Active ingredients: Oseltamivir
Tamiflu 30 mg hard capsules
Tamiflu package inserts are available for pack sizes:- Tamiflu 30 mg hard capsules
- Tamiflu 45 mg hard capsules
- Tamiflu 75 mg hard capsules
- Tamiflu 6 mg / ml powder for oral suspension
- Tamiflu 12 mg / ml powder for oral suspension
Why is Tamiflu used? What is it for?
- Tamiflu is used in adults, adolescents, children and infants (including full term babies) to treat flu. It can be used when you have flu symptoms and the flu virus is circulating in the community.
- Tamiflu can also be prescribed to adults, adolescents, children and infants over 1 year of age on a case-by-case basis to prevent flu, for example if you have been in contact with someone who has the flu.
- Tamiflu can be prescribed to adults, adolescents, children and infants (including term infants) as preventive treatment in exceptional circumstances, for example if there is a "global flu epidemic (flu pandemic) and seasonal flu vaccine fails." to ensure sufficient protection.
Tamiflu contains oseltamivir, which belongs to a group of drugs called neuraminidase inhibitors. These drugs prevent the spread of the flu virus in the body and thus help relieve or prevent the symptoms of infection caused by the flu virus.
Flu is an infection caused by a virus. Symptoms of flu often include sudden fever (above 37.8 ° C), cough, runny or stuffy nose, headache, muscle aches and extreme tiredness. These symptoms can also be caused by other infections. The true infection flu occurs only during annual outbreaks when the flu virus spreads to the local community. Outside the epidemic period, flu-like symptoms are generally caused by a different type of illness.
Contraindications When Tamiflu should not be used
Do not take Tamiflu
- if you are allergic (hypersensitive) to oseltamivir or any of the other ingredients of Tamiflu listed in section 6.
Consult your doctor if this applies to you. Do not take Tamiflu.
Precautions for use What you need to know before taking Tamiflu
Before taking Tamiflu make sure your prescriber knows
- if you are allergic to other medicines
- if you have any kidney disease. In this case, a dose adjustment may be required
- if you have a serious health condition, which may require immediate hospitalization
- if the immune system is not working
- if you have heart disease or chronic respiratory disease.
During treatment with Tamiflu, tell your doctor immediately
- if you have noticed changes in behavior and mood (neuropsychiatric events), especially in children and adolescents. These may be symptoms of rare but serious side effects.
Tamiflu is not a flu shot
Tamiflu is not a vaccine: it treats infection or prevents the spread of the flu virus. A vaccine provides antibodies to the virus. Tamiflu does not alter the effectiveness of a flu vaccine, and your doctor may prescribe both.
Interactions Which drugs or foods can modify the effect of Tamiflu
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.
The following medicines are particularly important:
- chlorpropamide (used to treat diabetes)
- methotrexate (used to treat for example "rheumatoid arthritis)
- phenylbutazone (used to treat pain and inflammation)
- probenecid (used to treat gout).
Warnings It is important to know that:
Pregnancy and breastfeeding
Tell your doctor if you are pregnant, if you think you are pregnant or if you are trying to get pregnant so that your doctor can decide if Tamiflu is suitable for you.
Effects on breastfed infants are unknown. If you are breast-feeding tell your doctor so he can decide if Tamiflu is suitable for you.
Ask your doctor or pharmacist for advice before taking this medicine.
Driving and using machines
Tamiflu does not affect your ability to drive or use machines.
Dose, Method and Time of Administration How to use Tamiflu: Posology
Take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
Take Tamiflu as soon as possible, ideally within two days of starting flu symptoms.
Recommended doses
For the treatment of influenza, take two doses a day. It is usually practical to take one dose in the morning and one in the evening.It is important that you complete the full 5 day cycle, even if you quickly start to feel better.
For the prevention of flu or after contact with an infected person, take one dose a day for 10 days. It is best to take this dose in the morning with breakfast.
In special situations, such as widespread flu or for patients with weak immune systems, treatment will continue for up to 6 or 12 weeks.
The recommended dose depends on the patient's body weight. You should use the amount of capsules or oral suspension prescribed by your doctor.
Adults and adolescents from 13 years of age
75 mg can be made up of one 30 mg capsule plus one 45 mg capsule.
Children from 1 to 12 years
75 mg can be made up of one 30 mg capsule plus one 45 mg capsule.
Infants under 1 year of age (0 - 12 months)
The administration of Tamiflu to infants less than 1 year of age for the prevention of influenza in the event of a pandemic influenza should be based on the judgment of the physician after considering the relationship between the potential benefit and the potential risk to the child.
mg per kg = mg for each kilogram of the child's body weight. For example: if a 6 month old baby weighs 8 kg the dose is 8 kg x 3 mg per kg = 24 mg
Method of administration
Swallow the capsules whole with water. Do not break or chew the capsules.
Tamiflu can be taken with or without food, although taking it with food can reduce the chance of feeling or being sick (nausea or vomiting).
People who have difficulty swallowing the capsules can use the liquid preparation, Tamiflu oral suspension. If you need Tamiflu oral suspension but it is not available in the pharmacy, you can make Tamiflu solution from capsules. For instructions, see the page Preparing Tamiflu in liquid form at home.
Overdose What to do if you have taken too much Tamiflu
If you take more Tamiflu than you should
Stop taking Tamiflu and consult your doctor or pharmacist immediately. In most cases of overdose people did not report any side effects. When side effects were reported, they were similar to those seen with normal doses as indicated. in paragraph 4.
Cases of overdose have been reported more frequently when Tamiflu was administered to children than adults and adolescents. Care must be taken when preparing Tamiflu solution for children and when administering Tamiflu capsules or Tamiflu suspension to children.
If you forget to take Tamiflu
Do not take a double dose to make up for a forgotten capsule.
If you stop taking Tamiflu
There are no side effects when Tamiflu administration is stopped. If Tamiflu is stopped earlier than your doctor told you, your flu symptoms may return. Always complete the therapy your doctor has prescribed for you.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Tamiflu
Like all medicines, this medicine can cause side effects, although not everybody gets them. Many of the side effects listed below can also be caused by the flu.
The following serious side effects have rarely been reported since oseltamivir went on the market:
- Anaphylactic or anaphylactoid reactions: severe allergic reactions with swelling of the face and skin, itchy skin rashes, low blood pressure and difficulty breathing;
- Liver disorders (fulminant hepatitis, liver function disorders and jaundice): yellowing of the skin and whites of the eye, change in stool color, changes in behavior;
- Angioneurotic edema: sudden onset of severe swelling of the skin especially around the head and neck, including the eyes and tongue, with difficulty breathing
- Stevens-Johnson syndrome and toxic epidermal necrolysis: complicated allergic reaction, which can lead to death, manifested by severe inflammation of the skin and internal mucous membranes initially accompanied by fever, sore throat, feeling of fatigue, rashes and consequent blistering, peeling of the skin with large areas of dermoepidermal detachment, possible difficulty in breathing and low blood pressure;
- Gastrointestinal bleeding: prolonged bleeding from the large intestine or expulsion of blood from the mouth;
- Neuro-psychiatric disorders, as described below.
If you notice any of these symptoms, ask your doctor for help immediately.
The most frequently reported (very common and common) side effects with Tamiflu are feeling sick or unwell (nausea, vomiting), stomach pain, stomach upset, headache and pain. These side effects mostly appear after the first dose of the drug and generally disappear with continued treatment. The frequency of these effects is reduced if the drug is taken with food.
Rare but serious effects: seek medical attention immediately
(may affect up to 1 in 1,000 people)
Rare events have been reported during treatment with Tamiflu including
- convulsions and delirium including altered level of consciousness
- confusion, abnormal behavior
- delirium, hallucinations, agitation, anxiety, nightmares
These events were mainly reported among children and adolescents and often came on suddenly and resolved quickly. Few cases have degenerated into self-harm (instinct to harm oneself) which in some cases has led to death. Such neuropsychiatric events have also been reported in patients with influenza who had not taken Tamiflu.
