Active ingredients: Ibandronic acid
Bonviva 150 mg film-coated tablets
Bonviva package inserts are available for pack sizes:- Bonviva 150 mg film-coated tablets
- Bonviva 3 mg solution for injection
Indications Why is Bonviva used? What is it for?
Bonviva belongs to a group of medicines called bisphosphonates. Contains the active substance ibandronic acid. Bonviva can reverse bone loss by blocking more bone loss and increasing bone mass in many women who take it, even if they won't be able to see or feel a difference. Bonviva can help decrease the chance of broken bones (fractures). This reduction of fractures has been demonstrated for the spine but not for the hip.
Bonviva was prescribed to you to treat postmenopausal osteoporosis because you have a high risk of fractures. Osteoporosis is the thinning and weakening of the bones, which is common in women after menopause. At menopause, a woman's ovaries stop producing a female hormone, estrogen, which helps maintain a healthy skeleton.
The earlier a woman reaches menopause, the greater the risk of fractures in osteoporosis.
Other factors that can increase the risk of fractures are:
- inadequate intake of calcium and vitamin D with food;
- smoking or the habit of drinking too much alcohol;
- insufficient physical activity (walking or doing other activity under load);
- familiarity with osteoporosis.
A healthy lifestyle will also help you get the most benefit from the treatment. This includes:
- follow a balanced diet rich in calcium and vitamin D;
- walking or doing other activities under load;
- do not smoke and do not drink too much alcohol.
Contraindications When Bonviva should not be used
Do not take Bonviva
- if you are allergic to ibandronic acid or any of the other ingredients of this medicine
- if you have certain problems with your throat / food channel (esophagus), such as narrowing or difficulty swallowing;
- if you are unable to stand or sit upright for at least one hour (60 minutes) in a row;
- if you have, or have had in the past, low levels of calcium in your blood. In this case, please contact your doctor.
Precautions for use What you need to know before you take Bonviva
Some people need to be especially careful when taking Bonviva.
Talk to your doctor before taking Bonviva:
- if you have any mineral metabolism disorders (such as vitamin D deficiency);
- if your kidneys are not functioning normally;
- if you have swallowing or digestive problems;
- if you are having dental treatment or are due to undergo dental surgery, please inform your dentist that you are being treated with Bonviva. If you have cancer, tell your dentist about this as well.
There may be irritation, inflammation or ulceration of the throat / food channel (esophagus) often with symptoms of severe chest pain, severe pain after ingestion of food and / or drink, severe nausea, or vomiting, especially if do not drink a full glass of water and / or lie down within one hour of taking Bonviva. If you develop these symptoms, stop taking Bonviva and tell your doctor immediately (see section 3).
Children and adolescents
Do not give Bonviva to children or adolescents under 18 years.
Interactions Which drugs or foods may change the effect of Bonviva
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Specially:
- Supplements containing calcium, magnesium, iron or aluminum, as these may affect the effects of Bonviva.
- Acetylsalicylic acid and other non-steroidal anti-inflammatory drugs (NSAIDs) (including ibuprofen, diclofenac sodium and naproxen) which can irritate the stomach and intestines. Bonviva can have the same effect. Be especially careful if you take pain relievers or anti-inflammatories at the same time as Bonviva
After taking your Bonviva monthly tablet, wait 1 hour before taking any other medicines, including digestive tablets, calcium supplements or vitamins.
Bonviva with food and drink
Do not take Bonviva with food. Bonviva is less effective when taken with food.
You can drink water but no other drinks.
After taking Bonviva, wait 1 hour before taking food and other drinks (see section "How to take Bonviva")
Warnings It is important to know that:
Pregnancy and breastfeeding
Bonviva can only be used by postmenopausal women and must not be taken by women who are still able to have children.
Do not take Bonviva if you are pregnant or breastfeeding.
Ask your doctor or pharmacist for advice before taking this medicine.
Driving and using machines
You can drive and use machines as Bonviva is expected to have no or negligible effect on the ability to drive and use machines.
