The durable outcomes (at week 48 and week 96) of patients treated with the recommended dose of ISENTRESS 400 mg twice daily from the overall evaluated BENCHMRK 1 and BENCHMRK 2 studies are shown in Table 2.
Table 2
Efficacy results at weeks 48 and 96
† Failure to complete is considered failure: Patients who discontinued treatment prematurely were subsequently registered as failure. The percentage of patients who responded to therapy with a 95% confidence interval is reported.
‡ In the analysis for prognostic factors, the approach was applied in case of virological failure carry-forward for baseline-carry-forward percentages.
§ The genotypic sensitivity score (GSS) was defined as the total oral ARTs present in the optimized background therapy (OBT) to which the "patient's viral isolate showed genotypic sensitivity based on the genotypic resistance test. L" use of enfuvirtide in the OBT setting in enfuvirtide naïve patients was counted as an active OBT drug. Similarly, darunavir use in the OBT setting in darunavir naïve patients was counted as an active OBT drug.
Raltegravir obtained virologic responses (using the Not Completed = Failure approach) of HIV RNA
Switch to raltegravir
SWITCHMRK studies 1 and 2 (Protocols 032 and 033) evaluated HIV-infected patients receiving suppressive therapy (HIV RNA screening; stable regimen> 3 months) with lopinavir 200 mg (+) ritonavir 50 mg 2 tablets twice daily plus at least 2 nucleoside reverse transcriptase inhibitors and randomized 1: 1 to continue with lopinavir (+) ritonavir 2 tablets twice daily (n = 174 and n = 178, respectively) or replace lopinavir (+) ritonavir with raltegravir 400 mg twice per day (n = 174 and n = 176, respectively). Patients with a previous history of virologic failure were not excluded and the number of previous antiretroviral therapies was not limited.
These studies were concluded after the primary efficacy analysis at week 24 because they did not demonstrate non-inferiority of raltegravir to lopinavir (+) ritonavir. In both studies at week 24, suppression of HIV RNA at less than 50 copies / mL was maintained in 84.4% of patients in the raltegravir group compared with 90.6% of patients in the lopinavir (+) ritonavir group (using the Not completed = Failure approach). See section 4.4 regarding the need to administer raltegravir with two other active agents.
Treatment-naïve adult patients
STARTMRK (multicenter, randomized, double-blind, active-controlled study) evaluated the safety profile and antiretroviral activity of ISENTRESS 400 mg taken twice daily compared to treatment with efavirenz 600 mg taken at bedtime, in combination with emtricitabine (+) tenofovir, in treatment-naïve HIV-infected patients with HIV RNA> 5,000 copies / mL. Randomisation was stratified by HIV RNA levels (≤50,000 copies / mL; and> 50,000 copies / mL) and a hepatitis B or C test (positive or negative).
Patient demographics (gender, age and race) and baseline characteristics were comparable between the ISENTRESS 400 mg twice daily group and the efavirenz 600 mg at bedtime group.
Results of the analysis at 48 weeks and at 240 weeks
Compared to the primary efficacy endpoint, the proportion (%) of patients who achieved HIV RNA values
Table 3
Efficacy results at weeks 48 and 240
† Failure to complete is considered failure: Patients who discontinued treatment prematurely were considered to be failure accordingly. The percentage of patients who responded to therapy with a 95% confidence interval is reported.
‡ In the analysis for prognostic factors, the approach was applied in cases of virological failure carry-forward for baseline-carry-forward percentages.
Notes: The analysis is based on all available data.
ISENTRESS and efavirenz were administered with emtricitabine (+) tenofovir.
Pediatric population
Children and adolescents from 2 to 18 years of age
IMPAACT P1066 is a multicentre open-label phase I / II study to evaluate the pharmacokinetic profile, safety, tolerability and efficacy of raltegravir in HIV-infected children. 126 children and adolescents aged 2 to 18 were enrolled in this study. years of age with treatment experience. Patients were stratified by age, enrolling adolescents first and then younger children thereafter. Patients received either the 400 mg tablet formulation (6 to 18 years of age) or the chewable tablet formulation (2 to less than 12 years of age) Raltegravir was administered with an optimized background regimen.
The initial stage of dose finding it included intensive pharmacokinetic evaluation. Dose selection was based on achieving raltegravir plasma exposure and trough concentration similar to those seen in adults, and an acceptable short-term safety profile. Following dose selection, additional patients were enrolled for a long-term evaluation of safety, tolerability and efficacy Of the 126 patients, 96 received the recommended dose of ISENTRESS (see section 4.2).