- Patients, particularly children and adolescents, should be carefully monitored for the behavioral changes described above.
If you notice any of these symptoms, particularly in younger patients, seek immediate medical attention.
Adults and adolescents from 13 years of age
Very common side effects:
(may affect more than 1 in 10 people)
- Headache
- Nausea.
Common side effects
(may affect up to 1 in 10 people)
- Bronchitis
- Cold sores
- Cough
- Dizziness
- Fever
- Ache
- Pain in the limbs
- A runny nose
- Sleep disorders
- Sore throat
- Stomach ache
- Fatigue
- Feeling of fullness in the upper abdominal tract
- Upper respiratory tract infections (inflammation of the nose, throat and nasal passages)
- Upset stomach
- He retched.
Uncommon side effects
(May affect up to 1 in 100 people)
- Allergic reactions
- Altered level of consciousness
- Convulsions
- Heart rhythm abnormality
- Mild to severe liver function abnormalities
- Skin reactions (inflammation of the skin, red and itchy rash, peeling of the skin).
Rare side effects:
(may affect up to 1 in 1,000 people)
- Thrombocytopenia (low platelet count)
- visual disturbances.
Children between the ages of 1 and 12
Very common side effects
(may affect more than 1 in 10 people)
- Cough
- Nasal congestion
- He retched.
Common side effects
(may affect up to 1 in 10 people)
- Conjunctivitis (red eyes and eye discharge or pain)
- Ear inflammation and other ear disorders
- Headache
- Nausea
- A runny nose
- Stomach ache
- Feeling of fullness in the upper abdominal tract
- Upset stomach.
Uncommon side effects
(may affect up to 1 in 100 people)
- Inflammation of the skin
- Disorders of the eardrum.
Infants under 1 year of age
The side effects reported in infants 0 to 12 months of age are mostly similar to the side effects reported for older children (1 year and older). Diarrhea and diaper rash have also been reported.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. Furthermore,
- if you or the child get sick often, or
- if the flu symptoms get worse or if the fever persists
tell your doctor as soon as possible.
Reporting of side effects
If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and blister after EXP / EXP. The expiry date refers to the last day of the month.
Do not store above 25 ° C.
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.
What Tamiflu contains
- Each hard capsule contains the equivalent of 30 mg of oseltamivir.
- The excipients are:
capsule contents: pregelatinised starch, talc, povidone, croscarmellose sodium and sodium stearyl fumarate
capsule shell: gelatin, yellow iron oxide (E172), red iron oxide (E172) and titanium dioxide (E171)
printing ink: shellac (E904), titanium dioxide (E171) and FD and C Blue 2 (indigo carmine E132).
Description of Tamiflu appearance and contents of the pack
The 30 mg hard capsule consists of a light yellow opaque body marked "ROCHE" and a light yellow opaque cap marked "30 mg". The inscriptions are in blue.
Tamiflu 30 mg hard capsules are available in blister packs of 10.
Information for the user
For people who have difficulty swallowing capsules, including very young children, the liquid preparation, Tamiflu oral suspension, is available.
If you need the liquid preparation, but it is not available, you can use an oral suspension prepared in a pharmacy from Tamiflu capsules (see Information for healthcare professionals). Liquid pharmacy preparation is the preferred option.
If the liquid preparation prepared in the pharmacy is also not available, you can prepare Tamiflu in liquid form at home from these capsules.
The dose is the same for the treatment and prevention of influenza. The difference is in the frequency of administration.
Preparation of Tamiflu in liquid form at home
- If you have the correct capsules available, for the required strength (one 30 mg or 60 mg dose), open the capsule and mix its contents with one teaspoon (or less) of a suitable sweet food. This procedure is usually suitable for children over 1 year of age. See the top of the instructions.
- If you need a lower dose, preparing Tamiflu in liquid form from capsules requires further steps. This procedure is suitable for younger children and infants, who usually need less than 30 mg of Tamiflu. See the bottom of the instructions.
Children from 1 to 12 years
To prepare a 30 mg or 60 mg dose, you will need:
- One or two capsules of Tamiflu of 30 mg
- Sharp scissors
- A small bowl
- Teaspoon (5ml teaspoon)
- Waterfall
- A sweet food to hide the bitter taste of the powder.
For example: chocolate or cherry syrup and dessert toppings, such as caramel or caramel sauce. Or you can make some sugar water by mixing a teaspoon of water with three quarters (3/4) of a teaspoon of sugar.
Step 1: Check that the dose is correct
To determine the correct amount of medicine to use, look for the patient's weight in the left column of the table.
Look in the right column for the number of capsules to be administered to the patient for each dose. The amount is the same for both treatment and prevention of influenza.
30 mg dose Roche 30 mg
60 mg dose Roche 30 mg Roche 30 mg
You should use the 30 mg capsules only for the 30 mg and 60 mg doses. Do not try to prepare a 45 mg or 75 mg dose using the contents of the 30 mg capsules. Instead, use the capsules of the appropriate strength.
Step 2: Pour all the powder into a bowl
Hold the 30 mg capsule vertically over a bowl and carefully cut off the rounded end with scissors.
Pour all the powder into the bowl.
Open a second capsule for a 60 mg dose. Pour all the powder into the bowl. Be careful with the dust, as it can irritate the skin and eyes.
Step 3: Soften the powder and administer it to the patient
Add a small amount - no more than one teaspoon - of the sweetened powdered food to the bowl.
This hides the bitter taste of Tamiflu powder.
Mix the mixture well.
Give the patient the entire contents of the bowl immediately.
If some of the mixture remains in the bowl, rinse the bowl with a small amount of water and give all of the contents to the patient to drink.
Repeat this procedure each time you need to administer the drug.
Children under the age of 1 year
To prepare a smaller single dose, you will need:
- One 30 mg Tamiflu capsule
- Sharp scissors
- Two small bowls (use a different pair of bowls for each child)
- A large oral dispenser for dosing water - a 5 or 10 ml dispenser
- A small oral dispenser that allows the measurement of 0.1 ml, to give the dose
- Teaspoon (5ml teaspoon)
- Waterfall
- Sweet foods to hide the bitter taste of Tamiflu.
For example: chocolate or cherry syrup and dessert toppings, such as caramel or caramel sauce.
Or you can make some sugar water by mixing a teaspoon of water with three quarters (3/4) of a teaspoon of pumpkins.
Step 1: Pour all the powder into a bowl
Hold a 30 mg capsule vertically over one of the bowls and carefully cut off the rounded end with scissors. Beware of dust: it can irritate the skin and eyes.
Pour all the powder into the bowl, whatever the dose you are preparing.
The amount is the same whether you are treating or preventing the flu.
Step 2: Add water to dilute the medicine
Use the larger dispenser to draw 5 ml of water.
Add the water to the powder in the bowl.
Stir the mixture with a teaspoon for about 2 minutes.
Don't worry if all the dust doesn't dissolve. The non-dissolving powder consists of excipients only.
Step 3: Choose the correct amount based on the weight of the child
Look for the weight on the left side of the table.
The column to the right of the table shows the amount of liquid mixture that will need to be drawn with an oral syringe.
Infants less than 1 year of age (including full term infants)
Step 4: Aspirate the liquid mixture
Make sure you have the right size dispenser (oral syringe)
Draw the correct amount of liquid mixture from the first bowl.
Aspirate upwards being careful not to include air bubbles.
Gently pour the correct dose into the second bowl.
Step 5: Sweeten and give it to the baby
Add a small amount - no more than one teaspoon - of the sweetened food to the second bowl.