Bonviva contains lactose
If you have been told by your doctor that you have an intolerance to some sugars (for example if you have galactose intolerance, a Lapp lactase deficiency or have problems with the absorption of glucose-galactose), contact your doctor before taking this medicine.
Dose, Method and Time of Administration How to use Bonviva: Posology
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
The usual dose of Bonviva is one tablet per month.
Taking your monthly tablet
It is important to follow the following instructions carefully. They are designed to help the Bonviva tablet reach your stomach quickly, so it is less likely to cause irritation.
Take one Bonviva 150 mg tablet once a month.
- Choose a day of the month that is easy to remember. To take the Bonviva tablet, you can choose a specific day of the month (for example the 1st of each month) or a day of the week (for example the 1st Sunday of the month), depending on what suits you best. habits.
- Take the Bonviva tablet at least 6 hours after eating or drinking anything other than water.
- Take the Bonviva tablet
- just got out of bed e
- before taking food and drink (on an empty stomach).
- Swallow the tablet with a full glass of plain water (at least 180 ml).
Do not take the tablet with water with a high concentration of calcium, fruit juice or any other beverage. It is recommended that you use bottled water with a low mineral content if there is a problem associated with potentially high levels of calcium in the body. tap water (hard water),
- Swallow the tablet whole, do not chew it, crush it, or allow it to dissolve in the mouth.
- In the hour following (60 minutes) after taking the tablet
- do not lie down; if you do not stay upright (standing or sitting), some of the medicine may flow back into your esophagus
- do not eat anything
- do not drink anything (except water if you need it)
- do not take any other medicines.
- After waiting for an hour, you can take food and drink for your morning meal. After eating, you can also lie down if you like and take other medicines if necessary.
Continuation of the recruitment of Bonviva
It is important to continue taking Bonviva every month, as long as your doctor prescribes it for you. After taking Bonviva for 5 years, ask your doctor whether to continue taking the medicine.
Overdose What to do if you have taken an overdose of Bonviva
If you take more Bonviva than you should
If you have taken more than one tablet by mistake, drink a full glass of milk and contact your doctor straight away.
Do not vomit and do not lie down - this could cause Bonviva to irritate your esophagus.
If you forget to take Bonviva
- If you forget to take your tablet on the morning of your chosen day, do not take it later in the day.
Instead, consult the calendar and check when your next hiring is due.
- If you have forgotten to take your tablet on your chosen day and there are only 1 to 7 days left until your next scheduled intake ...
Never take two Bonviva tablets in the same week. You must wait for the day of your next scheduled intake and take the tablet as usual; then continue to take one tablet once a month on the scheduled days marked on the calendar.
- If you have forgotten to take your tablet on your chosen day and your next scheduled intake is more than 7 days away ...
You must take one tablet the morning after the day you remember; then continue to take one tablet once a month on the scheduled days marked on the calendar.
Side Effects What are the side effects of Bonviva
Like all medicines, this medicine can cause side effects, although not everybody gets them.
See a nurse or doctor immediately if you notice any of the following serious side effects - you may need urgent medical treatment:
Uncommon (affects up to 1 in 100 people):
- severe chest pain, severe pain after swallowing food or drink, severe nausea or vomiting, difficulty swallowing. There may be severe inflammation of the throat / food channel, sometimes with sores or constriction of the throat / food channel.
Rare (affects up to 1 in 1000 people):
- itching, swelling of the face, lips, tongue and throat, with difficulty in breathing;
- persistent eye pain and inflammation;
- a new pain, weakness or discomfort in the thigh, hip or groin. You may have the first signs of a possible non-typical fracture of the femur.
Very rare (affects up to 1 in 10,000 people):
- pain or sore in the mouth or jaw pain. You may experience the first signs of serious jaw problems (necrosis, or death of the jaw bone);
- severe, potentially life-threatening allergic reaction.