Table 4
Baseline Characteristics and Efficacy Results at Weeks 24 and 48 from IMPAACT Study P1066 (2 to 18 years of age)
Infants and children from 4 weeks to less than 2 years of age
In the IMPAACT P1066 study, HIV-infected infants and children aged at least 4 weeks to less than 2 years of age who were previously treated with prophylactic antiretroviral therapy to prevent mother-to-child transmission (PMTCT) and / or as combination antiretroviral therapy for the treatment of HIV infection. Raltegravir was administered in the granules formulation for oral suspension, independent of food intake, in combination with an optimized background therapy that included lopinavir plus ritonavir in two thirds of the patients .
Table 5
Baseline Characteristics and Efficacy Results at Weeks 24 and 48 of IMPAACT P1066 (4 weeks to less than 2 years of age)
* One patient had a mutation in position 155.
The European Medicines Agency has deferred the obligation to submit the results of studies with ISENTRESS in one or more subsets of the pediatric population in human immunodeficiency virus infection (see section 4.2 for information on pediatric use).
05.2 Pharmacokinetic properties
Absorption
Raltegravir is rapidly absorbed, with a T of approximately 3 hours after a dose, as demonstrated in healthy volunteers who have taken single oral doses of raltegravir in the fasted state. The AUC and Cmax of raltegravir increase dose proportionally over a period of one range dose from 100 mg to 1,600 mg. The C12 h increases in proportion to the dose in the range of a range dose range from 100 mg to 800 mg, and increases slightly less than a dose proportional increase over the dose range from 100 mg to 1,600 mg. Dose proportionality has not been established in patients.
With a twice daily dose formulation, the equilibrium state of pharmacokinetics is achieved rapidly, within approximately the first 2 days of treatment. AUC and Cmax show little or no accumulation, while in C12 h there is little accumulation. The absolute bioavailability of raltegravir has not been established.
ISENTRESS can be taken with or without food. In the pilot efficacy and safety studies in HIV positive patients, raltegravir was given with or without food. Multiple dose administration of raltegravir following a moderately high fat meal did not alter AUC to any clinically relevant extent, with a 13% increase over fasted intake. The C12 h of raltegravir was 66% higher and the Cmax was 5% higher after a moderately high-fat meal than when taken in the fasted state. Administration of raltegravir after a high-fat meal increased the AUC and Cmax approximately 2-fold and increased C12 h by 4.1-fold. Administration of raltegravir after a low-fat meal reduced AUC and Cmax by 46% and 52%, respectively; C12h remained substantially unchanged. What appears is that food increases pharmacokinetic variability relative to fasting. .
Overall, considerable variability was observed in the pharmacokinetics of raltegravir. For the C12 h observed in BENCHMRK 1 and 2, the coefficient of variation (CV) for inter-individual variability is 212%, while the CV for intra-individual variability is 122%.Sources of variability may include differences in concomitant food and drug intake.
Distribution
Raltegravir is approximately 83% bound to human plasma proteins in a range of concentrations from 2 to 10 mcM.
Raltegravir easily crossed the placenta in the rat, but did not penetrate the brain in detectable quantities.
In two studies in HIV-1 infected patients receiving raltegravir 400 mg twice daily, raltegravir was readily detected in the cerebrospinal fluid. In the first study (n = 18), the median CSF concentration was 5.8% (range 1 to 53.5%) of the corresponding plasma concentration. In the second study (n = 16), the median CSF concentration was 3% (range 1 to 61%) of the corresponding plasma concentration. These median proportions are approximately 3 to 6 times lower than the free fraction of raltegravir in plasma.
Biotransformation and excretion
The apparent terminal half-life of raltegravir is approximately 9 hours with a shorter phase? Half-life (approximately 1 hour) accounting for most of the AUC. Following administration of an oral dose of radiolabelled raltegravir, approximately 51% and 32% of the dose was excreted in faeces and urine, respectively. Only raltegravir was present in faeces, most of which is probably derived from hydrolysis of raltegravir-glucuronide excreted in the bile, as observed in preclinical studies. Two components, identified as raltegravir and raltegravir-glucuronide, were detected in the urine in approximately 9% and 23% of the dose, respectively. The main circulating entity was raltegravir and it represented about 70% of the total radioactivity; the remaining radioactivity detected in plasma was represented by raltegravir-glucuronide. Studies using selective isoforms of chemical inhibitors and UDP-glucuronosyltransferase (UGT) expressed by cDNA show that UGT1A1 is the primary enzyme responsible for the formation of raltegravir-glucuronide. This indicates that the primary mechanism of raltegravir clearance in humans it is UGT1A1-mediated glucuronidation.
Polymorphism of UGT1A1
In a comparison of 30 subjects with * 28 / * 28 genotype vs 27 subjects with wild type genotype, the ratio of geometric means (90% CI) of AUC was 1.41 (0.96-2.09) and the ratio of geometric means of C12 h was 1.91 (1.43-2.55). A dose adjustment is not considered necessary in subjects with UGT1A1 activity due to genetic polymorphism.