This hides the bitter taste of the Tamiflu suspension.
Mix the sweetened food and Tamiflu liquid form well.
Immediately give the entire contents of the second bowl (food sweetened with Tamiflu liquid mixture) to the child.
If any residue remains in the second bowl, rinse the bowl with a small amount of water and give the child all of the contents to drink. For children who are unable to drink from the bowl, use a teaspoon or bottle to give the child the remaining liquid mixture.
Give the child something to drink.
Throw away any unused liquid left in the first bowl.
Repeat this step each time you need to administer the drug.
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
TAMIFLU 30 MG HARD CAPSULES
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each hard capsule contains oseltamivir phosphate equivalent to 30 mg of oseltamivir.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Hard capsule (capsule).
The hard capsule consists of a light yellow opaque body marked "ROCHE" and a light yellow opaque cap marked "30 mg". The inscriptions are in blue.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Treatment of the flu
Tamiflu is indicated in adults and children, including full-term infants, who exhibit typical flu symptoms when the flu virus is circulating in the community. Treatment was effective when started within two days of the first symptoms appearing.
Prevention of the flu
• Post-exposure prevention in individuals 1 year of age or older after contact with a clinically diagnosed case of influenza when the influenza virus is circulating in the community.
• The appropriate use of Tamiflu for the prevention of influenza should be defined on a case-by-case basis based on the circumstances and population in need of protection. In exceptional conditions (for example, in the event of a discrepancy between the circulating viral strain and that present in the vaccine, and in the presence of a pandemic), seasonal prevention may be considered in individuals aged 1 year or older.
• Tamiflu is indicated for the post-exposure prevention of influenza in infants below 1 year of age during an influenza pandemic (see section 5.2).
Tamiflu is not a substitute for the flu shot.
The use of antivirals for the treatment and prevention of influenza should be based on official recommendations. Decisions regarding the use of oseltamivir for treatment and prophylaxis must take into account what is known about the characteristics of circulating influenza viruses, the information available on drug susceptibility patterns for each season and the impact of the disease in different areas. geographical areas and in various patient populations (see section 5.1).
04.2 Posology and method of administration
Dosage
Tamiflu hard capsules and Tamiflu oral suspension are bioequivalent formulations. Doses of 75 mg can be administered in the following ways:
• with a 75 mg capsule or
• with one 30 mg capsule plus one 45 mg capsule or
• with a 30 mg dose of oral suspension plus a 45 mg dose of oral suspension.
Tamiflu powder for oral suspension (6 mg / ml) ready for use is the preferred formulation for pediatric and adult patients who have difficulty swallowing capsules or where lower doses are required.
Adults and adolescents from 13 years of age
Treatment : The recommended oral dose of oseltamivir is 75 mg twice daily for 5 days for adolescents (13 to 17 years of age) and adults.
Treatment should be started as soon as possible, within the first two days after the onset of flu symptoms.
Post-exposure prevention : The recommended dose for the prevention of influenza after close contact with an infected individual is 75 mg oseltamivir once daily for 10 days for adolescents (13 to 17 years of age) and adults.
Treatment should begin as soon as possible, within two days of exposure to an infected individual.
Prevention during a "community flu epidemic:" The recommended dose for preventing influenza during a community outbreak is 75 mg oseltamivir once daily for up to 6 weeks.
Pediatric population
Children between the ages of 1 and 12
Tamiflu 30 mg, 45 mg and 75 mg capsules and oral suspension are available for children aged 1 year and over.
Treatment : The following weight-related dosing regimens are recommended for the treatment of children 1 year of age and older:
Treatment should be started as soon as possible, within the first two days after the onset of flu symptoms.
Post-exposure prevention : The recommended dose of Tamiflu for post-exposure prevention is:
Prevention during a "community flu" epidemic: prevention during a flu outbreak has not been studied in children under 12 years of age.
Infants aged between 0 and 12 months
Treatment : The recommended dose for infants aged 0 to 12 months is 3 mg / kg twice daily. This is based on pharmacokinetic and safety data indicating that this dose in infants aged 0 to 12 months produces plasma concentrations of pro-drug and active metabolite that are expected to be clinically effective, with a safety profile comparable to that of that observed in older children and adults (see section 5.2). The following dosage regimen is recommended for the treatment of infants aged 0 to 12 months:
* This table is not intended to be inclusive of every possible body weight of this population. For all patients less than 1 year of age, the 3 mg / kg dose should be used regardless of the patient's weight.
Treatment should be started as soon as possible, within the first two days after the onset of flu symptoms.
This dosing recommendation is not applicable to premature babies, ie those with a post-conception age of less than 36 weeks. Insufficient data are available for these patients, in whom a different dosage may be required due to immaturity of physiological functions.
Post-exposure prevention : The recommended dose for influenza pandemic prophylaxis of infants less than 1 year of age is half the daily treatment dose. This is based on clinical data from children 1 year of age and older and adults showing that a prophylactic dose equivalent to half the daily treatment dose is clinically effective for the prevention of influenza. The following is recommended. Age-related dosing regimen for the prophylaxis of infants aged 0-12 months:
This dosing recommendation is not applicable to premature babies, ie those with a post-conception age of less than 36 weeks. Insufficient data are available for these patients, in whom a different dosage may be required due to immaturity of physiological functions.
Prevention during a "community flu epidemic:" prevention during a flu outbreak has not been studied in children aged 0 to 12 months.
For instructions on preparing the extemporaneous formulation, see section 6.6.
Special populations
Hepatic insufficiency
No dosage adjustment is required for patients with hepatic dysfunction for either treatment or prevention. No studies have been performed in pediatric patients with hepatic impairment.
Kidney failure
Treatment of the flu : Dosage modification is recommended for adults and adolescents (13 to 17 years of age) with moderate or severe renal impairment. Recommended dosages are detailed in the table below.
* Data from studies in patients undergoing continuous ambulatory peritoneal dialysis (CAPD); when using automated peritoneal dialysis (APD), a higher clearance of oseltamivir carboxylate is possible. If the nephrologist deems it necessary, the treatment modality can be changed from APD to CAPD.
Prevention of the flu : Dosage modification is recommended for adults and adolescents (13 to 17 years of age) with moderate or severe renal impairment as detailed in the table below.
* Data from studies in patients undergoing continuous ambulatory peritoneal dialysis (CAPD); when using automated peritoneal dialysis (APD), a higher clearance of oseltamivir carboxylate is possible. If the nephrologist deems it necessary, the treatment modality can be changed from APD to CAPD.
There is insufficient clinical data in infants and children (12 years of age and younger) with renal impairment to be able to make dosing recommendations.
Senior citizens
No dosage adjustment is required unless there is evidence of moderate or severe renal insufficiency.
Immunocompromised patients
A longer duration of seasonal prophylaxis up to 12 weeks in immunocompromised patients has been evaluated (see sections 4.4, 4.8 and 5.1).
Method of administration
Oral use.
Patients who are unable to swallow capsules can take appropriate doses of Tamiflu oral suspension.
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
Oseltamivir is only effective against diseases caused by the influenza virus. There is no evidence of the efficacy of oseltamivir in diseases caused by agents other than influenza viruses (see section 5.1).
Tamiflu is not a substitute for the flu shot. The use of Tamiflu should not change the assessment of individuals regarding the annual flu vaccination. Protection from the flu remains only as long as Tamiflu is administered. Tamiflu should be used for the treatment and prevention of influenza only when reliable epidemiological data indicate that the influenza virus is circulating in the community.
The susceptibility of circulating influenza virus strains to oseltamivir has been shown to be highly variable (see section 5.1). Therefore, prescribers should consider the most recent information available on oseltamivir susceptibility patterns of circulating viruses at that time. in order to decide on the appropriate use of Tamiflu.