Other possible side effects
Common (affects up to 1 in 10 people):
- headache;
- heartburn, trouble swallowing, stomach or belly pains (could be due to stomach inflammation), indigestion, nausea, diarrhea;
- muscle cramps, stiffness in the joints and limbs;
- flu-like symptoms, including fever, shaking and chills, feeling unwell, pain in bones and aching muscles and joints. Talk to a nurse or doctor if any effects become troublesome or last more than a couple of days.
- rash.
Uncommon (affects up to 1 in 100 people):
- dizziness;
- flatulence (intestinal gas, bloating);
- backache;
- feeling of tiredness and exhaustion;
- asthma attacks.
Rare (affects up to 1 in 1000 people):
- inflammation of the duodenum (first part of the intestine) causing stomach pain;
- urticaria.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. 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 this medicine out of the sight and reach of children.
This medicinal product does not require any special storage conditions.
Do not use this medicine after the expiry date which is stated on the carton after "EXP". The expiry date refers to the last day of the month.
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 Bonviva contains
- The active substance is ibandronic acid. One tablet contains 150 mg of ibandronic acid (as sodium monohydrate).
- The excipients are:
tablet core: lactose monohydrate, povidone, microcrystalline cellulose, crospovidone, purified stearic acid, anhydrous colloidal silica;
tablet coating: hypromellose, titanium dioxide (E171), talc, macrogol 6000.
What Bonviva looks like and contents of the pack
Bonviva tablets are white to off-white, elongated in shape, marked "BNVA" on one side and "150" on the other side. The tablets are supplied in blisters containing 1 or 3 tablets.
Not all pack sizes may be marketed.
TEXT FOR REMINDER STICKERS
PLANNING OF THE RECRUITMENT OF BONVIVA
The dosage of Bonviva is one tablet once a month. Choose a day of the month that is easy to remember:
- always on the same day of the month (for example the 1st day of each month)
- or the same day of the week (for example the 1st Sunday of each month).
Mark the days on the calendar with the detachable stickers below.
Once you have taken your tablet, check the box on the sticker
DETACHABLE STICKERS FOR YOUR PERSONAL CALENDAR
Monthly tablet Monthly tablet Monthly tablet
Bonviva Bonviva Bonviva
It is important to continue taking Bonviva every month.
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
BONVIVA 150 MG TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 150 mg of ibandronic acid (as, sodium monohydrate).
Excipient (s) with known effect:
Contains 154.6 mg of anhydrous lactose (equivalent to 162.75 mg of lactose monohydrate).
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablet.
White to off-white, elongated, film-coated tablets debossed "BNVA" on one side and "150" on the other side.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Treatment of osteoporosis in postmenopausal women at high risk of fracture (see section 5.1).
A reduction in the risk of vertebral fractures has been demonstrated; Efficacy on femoral neck fractures has not been established.
04.2 Posology and method of administration
Dosage:
The recommended dose is one 150 mg film-coated tablet once a month. It is preferable to take the tablet on the same day of each month.
Bonviva should be taken after an overnight fast (of at least 6 hours) and 1 hour before taking food and drink (other than water) in the morning (see section 4.5) or any other oral medicine or supplement (including football):
If a dose is missed, patients should be instructed to take one Bonviva 150 mg tablet the morning after the day they remember, unless there is less than 7 days to their next scheduled intake.
Thereafter, patients should continue taking the tablet once a month at the initially scheduled expiration date.
In the event that there are less than 7 days to the next scheduled intake, patients should wait until the day of the next intake and then continue taking one tablet once a month as originally scheduled.
Patients should not take two tablets in the same week.
Patients should receive calcium and / or vitamin D supplementation if food intake is inadequate (see sections 4.4 and 4.5).
The optimal duration of bisphosphonate treatment for osteoporosis has not been established. The need for continued treatment should be reassessed in each individual patient periodically based on the potential benefits and risks of Bonviva, particularly after 5 or more years of use. .
Special populations
Patients with renal insufficiency
As a result of limited clinical experience (see sections 4.4 and 5.2) treatment with Bonviva is not recommended in patients with a creatinine clearance below 30 ml / min.
No dose adjustment is required in patients with mild to moderate renal impairment with creatinine clearance of 30 ml / min or more.