Special populations
Pediatric population
Based on a formulation comparison study in healthy adult volunteers, the chewable tablet and granules for oral suspension have a higher oral bioavailability than the 400 mg tablet. In this study, administration of the chewable tablet with a high-fat meal resulted in an average 6% reduction in AUC, 62% reduction in Cmax, and 188% increase in C12h compared to dosing in the fasted state. Administration of the chewable tablet with a high-fat meal does not affect the pharmacokinetics of raltegravir in a clinically relevant manner and the chewable tablet can be administered regardless of food intake. The effect of food on the granules for oral suspension formulation has not been studied.
Table 6 shows the pharmacokinetic parameters for the 400 mg tablet, chewable tablet and granules for oral suspension based on body weight.
Table 6
IMPAACT P1066 pharmacokinetic parameters of raltegravirin following administration of the doses listed in section 4.2
The pharmacokinetics of raltegravir in infants less than 4 weeks old have not been established.
Senior citizens
There was no clinically significant effect of age on the pharmacokinetics of raltegravir in the range of age studied (19 - 71 years, with a limited number of subjects over the age of 65).
Gender, race and BMI
In adults, no clinically important pharmacokinetic differences attributable to gender, race or body mass index (BMI) were found.
Renal impairment
Renal clearance of the unchanged medicinal product represents a small part of the elimination route. In adults, there were no clinically relevant differences in pharmacokinetics between patients with severe renal impairment and healthy subjects (see section 4.2). As it is not known to what extent raltegravir can be dialysed, administration should be avoided prior to a dialysis session.
Hepatic impairment
Raltegravir is eliminated in the liver mainly by glucuronidation. In adults, there were no clinically relevant differences in pharmacokinetics between patients with moderate hepatic impairment and healthy subjects. The effect of severe hepatic impairment on raltegravir pharmacokinetics has not been studied (see sections 4.2 and 4.4).
05.3 Preclinical safety data
Non-clinical toxicology studies including conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, embryo-fetal toxicity and juvenile toxicity with raltegravir were performed in mice, rats, dogs and rabbits. Effects at exposure levels sufficiently in excess of clinical exposure levels do not indicate a particular risk to humans.
Mutagenicity
No evidence of mutagenicity and genotoxicity was observed in the microbial mutagenesis tests (Ames) in vitro, in alkaline elution tests in vitro for DNA breakdown, and in chromosomal aberration studies in vitro And in vivo.
Carcinogenicity
A carcinogenicity study of raltegravir in mice showed no carcinogenic potential. At the highest dose levels, 400 mg / kg / day in females and 250 mg / kg / day in males, the systemic exposure was similar to that of the clinical dose of 400 mg twice daily. In rats they were identified. tumors (squamous cell carcinoma) of the nose / nasopharynx with doses of 300 and 600 mg / kg / day in females and 300 mg / kg / day in males. These tumors could be due to deposition and / or aspiration of the drug to level of the mucous membrane of the nose / nasopharynx during gavage dose administration and subsequent chronic irritation and inflammation; they are likely to have little relevance in clinical use. Systemic exposure to NOAEL was similar to that of the clinical dose of 400 mg twice daily. Standard genotoxicity studies for the evaluation of mutagenicity and clastogenicity were negative.
Embryo-fetal toxicity
In embryo-fetal toxicity studies in rats and rabbits, raltegravir was not teratogenic. A slight increase in supernumerary ribs was observed in neonatal rats of mothers with exposures to raltegravir approximately 4.4 times the human exposure at 400 mg twice daily, calculated on the basis of an AUC0-24 h. No developmental effects were observed at exposures 3.4 times the human exposure achieved at 400 mg twice daily, calculated based on AUC0-24 h (see section 4.6). Similar data were not observed. observed in rabbits.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Inside of the tablet
• Microcrystalline cellulose
• Lactose monohydrate
• Anhydrous dibasic calcium phosphate
• Hypromellose 2208
• Poloxamer 407
• Sodium stearyl fumarate
• Magnesium stearate
Tablet coating
• Polyvinyl alcohol
• Titanium dioxide
• Polyethylene glycol 3350
• Talc
• Red iron oxide
• Black iron oxide
06.2 Incompatibility
Not relevant.
06.3 Period of validity
30 months
06.4 Special precautions for storage
This medicine does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package
High density polyethylene (HDPE) bottles with child resistant polypropylene closure.
Two pack sizes are available: 1 bottle of 60 tablets and 3 bottles of 60 tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions for disposal.
07.0 MARKETING AUTHORIZATION HOLDER
Merck Sharp & Dohme Limited
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
UK
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/07/436/001
EU / 1/07/436/002
038312017
038312029
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 20 December 2007
Date of most recent renewal: May 14, 2014
10.0 DATE OF REVISION OF THE TEXT
November 14, 2016