Concomitant severe medical condition
No information is available regarding the safety and efficacy of oseltamivir in patients with a medical condition severe enough or unstable to be considered to be at imminent risk of hospitalization.
Immunocompromised patients
The efficacy of oseltamivir for both treatment and prophylaxis of influenza has not been clearly established in immunocompromised patients (see section 5.1).
Heart disease / lung disease
The efficacy of oseltamivir in the treatment of subjects with chronic heart and / or lung disease has not been established. No difference in the incidence of complications was observed between the treatment group and the placebo group in this patient population (see section 5.1).
Pediatric population
No data are currently available to allow a dose recommendation for preterm infants (post-conception age
Severe renal insufficiency
Dosage modification is recommended for both treatment and prevention in adolescents (13 to 17 years of age) and in adults with severe renal impairment. Insufficient clinical data in infants and children (1 year of age and older) with renal impairment are available to make dosing recommendations (see sections 4.2 and 5.2).
Neuropsychiatric events
Neuropsychiatric events have been reported during treatment with Tamiflu in patients with influenza, particularly in children and adolescents. These events also occurred in influenza patients not treated with oseltamivir. Patients should be carefully monitored for mood changes and the benefits and risks of continuing treatment should be carefully weighed for each patient (see section 4.8).
04.5 Interactions with other medicinal products and other forms of interaction
The pharmacokinetic properties of oseltamivir, such as low protein binding and metabolism independent of CYP450 and glucuronidase systems (see section 5.2), indicate that clinically significant drug interactions via these mechanisms are unlikely.
Probenecid
No dosage adjustment is required during co-administration of probenecid in patients with normal renal function. Co-administration of probenecid, a potent inhibitor of the anion pathway of renal tubular secretion, increases exposure to the active metabolite of oseltamivir approximately 2-fold.
Amoxicillin
Oseltamivir has no kinetic interactions with amoxicillin, which is eliminated by the same route, suggesting that oseltamivir's interaction with this route is weak.
Renal elimination
Clinically significant interactions between drugs that compete for renal tubular secretion are unlikely due to the known safety margin of most of these substances, due to the elimination characteristics of the active metabolite (glomerular filtration and anionic tubular secretion) and the ability to excrete. However, caution should be exercised when administering oseltamivir to subjects taking molecules with a narrow therapeutic range excreted by the same route (eg chlorpropamide, methotrexate, phenylbutazone).
Additional information
No pharmacokinetic interactions were observed between oseltamivir, or its major metabolite, when administered concomitantly with paracetamol, acetylsalicylic acid, cimetidine, antacids (magnesium and aluminum hydroxides, and calcium carbonates), rimantadine or warfarin (in stable subjects with warfarin and without influence).
04.6 Pregnancy and lactation
Pregnancy
Although controlled clinical studies on the use of oseltamivir in pregnant women have not been conducted, there are data on use in pregnancy from post-marketing and observational studies (see section 5.1 "Treatment of influenza in pregnant women"; for data on exposure in pregnant women see section 5.2).
These data, when combined with animal studies, do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal / fetal or postnatal development (see section 5.3). Pregnant women can be treated with Tamiflu after considering the available safety information, the pathogenicity of the circulating influenza virus strain and the underlying condition of the pregnant woman.
Feeding time
In lactating female rats, oseltamivir and the active metabolite are excreted in breast milk. Very limited information is available regarding breastfed infants of mothers who received oseltamivir and the excretion of oseltamivir in breast milk. The limited data available demonstrated that oseltamivir and the active metabolite were detected in breast milk, but the levels were low enough to result in a sub-therapeutic dosage in the infant. Taking into account this information, the pathogenicity of the circulating influenza virus strain and the underlying condition of the lactating woman, administration of oseltamivir may be considered if any clear potential benefits for nursing mothers.
Fertility
Based on preclinical data there was no evidence of effects of Tamiflu on male or female fertility (see section 5.3).
04.7 Effects on ability to drive and use machines
Tamiflu does not affect the ability to drive or use machines.
04.8 Undesirable effects
Summary of the safety profile
The overall safety profile of Tamiflu is based on data from 6049 adult / adolescent patients and 1473 pediatric patients treated with Tamiflu or placebo for influenza, and on data from 3990 adult / adolescent patients and 253 pediatric patients. treated with Tamiflu or placebo / no treatment for influenza prophylaxis in clinical trials. In addition, 475 immunocompromised patients (including 18 children, of these 10 treated with Tamiflu and 8 with placebo) received Tamiflu or placebo for the flu prophylaxis.
In adults / adolescents the most frequently reported adverse reactions were nausea and vomiting in the treatment studies, and nausea in the prevention studies. Most of these adverse reactions were reported on a single occasion on the first or second day of treatment and resolved spontaneously within 1 or 2 days. In children, the most frequently reported adverse reaction was vomiting. For the majority of patients, the occurrence of these adverse reactions did not lead to discontinuation of Tamiflu therapy.
The following serious adverse reactions have been reported rarely since oseltamivir was marketed: anaphylactic or anaphylactoid reactions, liver disease (fulminant hepatitis, liver function disorders and jaundice), angioneurotic edema, Stevens-Johnson syndrome and toxic epidermal necrolysis, gastrointestinal bleeding and neuropsychiatric disorders (for neuropsychiatric disorders see section 4.4).
Tabular list of adverse reactions
Adverse reactions listed in the table below fall into the following frequency categories: very common (≥ 1/10), common (from ≥ 1/100 to), uncommon (from ≥ 1/1.000 to ), rare (from ≥ 1/10.000 to ) and very rare (). Adverse reactions were placed in the appropriate category in the tables based on the pooled data analysis conducted on clinical trials.
Treatment and prevention of influenza in adults and adolescents:
In treatment and prevention studies in adults / adolescents, adverse reactions reported most frequently with the recommended dose (75 mg twice daily for 5 days of treatment and 75 mg once daily for up to 6 weeks for prophylaxis) are listed in Table 1.
The safety profile reported in subjects who were treated with the recommended dose of Tamiflu for prophylaxis (75 mg once daily for up to 6 weeks) was qualitatively similar to that observed in the treatment studies, despite the prophylaxis studies. the dose had been administered for a longer period of time.
Table 1 Adverse reactions in studies with Tamiflu in the treatment and prevention of influenza in adults and adolescents or from post-marketing reports
Treatment and prevention of influenza in children:
A total of 1473 children (including healthy children aged 1-12 years and asthmatic children aged 6-12 years) were enrolled in clinical trials with oseltamivir administered for the treatment of influenza. Of these, 851 children were treated with oseltamivir suspension. A total of 158 children received the recommended dose of Tamiflu once daily in a post-exposure prophylaxis study within households (n = 99), in a seasonal study of 6-week prophylaxis (n = 49) and in a 12-week seasonal prophylaxis study in immunocompromised pediatric subjects (n = 10).
Table 2 shows the most frequently reported adverse reactions in clinical trials in the pediatric population.
Table 2 Adverse reactions in studies with Tamiflu for the treatment and prevention of influenza in children (dosing based on age / body weight ratio [30 mg to 75 mg once daily])
Description of a selection of adverse reactions
Psychiatric disorders and pathologies of the nervous system
The flu can be associated with a variety of neurological and behavioral symptoms which can include events such as hallucinations, delirium and abnormal behavior, in some cases with a fatal outcome. These events can occur in the context of encephalitis or encephalopathy but without a disease severe evident.
In patients with influenza who received Tamiflu there have been post-marketing reports of seizures and delirium (including symptoms such as altered level of consciousness, confusion, abnormal behavior, delirium, hallucinations, agitation, anxiety, nightmares), which in rare cases resulted in self-harm or fatal outcome. These events were reported mainly among pediatric and adolescent patients and often had a "sudden onset and rapid resolution. The contribution of Tamiflu to the occurrence of these events is not known. These neuropsychiatric events have also been reported in patients with influenza which they had not taken Tamiflu.