Patients with hepatic insufficiency
No dose adjustment is required (see section 5.2).
Elderly population (> 65 years)
No dose adjustment is required (see section 5.2).
Pediatric population
There is no indicated use in children below 18 years and Bonviva has not been studied in this population (see sections 5.1 and 5.2).
Method of administration:
For oral use.
• The tablets should be swallowed whole with the help of a glass of water (180 to 240 ml) with the patient in a sitting or standing position. Water with a high concentration of calcium should not be used. It is recommended to use water in bottle with a low mineral content if there is a problem associated with potentially high levels of calcium in tap water (hard water).
• Patients should not lie down for 1 hour after taking Bonviva.
• Water is the only drink that can be taken with Bonviva.
• Patients should neither chew nor suck the tablets due to the risk of oropharyngeal ulceration.
04.3 Contraindications
• Hypersensitivity to ibandronic acid or to any of the excipients listed in section 6.1.
• Hypocalcemia
• Abnormalities of the esophagus that delay esophageal emptying, such as stricture or achalasia - Inability to stand or sit upright for at least 60 minutes.
04.4 Special warnings and appropriate precautions for use
Hypocalcemia
An existing hypocalcaemia must be corrected before initiating therapy with Bonviva. Other disorders of bone and mineral metabolism must also be treated effectively. Adequate calcium and vitamin D intake is important in all patients.
Gastrointestinal irritation
Orally administered bisphosphonates can cause local irritation of the upper gastrointestinal mucosa. Due to these possible irritating effects and the potential for worsening of the underlying disease, caution should be exercised when Bonviva is administered to patients with ongoing upper gastrointestinal problems (e.g. Barrett's esophagus, dysphagia, other oesophageal diseases, gastritis, duodenitis or known ulcers).
Adverse events such as oesophagitis, oesophageal ulcers and oesophageal erosions, in some cases severe and requiring hospitalization, rarely with bleeding or followed by esophageal stricture or perforation, have been reported in patients receiving oral bisphosphonates. The risk of serious adverse events esophageal level appears to be greater in patients who have not followed dosing instructions and / or who continue to take oral bisphosphonates after developing symptoms suggestive of oesophageal irritation. Patients should be especially careful and be able to follow the dosing instructions (see section 4.2).
Physicians should be alert for any signs or symptoms that indicate a possible oesophageal reaction and patients should be advised to discontinue Bonviva and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain, or development or worsening of heartburn.
While no increased risk was observed in controlled clinical trials, there have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some of which were serious and associated with complications.
Since non-steroidal anti-inflammatory drugs and bisphosphonates are both associated with the occurrence of gastrointestinal irritation, caution should be exercised during co-administration.
Osteonecrosis of the jaw
Osteonecrosis of the jaw, usually associated with tooth extractions and / or local infections (including osteomyelitis), has been reported in cancer patients treated primarily with intravenous bisphosphonates. Most of these patients were also being treated with chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in patients with osteoporosis treated with oral bisphosphonates.
Dental examination with appropriate dental prophylaxis should be considered prior to bisphosphonate treatment in patients with concomitant risk factors (eg cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene).
During treatment, these patients should avoid invasive dental procedures wherever possible. In patients who develop osteonecrosis of the jaw during bisphosphonate treatment, dental surgery may worsen the condition. For patients requiring dental treatment, there are no data available to indicate whether discontinuing bisphosphonate treatment reduces the risk of osteonecrosis of the jaw The clinical judgment of the treating physician must be the basis of the management of each patient, based on the individual assessment of the risk / benefit ratio.
Atypical fractures of the femur
Atypical subtrochanteric and diaphyseal fractures of the femur have been reported, mainly in patients on long-term bisphosphonate therapy for osteoporosis. These short transverse or oblique fractures can occur anywhere in the femur from just below the lesser trochanter to above the supracondylar line. These fractures occur spontaneously or after minimal trauma and some patients experience thigh or groin pain, often associated with imaging evidence of stress fractures, weeks or months before a hip fracture occurs. complete. Fractures are often bilateral; therefore in bisphosphonate-treated patients who have sustained a femoral shaft fracture, the contralateral femur should be examined. Limited healing of these fractures has also been reported. In patients with suspected atypical femoral fracture, consideration should be given to discontinuation of bisphosphonate therapy pending an assessment of the patient based on individual benefit risk.