Hepatobiliary disorders
Disorders of the hepatobiliary system, including hepatitis and elevated liver enzymes in patients with flu-like illness. These cases include fatal fulminant hepatitis / liver failure.
Other special populations
Pediatric population (infants less than 1 year of age)
In two studies to characterize the pharmacokinetic, pharmacodynamic and safety profile of oseltamivir-based therapy in 135 infants less than 1 year of age with influenza infection, the safety profile was similar between age cohorts, with vomiting, diarrhea. and diaper rash as the most frequently reported adverse events (see section 5.2). For infants less than 36 weeks of post-conception age, the available data are insufficient.
Available information on the safety of oseltamivir administered for the treatment of influenza in infants less than 1 year of age, from prospective and retrospective observational studies (collectively more than 2,400 infants of this age group), from epidemiological database searches and from post-marketing reports, suggest that the safety profile in infants aged less than 1 year is comparable with the safety profile established in infants aged 1 year or older.
Elderly patients and patients with chronic heart disease and / or chronic respiratory disease
The population included in the influenza treatment studies included healthy adults / adolescents and 'at risk' patients (patients at increased risk of developing influenza-associated complications, e.g. elderly patients and patients with heart or respiratory disease chronic). Overall, the safety profile in "at risk" patients was qualitatively similar to that observed in healthy adult / adolescent patients.
Immunocompromised patients
In a 12-week prophylaxis study involving 475 immunocompromised patients, including 18 children aged 1 to 12 years and older, the safety profile in the 238 patients treated with oseltamivir was similar to that previously observed in the clinical trials for Tamiflu prophylaxis.
Children with pre-existing bronchial asthma
In general, the adverse reaction profile in children with pre-existing bronchial asthma was qualitatively similar to that of healthy children.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address http://www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
Reports of overdose with Tamiflu have been collected in clinical trials and during post-marketing experience. In the majority of reported overdose cases, no adverse events were reported.
Adverse events reported following overdose were similar in nature and distribution to those observed at therapeutic doses of Tamiflu described in section 4.8 "Undesirable effects".
No specific antidote is known.
Pediatric population
Cases of overdose have been reported more frequently in children than in adults and adolescents. Care should be taken when preparing Tamiflu oral suspension and when administering Tamiflu to children.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antivirals for systemic use, neuraminidase inhibitors, ATC code: J05AH02
Oseltamivir phosphate is a pro-drug of the active metabolite (oseltamivir carboxylate). The active metabolite is a selective inhibitor of influenza virus neuraminidase enzymes, which are glycoproteins present on the virion's surface. The activity of the viral neuraminidase enzyme is important both for virus penetration into uninfected cells and for release from infected cells of recently formed viral particles and for the subsequent spread of the infectious virus in the organism.
Oseltamivir carboxylate inhibits in vitro influenza A and B virus neuraminidases. Oseltamivir inhibits phosphate in vitro Infection and replication of the influenza virus. Oseltamivir administered orally inhibits in vivo the replication and pathogenicity of influenza A and B viruses in animal models of influenza infection at antiviral concentrations similar to those achieved in humans with 75 mg twice daily.
The antiviral activity of oseltamivir against influenza A and B is supported by experimental challenge studies in healthy volunteers.
The values of the IC50 of the neuraminidase enzyme for oseltamivir were between 0.1 nM and 1.3 nM for the clinically isolated influenza A virus and equal to 2.6 nM for the influenza B virus. Higher IC50s for influenza B virus, up to a median of 8.5 nM, were observed in published studies.
Clinical studies
Treatment of influenza infection
The indication is based on clinical studies conducted on naturally transmitted influenza cases, mainly influenza A infections.
Oseltamivir is only effective against diseases caused by the influenza virus. Statistical analyzes are therefore presented only in reference to individuals infected with the influenza virus. Across the population treated in the studies, which includes both influenza positive and ITT negative (intention to treat) subjects, primary efficacy was reduced in proportion to the number of influenza negative individuals. In the overall population treated, influenza infection was confirmed in 67% (range: 46% -74%) of the recruited patients. 64% of elderly patients were positive for influenza and 62% of those with heart disease and / or chronic respiratory was positive for influenza. In all phase III treatment studies, patients were recruited only during periods when influenza was circulating in the local community.
Adults and adolescents aged 13 years or older : To be eligible, patients had to present within 36 hours of symptom onset, with fever ≥ 37.8 ° C associated with at least one respiratory symptom (cough, nasal symptoms, or sore throat) and at least one systemic symptom (myalgia (chills / sweating, general malaise, fatigue or headache). In the pooled analysis of all influenza-positive adults and adolescents (n = 2413) enrolled in the treatment studies, oseltamivir 75 mg twice daily for 5 days reduced the median duration of influenza illness of approximately one day, from 5.2 days (95% CI: 4.9-5.5 days) in the placebo group to 4.2 days (95% CI: 4.0 -4.4 days; p ≤ 0.0001).
The percentage of subjects who developed specific complications affecting the lower respiratory tract (mainly bronchitis) treated with antibiotics decreased from 12.7% (135/1063) in the placebo group to 8.6% (116/1350) in the population treated with oseltamivir (p = 0.0012).
Treatment of influenza in high-risk populations : in elderly subjects (≥ 65 years) and in subjects with chronic heart and / or respiratory disease who received oseltamivir 75 mg twice daily for 5 days the median duration of influenza illness Not has shrunk significantly. In the oseltamivir groups the total duration of fever was reduced by one day. In influenza-positive elderly oseltamivir significantly reduced the incidence of specific lower airway complications (mainly bronchitis) treated with antibiotics from 19% (52/268) in the placebo group to 12% (29/250) in the population. treated with oseltamivir (p = 0.0156).
In influenza positive patients with chronic heart and / or respiratory diseases the joint incidence of lower airway complications (mainly bronchitis) treated with antibiotics was 17% (22/133) in the placebo group and 14% ( 16/118) in the oseltamivir-treated population (p = 0.5976).
Treatment of influenza in pregnant women : No controlled clinical studies have been conducted on the use of oseltamivir in pregnant women, however evidence from post-marketing and retrospective observational studies shows benefit of the current dosing regimen in this patient population in terms of lower morbidity / mortality. Results from pharmacokinetic analyzes indicate low exposure to the active metabolite, however no dose adjustments are recommended for pregnant women under treatment or prophylaxis for influenza (see section 5.2, Pharmacokinetic Properties, Special Populations).
Treatment of Influenza in Children : in a study of otherwise healthy children (65% flu positive) aged 1 to 12 years (mean age 5.3 years) who had fever (≥ 37.8 ° C) plus cough or nasal congestion, 67% of the flu-positive patients were infected with the influenza A virus and 33% with the influenza B virus.Treatment with oseltamivir, initiated within 48 hours of symptom onset, significantly reduced the time to resolution of the disease (defined as simultaneous return to normal health and activity and relief of fever, cough and nasal congestion) by 1, 5 days (95% CI: 0.6-2.2 days; mean acute p otitis from 26.5% (53/200) in the placebo group to 16% (29/183) in children treated with oseltamivir (p = 0.013).
A second study was completed in 334 asthmatic children aged 6 to 12 years, 53.6% of whom positive for influenza. In the oseltamivir group, the median duration of disease Not has shrunk significantly. In this population, on day 6 (last day of treatment) the forced expiratory volume in the first second (FEV1) was increased by 10.8% in the oseltamivir group compared to 4.7% in the placebo group (p = 0.0148).
The European Medicines Agency has deferred the obligation to submit the results of studies with Tamiflu in one or more subsets of the pediatric population for influenza (see section 4.2 for information on pediatric use).