During treatment with bisphosphonates, patients should be advised to report any pain in the thigh, hip or groin and any patient who exhibits such symptoms should be evaluated for the presence of an incomplete fracture of the femur.
Kidney failure
Due to limited clinical experience, Bonviva is not recommended in patients with a creatinine clearance below 30 ml / min (see section 5.2).
Galactose intolerance
This medicinal product contains 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
Drug-food interaction
The oral bioavailability of ibandronic acid is generally reduced by the presence of food. In particular, products containing calcium, including milk, and other polyvalent cations (such as aluminum, magnesium and iron) can interfere with the absorption of Bonviva, which is in agreement with the findings in animal studies. Patients should therefore take Bonviva after an overnight fast (at least 6 hours) and continue fasting for 1 hour after taking Bonviva (see section 4.2).
Interactions with other medicines
Since ibandronic acid does not inhibit the major human hepatic isoenzymes of P450 and has been shown not to induce the hepatic cytochrome P450 system in rats (see section 5.2), metabolic interactions are not considered likely. Ibandronic acid is eliminated exclusively. by renal excretion and does not undergo any biotransformation.
Calcium supplements, antacids and some oral medications containing polyvalent cations
Calcium supplements, antacids and some oral medications containing polyvalent cations (such as aluminum, magnesium and iron) can interfere with the absorption of Bonviva. Therefore, patients should not take other medications by mouth for at least 6 hours before taking take Bonviva and for 1 hour after taking Bonviva.
Acetylsalicylic acid and NSAIDs
Since acetylsalicylic acid, non-steroidal anti-inflammatory drugs (NSAIDs) and bisphosphonates are associated with gastrointestinal irritation, caution should be exercised during concomitant administration (see section 4.4).
H2 receptor blockers or proton pump inhibitors
Of the more than 1,500 patients enrolled in study BM16549, which compared a monthly and daily dosing regimen of ibandronic acid, 14% and 18% were on histaminergic H2 receptor blockers or proton pump inhibitors after one and two years, respectively. Among these patients, the incidence of upper gastrointestinal events in those treated with Bonviva 150 mg once monthly was similar to that in patients treated with ibandronic acid 2.5 mg daily.
In healthy male volunteers and postmenopausal women, intravenous ranitidine resulted in an increase in the bioavailability of ibandronic acid by about 20%, possibly as a result of reduced gastric acidity. Since this increase, however, is within the range. Due to the normal variability of ibandronic acid bioavailability, no dose adjustments are deemed necessary when Bonviva is coadministered with H2 antagonists or other active substances that increase gastric pH.
04.6 Pregnancy and lactation
Pregnancy
Bonviva is intended for use by postmenopausal women only and must not be administered to women of childbearing potential.
There are no adequate data from the use of ibandronic acid in pregnant women. Studies in rats have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.
Bonviva should not be used during pregnancy.
Feeding time
It is not known whether ibandronic acid is excreted in human breast milk. Studies in lactating female rats have shown low levels of ibandronic acid in breast milk following intravenous administration.
Bonviva must not be used in patients who are breastfeeding.
Fertility
There are no data on the effects of ibandronic acid in humans. In reproduction studies conducted in rats using oral administration, ibandronic acid reduced fertility. In studies conducted in rats using intravenous administration, ibandronic acid reduced fertility at high daily doses (see section 5.3).
04.7 Effects on ability to drive and use machines
Based on the pharmacodynamic and pharmacokinetic profile and the reports of adverse reactions, it can be expected that Bonviva has no or negligible influence on the ability to drive and operate machinery.