The indication in infants less than 1 year of age is based on extrapolation of efficacy data from older children, while the recommended posology is based on data from the pharmacokinetic model (see section 5.2).
Treatment of influenza B infection : Overall, 15% of the influenza-positive population was infected with influenza B, with percentages ranging from 1 to 33% in individual studies. The median duration of illness in subjects with influenza B infection showed no significant differences between the treatment groups in the individual studies. Data from 504 influenza B infected subjects from all studies were pooled for the analysis. Compared to placebo, oseltamivir reduced by 0.7 days (95% CI: 0.1-1.6 days; p = 0.022) the time to alleviation of all symptoms is one day (95% CI: 0.4-1.7 days; p
Prevention of the flu
The efficacy of oseltamivir in the prevention of naturally transmitted influenza disease was demonstrated in a study on post-exposure prevention within households and in two studies on seasonal prevention. In all these studies, the main measure of effectiveness was the incidence of laboratory-confirmed cases of influenza. The virulence of influenza outbreaks is unpredictable and varies within a region and from season to season, hence the number of subjects to treat (Number Needed to Treat, NNT) to prevent a case of influenza illness is variable.
Post-exposure prevention : During one study, individuals (12.6% vaccinated against influenza) in contact with a subject with suspected influenza (index case) were given a 75 mg dose of oseltamivir once daily starting within 2 days of "onset of symptoms in the index case and continuing for seven days. Influenza was confirmed in 163 of the 377 index cases. Oseltamivir significantly reduced the incidence of clinical cases of influenza illness occurring in subjects in contact with confirmed influenza cases, from 24/200 (12%) in the placebo group to 2/205 (1%) in the oseltamivir group (92% reduction [95% CI: 6-16; p ≤ 0.0001]). The NNT was 10 (95% CI: 9-12) among individuals in contact with real cases of influenza and 16 (95% CI: 15-19) over the whole population (ITT), regardless of status infectious of the index case.
The efficacy of oseltamivir in preventing naturally acquired influenza was demonstrated in a post-exposure prevention study within households that included adults, adolescents and children aged 1 to 12 years, both as suspected cases ( index cases) and as subjects in family contact. The primary efficacy parameter for this study was the incidence of laboratory-confirmed clinical influenza in households. Oseltamivir prophylaxis lasted for 10 days. In the total population there was a reduction in the incidence of laboratory-confirmed clinical influenza in households from 20% (27/136), in the group that did not receive prevention, to 7% (10/135), in the group that received prevention (62.7% reduction [95% CI: 26.0-81.2; p = 0.0042]). In the families of the index cases with influenza infection there was a reduction in the incidence of influenza from 26% (23/89), in the group that did not receive prevention, to 11% (9/84), in the group that received prevention (58.5% reduction [95% CI: 15.6-79.6; p = 0.0114]).
According to an analysis conducted in a subgroup of children aged 1 to 12 years, the incidence of laboratory-confirmed clinical influenza among children was significantly reduced from 19% (21/111), in the group that did not receive prevention, at 7% (7/104), in the group that received prevention (reduction of 64.4% [95% CI: 15.8-85.0; p = 0.0188]) . Among children who, at baseline, were not already shedding the virus, the incidence of laboratory-confirmed clinical influenza decreased from 21% (15/70), in the group that did not receive prevention, to 4% (2/47), in the group that received the prevention (reduction of 80.1% [95% CI: 22.0-94.9; p = 0.0206]). The NNT for the total pediatric population was 9 (95% CI: 7-24) in the whole population (ITT) and 8 (95% CI: 6, upper limit not estimable) in the pediatric contacts of the cases index with infection (ITTII).
Prevention during a "community flu epidemic." : In a pooled analysis of two other studies conducted in otherwise healthy unvaccinated adults, oseltamivir 75 mg given once daily for 6 weeks significantly reduced the incidence of clinical cases of influenza from 25/519 (4.8% ) in the placebo group to 6/520 (1.2%) in the oseltamivir group (76% reduction [95% CI: 1.6-5.7, p = 0.0006]) during a "influenza epidemic in the community. In this study, the NNT was 28 (95% CI: 24-50).
In a study of elderly patients admitted to nursing homes, 80% of whom had been vaccinated in the study season, the dose of 75 mg oseltamivir once daily for 6 weeks significantly reduced the incidence of clinical cases. influenza illness from 12/272 (4.4%) in the placebo group to 1/276 (0.4%) in the oseltamivir group (92% reduction [95% CI: 1.5-6.6; p = 0.0015]). In this study, the NNT was 25 (95% CI: 23-62).
Flu prophylaxis in immunocompromised patients : A randomized, placebo-controlled, double-blind study for seasonal influenza prophylaxis was conducted in 475 immunocompromised patients (388 solid organ transplant patients [195 with placebo, 193 with oseltamivir], 87 patients with hematopoietic stem cells [43 with placebo, 44 with oseltamivir], no patients with other immunosuppressive conditions), including 18 children aged 1 to 12 years. The primary endpoint of this study was the incidence of laboratory-confirmed clinical influenza as determined by viral culture and / or four-fold growth of the antibody titre against hemagglutinin (Haemoagglutinin Inhibition, HAI). The incidence of clinical influenza laboratory confirmed was 2.9% (7/238) in the placebo arm and 2.1% (5/237) in the oseltamivir exposed group (95% CI: 2.3-4.1; p = 0.772).
No specific studies have been conducted to evaluate the reduction of the risk of complications.
Resistance to oseltamivir
Clinical studies : The risk of developing influenza viruses with reduced susceptibility or net resistance to oseltamivir was investigated in clinical trials sponsored by Roche. All patients who were found to be carriers of oseltamivir-resistant virus were transiently, cleared the virus normally, and showed no worsening of clinical condition.
* Complete genotyping was not performed in all studies.
There is no evidence of the onset of drug resistance phenomena associated with the use of Tamiflu in clinical trials conducted to date in the prevention of influenza post-exposure (7 days), post-exposure within families (10 days) and seasonal (42 days) in immunocompetent patients. No resistance was observed during the prophylaxis study up to 12 weeks in immunocompromised patients.
Clinical and surveillance data : spontaneous mutations associated with reduced susceptibility to oseltamivir in vitro have been found in influenza A and influenza B viral isolates from patients with no prior oseltamivir exposure. Resistant strains selected during oseltamivir treatment have been isolated from both immunocompetent and immunocompromised patients. Immunocompromised patients and young children are at a higher risk of developing resistant viral strains during treatment with oseltamivir.
Oseltamivir-resistant viruses isolated from oseltamivir-treated patients and laboratory strains of oseltamivir-resistant influenza viruses have been shown to contain mutations in neuraminidases N1 and N2. Resistance mutations tend to be specific to viral subtypes. Since 2007, the resistance-associated H275Y mutation in seasonal H1N1 strains has become widespread. Susceptibility to oseltamivir and the prevalence of these viruses appear to vary according to both the season and the geographic region. In 2008 H275Y was found in> 99% of circulating H1N1 influenza virus isolates in Europe. The 2009 H1N1 flu ("swine flu") was uniformly susceptible to oseltamivir with only sporadic cases of resistance in relation to both therapeutic and prophylactic regimens.
05.2 "Pharmacokinetic properties
General informations
Absorption
Oseltamivir is readily absorbed from the gastrointestinal tract following oral administration of oseltamivir phosphate (pro-drug) and is largely converted to the active metabolite (oseltamivir carboxylate) mainly by hepatic esterases. At least 75% of the orally administered dose reaches the systemic circulation as an active metabolite. Exposure to the pro-drug is less than 5% of that to the active metabolite. Plasma concentrations of the pro-drug and the active metabolite are dose proportional and are not affected by concomitant food intake.