04.8 Undesirable effects
Summary of the safety profile
The most serious adverse reactions that have been reported are anaphylactic reaction / shock, atypical fractures of the femur, osteonecrosis of the jaw, gastrointestinal irritation and ocular inflammation (see section "Description of some adverse reactions" and section 4.4).
The most frequently reported adverse reactions are arthralgia and flu-like symptoms. These symptoms, usually of short duration, mild or moderate in intensity, are typically associated with the first dose and usually resolve during continued treatment without the need for corrective action (see section "Flu-like illness").
Tabulated list of adverse reactions
A complete list of known adverse reactions is presented in Table 1. The safety of oral treatment with ibandronic acid 2.5 mg once daily was evaluated in 1251 patients treated in 4 placebo-controlled clinical trials, the majority of which were from the pivotal three-year fracture study ( MF4411).
In the pivotal two-year study of postmenopausal women with osteoporosis (BM16549), the overall safety of Bonviva 150 mg once monthly was similar to that of ibandronic acid 2.5 mg daily. The overall percentage of patients reporting an adverse reaction was 22.7% and 25.0% when given Bonviva 150 mg once monthly, after one and two years, respectively. The majority of cases did not lead to discontinuation of treatment.
Adverse reactions are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following conventions: very common (> 1/10), common (≥ 1/100 a
Table 1: Adverse reactions occurring in postmenopausal women receiving Bonviva 150 mg once monthly or ibandronic acid 2.5 mg daily in phase III studies BM16549 and MF4411 and in post-marketing experience.
* For more information see below.
- Identified during post marketing experience.
Description of some adverse reactions
Gastrointestinal adverse reactions
The monthly treatment study included patients with a history of gastrointestinal disease, including patients with peptic ulcer, no recent bleeding or hospitalization, and patients with dyspepsia or reflux under drug control. For these patients, there was no difference in the incidence of upper gastrointestinal adverse events between the 150 mg once monthly and 2.5 mg daily regimens.
Flu-like illness
Flu-like illness includes events reported as acute phase reactions or symptoms such as myalgia, arthralgia, fever, chills, fatigue, nausea, loss of appetite or bone pain.
Osteonecrosis of the jaw
Osteonecrosis of the jaw has been reported in patients being treated with bisphosphonates. Most cases refer to patients with cancer, but some cases have also occurred in patients treated for osteoporosis. Osteonecrosis of the jaw is generally associated with tooth extractions and / or local infections (including osteomyelitis). Diagnosis of cancer, chemotherapy, radiotherapy, corticosteroids and poor oral hygiene are also believed to be risk factors (see section 4.4).
Ocular inflammation
Ocular inflammatory events such as uveitis, episcleritis and scleritis have been reported with the use of ibandronic acid. In some cases, these events did not resolve until ibandronic acid therapy was discontinued.
Anaphylactic reaction / shock
Cases of anaphylactic reaction / shock, including fatal events, have occurred in patients treated with intravenous ibandronic acid.
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
No specific information is available on the treatment of overdose with Bonviva.
However, based on the knowledge of this class of drugs, oral overdose can lead to adverse reactions of the upper gastrointestinal tract (such as stomach upset, dyspepsia, oesophagitis, gastritis or ulcer) or hypocalcaemia. Milk or antacids should be administered to bind Bonviva and any adverse reactions should be treated symptomatically. Due to the risk of esophageal irritation, vomiting should not be induced and the patient should remain standing.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs for the treatment of bone diseases, bisphosphonates, ATC code: M05BA06
Mechanism of action
Ibandronic acid is an extremely potent bisphosphonate, belonging to the nitrogen-containing group of bisphosphonates, which acts selectively on bone tissue and specifically inhibits osteoclastic activity without directly affecting bone formation. It does not interfere with osteoclast recruitment. L " Ibandronic acid leads to progressive net increases in bone mass and a reduced incidence of fractures by reducing increased bone turnover towards pre-menopausal values in postmenopausal patients.