Distribution
At steady state, the mean volume of distribution of oseltamivir carboxylate in humans is approximately 23 liters, a volume equivalent to extracellular body fluid. Since neuraminidase activity is extracellular, oseltamivir carboxylate is distributed to all sites where the flu virus.
The binding of oseltamivir carboxylate to human plasma proteins is negligible (approximately 3%).
Biotransformation
Oseltamivir is extensively converted to oseltamivir carboxylate by esterases mainly present in the liver. Education in vitro demonstrated that neither oseltamivir nor the active metabolite is a substrate or inhibitor of the major isoforms of cytochrome P450. They have not been identified in vivophase 2 conjugates for none of the compounds.
Elimination
Absorbed oseltamivir is eliminated mainly (> 90%) by conversion to oseltamivir carboxylate. It is not further metabolised and is eliminated in the urine. In most subjects, maximum plasma concentrations of oseltamivir carboxylate decrease with a half-life of between 6 and 10 hours. The active metabolite is completely eliminated by renal excretion. Renal clearance (18.8 l / h) exceeds the rate of glomerular filtration (7.5 l / h) indicating that tubular secretion occurs in addition to glomerular filtration Less than 20% of a radiolabelled oral dose is eliminated in faeces.
Other special populations
Pediatric population
Infants under 1 year of age : The pharmacokinetics, pharmacodynamics and safety of Tamiflu were evaluated in two open-label uncontrolled studies which included infants less than 1 year of age infected with influenza virus (n = 135). The rate of elimination of the active metabolite corrected for body weight, it decreases in patients less than one year of age. Exposure to the metabolite is also more variable in younger children. Available data indicate that exposure after a 3 mg / kg dose in infants aged 0-12 months produces pro-drug and metabolite exposures that are expected to be effective, with a safety profile comparable to that observed. in older children and adults with the approved dose (see sections 4.1 and 4.2) The adverse events reported were consistent with the safety profile established for older children.
There are no data available for infants less than 1 year of age for post-exposure influenza prevention. Prevention during a community-based influenza epidemic has not been studied in children below 12 years of age.
Children aged 1 year or older: the pharmacokinetics of oseltamivir were evaluated in single dose pharmacokinetic studies in children and adolescents aged 1 to 16 years. Multiple dose pharmacokinetics were studied in a small number of children enrolled in a clinical efficacy study. Younger children cleared both the pro-drug and the active metabolite faster than adults, resulting in more exposure. low for a given mg / kg dose. Doses of 2 mg / kg confer an oseltamivir carboxylate exposure similar to that achieved in adults taking a single 75 mg dose (approximately 1 mg / kg). The pharmacokinetics of oseltamivir in children and adolescents aged 12 years and older are similar to that in adults.
Senior citizens
At steady state, exposure to the active metabolite in the elderly (aged 65 to 78 years) was 25 to 35% higher than reported in adults below the age of 65 given similar doses of oseltamivir. L "half-life observed in the elderly was similar to that observed in young adults. Based on drug exposure and tolerability, no dosage adjustments are required in elderly patients unless there is evidence of moderate or severe renal impairment (creatinine clearance less than 60 ml / min) (see section 4.2). .
Kidney failure
Administration of oseltamivir phosphate 100 mg twice daily for 5 days to patients with varying degrees of renal impairment has shown that exposure to oseltamivir carboxylate is inversely proportional to the decline in renal function. For dosage, see section 4.2.
Hepatic insufficiency
Education in vitro determined that neither a significant increase in oseltamivir exposure nor a significant decrease in exposure to the active metabolite is expected in patients with hepatic impairment (see section 4.2).
Pregnant women
An "analysis of pooled population pharmacokinetic data indicates that the Tamiflu dosing regimen reported in section 4.2 Posology and method of administration results in" lower exposure (30% as mean of all trimesters) to the active metabolite in pregnant women than to non-pregnant women. However, the lowest expected exposure remains above inhibitory concentrations (IC95 values) and at a therapeutic level against a range of influenza virus strains. Furthermore, observational studies show a benefit of the current dosing regimen in this patient population. Therefore, no dose adjustments are recommended in the treatment or prophylaxis of influenza in pregnant women (see section 4.6 Fertility, pregnancy and lactation).
05.3 Preclinical safety data
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity. The results of conventional rat carcinogenicity studies have shown a trend towards a dose-dependent increase in "incidence of some types of tumors characteristic of the rat strains used. Taking into account the exposure margins in relation to the expected exposure in human use, these results do not modify the benefit-risk ratio of the use of Tamiflu in its approved therapeutic indications.
Teratogenicity studies were conducted in rats and rabbits up to doses of 1500 mg / kg / day and 500 mg / kg / day, respectively. No effects on fetal development were observed. A fertility study in rats with a dose up to 1500 mg / kg / day revealed no adverse reactions on either sex. In pre- and postnatal studies in rats, a prolongation of the duration of parturition was observed at the dose of 1500 mg / kg / day: the safety margin between human exposure and the highest no effect dose (500 mg / day). kg / day) in the rat is 480 times for oseltamivir and 44 times for the active metabolite. In the rat and rabbit the fetal exposure was approximately 15-20% of that of the mother.
In lactating rats, oseltamivir and the active metabolite are excreted in human milk. Limited data indicate that oseltamivir and the active metabolite are excreted in human breast milk. Extrapolation from animal data leads to an estimate of 0.01 mg / day and 0.3 mg / day for the two compounds, respectively.
The possibility of skin sensitization to oseltamivir was observed in the "maximization" test conducted in guinea pigs. Approximately 50% of the animals treated with the non-formulated active ingredient showed erythema after stimulation of the induced animals. Reversible eye irritation was noted in rabbits.
While very high single oral dosages of oseltamivir phosphate salt, up to the highest dose level tested (1310 mg / kg), did not result in adverse reactions in adult rats, the same dose levels resulted in toxicity in young 7-day-old rats. age, including death. These reactions were observed at doses of 657 mg / kg and above. At doses of 500 mg / kg no adverse reactions were observed, even in the case of chronic treatment (500 mg / kg / day administered 7 to 21 days after delivery).
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Capsule contents
Pregelatinised starch (derived from corn starch)
Talc
Povidone
Croscarmellose sodium
Sodium stearyl fumarate.
Capsule shell
Jelly
Yellow iron oxide (E172)
Red iron oxide (E172)
Titanium dioxide (E171).
Ink for printing
Shellac
Titanium dioxide (E171)
FD and C Blue 2 (indigo carmine, E132).
06.2 Incompatibility
Not relevant.
06.3 Period of validity
7 years.
Storage of the suspension prepared in the pharmacy.
Shelf life of 10 days when stored at temperatures below 25 ° C.
06.4 Special precautions for storage
Do not store above 25 ° C.
For storage conditions of the pharmacy prepared suspension, see section 6.3.
06.5 Nature of the immediate packaging and contents of the package
Triple blister (PVC / PE / PVDC, sealed with aluminum).
Pack of 10 capsules.
06.6 Instructions for use and handling
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
Extemporaneous formulation
When Tamiflu powder for oral suspension is not available
Tamiflu for oral suspension (6 mg / ml) ready for use is the preferred formulation for pediatric and adult patients who have difficulty swallowing capsules or where lower doses are required. In case Tamiflu powder for oral suspension is ready to use the use is not available, the pharmacist can prepare a suspension (6 mg / ml) from Tamiflu capsules or the same patients can use the capsules to prepare the suspension at home.
The preparation prepared in the pharmacy should be preferred over that prepared at home. Detailed information regarding the preparation at home can be found in the paragraph "Preparation of Tamiflu in liquid form at home" of the package leaflet of Tamiflu capsules.
Oral syringes of appropriate volume and graduation should be provided both for administration of the pharmacy-prepared suspension and for procedures related to home preparation. In both cases, the correct volume should preferably be marked on the syringes.
Preparation in the pharmacy
6 mg / ml suspension prepared in a pharmacy from the capsule
Adults, adolescents, children aged 1 year and over who are unable to swallow the capsules whole
This procedure describes the preparation of a 6 mg / ml suspension that will provide a patient with a sufficient amount of medicine for a 5-day treatment or 10-day prophylaxis.
The pharmacist can prepare a 6 mg / ml suspension from Tamiflu 30 mg, 45 mg or 75 mg capsules using water containing 0.05% weight / volume sodium benzoate added as a preservative.
First, calculate the total volume that needs to be prepared and dispensed to provide 5-day treatment or 10-day prophylaxis to the patient. The total volume required is determined by the patient's weight according to the recommendations in the table below. To allow accurate withdrawal of up to 10 doses (2 withdrawals per daily dose for one treatment for 5 days), the column indicating the loss estimate must be considered in the preparation.
Volume of the 6 mg / ml suspension prepared in the pharmacy based on the patient's weight
* It depends on the dosage of the capsules used.
Secondly, determine the number of capsules and the amount of vehicle (water containing 0.05% w / v sodium benzoate added as a preservative) needed to prepare the total volume (calculated from the table above) of 6 mg / v suspension. ml prepared in the pharmacy, as shown in the table below:
Number of capsules and amount of vehicle needed to prepare the total volume of a pharmacy-prepared 6 mg / ml suspension
* This combination of capsule strengths cannot be used to achieve the required strength, so use different strength capsules.
Thirdly, follow the procedure below for preparing the 6 mg / ml suspension from Tamiflu capsules:
1. Pour the correct amount of water into a glass measuring beaker of suitable size and add 0.05% weight / volume sodium benzoate as a preservative.
2. Open the Tamiflu capsules in the indicated quantity and pour the contents of each capsule directly into the water contained in the graduated glass.
3. With a suitable stirring tool, mix for 2 minutes.
(Note: the active substance, oseltamivir phosphate, dissolves easily in water. The suspension is caused by some insoluble excipients present in Tamiflu capsules.)
4. Transfer the suspension to an amber glass or polyethylene terephthalate (PET) bottle. A pipette can be used to avoid any leaks.
5. Close the bottle with a child resistant safety closure.
6. Place an "auxiliary label on the bottle that reads" Shake Gently Before "Use".
(Note: the suspension should be shaken gently before administration to reduce the formation of air bubbles).
7. Instruct the parent or caregiver that material left unused after completion of therapy must be disposed of properly. It is recommended that this information be provided by attaching an auxiliary label to the bottle or by adding a sentence to the pharmacy label instructions.
8. Apply a label with the appropriate expiration date in accordance with the storage conditions (see section 6.3).
Place a pharmacy label on the bottle that includes the patient's name, dosage instructions, expiration date, medicine name, and any other information needed to comply with local pharmaceutical regulations. Refer to the table below for instructions on the correct dosage.
Dosage for 6 mg / ml suspension prepared in pharmacy from Tamiflu capsules for infants and children aged one year or older
Administer the pharmacy-prepared suspension with a graduated oral syringe to measure small amounts of the suspension. If possible, mark or highlight on the oral syringe the level that corresponds to the appropriate dose (according to the dosage table above) for each patient.
The appropriate dose should be mixed by the caregiver with an equal amount of sweet liquid food, such as sugar water, chocolate syrup, cherry syrup, dessert toppings (such as caramel or caramel sauce) to mask the bitter taste.
Children less than 1 year old
This procedure describes the preparation of a 6 mg / ml suspension that will provide a patient with a sufficient amount of drug for a 5-day treatment or 10-day prophylaxis.
The pharmacist can prepare a 6 mg / ml suspension from Tamiflu 30 mg, 45 mg or 75 mg capsules using water containing 0.05% weight / volume sodium benzoate added as a preservative.
First, calculate the total volume that needs to be prepared and dispensed to each patient. The total volume required is determined by the patient's weight according to the recommendations in the table below. To allow accurate withdrawal of up to 10 doses (2 withdrawals per daily treatment dose for 5 days), the column indicating the loss estimate must be considered in the preparation.
Suspension volume of 6 mg / ml prepared in the pharmacy based on the weight of the patient
* It depends on the dosage of the capsules used.
Secondly, determine the number of capsules and the amount of vehicle (water containing 0.05% w / v sodium benzoate added as a preservative) needed to prepare the total volume (calculated from the table above) of 6 mg / v suspension. ml prepared in the pharmacy, as shown in the table below:
Number of capsules and amount of vehicle needed to prepare the total volume of a pharmacy-prepared 6 mg / ml suspension
* This combination of capsule strengths cannot be used to achieve the required concentration; therefore to use capsules of different strengths.
Thirdly, follow the procedure below for preparing the 6 mg / ml suspension from Tamiflu capsules:
1. Pour the correct amount of water into a glass measuring beaker of suitable size and add 0.05% by weight of sodium benzoate as a preservative.
2. Open the Tamiflu capsules in the indicated quantity and pour the contents of each capsule directly into the water contained in the graduated glass.
3. With a suitable stirring tool, mix for 2 minutes.
(Note: The active substance, oseltamivir phosphate, dissolves easily in water. The suspension is caused by some insoluble excipients present in Tamiflu capsules.)
4. Transfer the suspension to an amber glass or polyethylene terephthalate (PET) bottle. A pipette can be used to avoid any leaks.
5. Close the bottle with a child resistant closure.
6. Place an "auxiliary label on the bottle that reads" Shake Gently Before "Use".
(Note: the suspension should be shaken gently before administration to reduce the formation of air bubbles).
7. Instruct the parent or patient caregiver that material left unused after completion of therapy should be disposed of properly. It is recommended that this information be provided by attaching an auxiliary label to the bottle or by adding a sentence to the pharmacy label instructions.
8. Apply a label with the appropriate expiration date in accordance with the storage conditions (see section 6.3).
Place a pharmacy label on the bottle that includes the patient's name, dosage instructions, expiration date, medicine name, and any other information needed to comply with local pharmaceutical regulations. Refer to the table below for instructions on the correct dosage.
Dosage for pharmacy-prepared 6 mg / ml suspension from Tamiflu capsules for infants under 1 year of age
Administer the pharmacy-prepared suspension with a graduated oral syringe to measure small amounts of the suspension. If possible, mark or highlight on the oral syringe the level that corresponds to the appropriate dose (according to the dosage table above) for each patient.
The appropriate dose should be mixed by the caregiver with an equal amount of sweet liquid food, such as sugar water, chocolate syrup, cherry syrup, dessert toppings (such as caramel or caramel sauce) to mask the bitter taste.
Preparation at home
In the event that Tamiflu oral suspension ready for use is not available, a pharmacy prepared suspension from Tamiflu capsules should be used (for detailed instructions, see above). If neither ready-to-use Tamiflu oral suspension is available. use, nor the pharmacy-prepared suspension, Tamiflu suspension can be prepared at home.
When the appropriate capsule strength is available at the required doses, the dose is obtained by opening the capsule and mixing its contents with no more than one teaspoon (5ml) of a suitable sweetened food. The bitter taste can be masked with products like sugar water, chocolate syrup, cherry syrup, dessert toppings (like caramel or caramel sauce). The mixture should be shaken and the entire contents administered to the patient. The mixture should be swallowed immediately after its preparation.
When only 75 mg capsules are available and 30 mg or 45 mg doses are required, preparation of the Tamiflu suspension requires additional steps. Detailed instructions are given in the "Preparation of Tamiflu liquid form at home" section of the package leaflet of Tamiflu capsules.
07.0 MARKETING AUTHORIZATION HOLDER
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
UK
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/02/222/003
035943036
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 20 June 2002.
Date of last renewal: June 20, 2012.
10.0 DATE OF REVISION OF THE TEXT
May 2015