Pharmacodynamic effects
The pharmacodynamic action of ibandronic acid is the inhibition of bone resorption. In vivo, ibandronic acid prevents experimentally induced bone destruction caused by cessation of gonadal activity, by retinoids, tumors or tumor extracts. In juvenile (rapidly growing) rats, endogenous bone resorption is also inhibited, resulting in an increase in normal bone mass compared to untreated animals.
Animal models have confirmed that ibandronic acid is a very potent inhibitor of osteoclastic activity. In growing rats, there is no evidence of a mineralization defect even with doses 5,000 times higher than that required for the treatment of osteoporosis.
Long-term administration, both daily and intermittent (with prolonged intervals between doses), in rats, dogs and monkeys, was associated with the formation of new bone of normal quality and of preserved or increased mechanical strength, even with doses in the toxicity range. In humans, the efficacy of ibandronic acid for both daily and intermittent dosing with an interval of 9-10 weeks between doses has been confirmed in a clinical study (MF4411) in which ibandronic acid has demonstrated its efficacy. anti-fracture efficacy.
In animal models, ibandronic acid produced biochemical modifications indicative of a dose-dependent inhibition of bone resorption, including the suppression of urinary biochemical markers of bone collagen degradation (such as deoxypyridinoline and cross-chain collagen N-telopeptides type I (NTX)).
In a phase 1 bioequivalence study conducted on 72 postmenopausal women treated with 150 mg orally every 28 days, for a total of four administrations, inhibition of serum CTX following the first administration was observed as early as 24 hours from the same (median inhibition of 28%); the maximum median inhibition (69%) was observed after 6 days. After the third and fourth administration, the maximum median inhibition at 6 days post dose was 74%, falling to a median inhibition of 56% 28 days after the fourth administration. In the absence of further administration, the suppression of biochemical markers of bone resorption is reduced.
Clinical efficacy
Independent risk factors such as, for example, low BMD, age, presence of previous fractures, family history of fractures, high bone turnover and low body mass index, must be considered in order to identify women at high risk of osteoporotic fractures.
Bonviva 150 mg once a month
Bone mineral density (BMD)
In a multicenter, double-blind, two-year study (BM16549) in postmenopausal women with osteoporosis (BMD baseline lumbar spine T-score less than -2.5 SD), Bonviva 150 mg once per month were shown to be at least as effective as 2.5 mg ibandronic acid per day in increasing BMD. This was demonstrated by both the one-year primary and two-year confirmatory endpoint analyzes (Table 2 ).
Table 2: Mean relative change from baseline in lumbar spine, total hip, femoral neck, and trochanter BMD after one year (primary analysis) and after two years of treatment (population per protocol) in study BM16549 .
In addition, in a prospective planned analysis, Bonviva 150 mg once monthly was shown to be greater than 2.5 mg ibandronic acid daily in increasing lumbar spine BMD values at one year (p = 0.002). and two years (p
At one year (primary analysis), 91.3% (p = 0.005) of patients treated with Bonviva 150 mg once monthly achieved an increase in lumbar spine BMD greater than or equal to baseline (responder in terms of BMD) compared to 84.0% of patients treated with 2.5 mg ibandronic acid daily. At two years, 93.5% (p = 0.004) and 86.4% of patients treated with 150 mg of Bonviva once monthly or with 2.5 mg of ibandronic acid daily respectively.
As for total hip BMD, 90.0% at one year (p
Using a more restrictive criterion, which combines the BMD of the lumbar spine and that of the hip as a whole, 83.9% (the arms of 150 mg per month and that of 2.5 mg per day met this criterion.
Biochemical markers of bone turnover
Clinically significant reductions in serum CTX levels were observed at each measurement, ie at 3, 6, 12 and 24 months. After one year (primary analysis), the median relative change from baseline was -76% with Bonviva 150 mg once monthly and -67% with ibandronic acid 2.5 mg daily. At two years, the median relative change was -68% and -62% in the 150 mg / month and 2.5 mg / day arms, respectively.
At one year, 83.5% (p = 0.006) of patients treated with Bonviva 150 mg once monthly and 73.9% of patients treated with ibandronic acid 2.5 mg daily were classified as responders (i.e. reported a reduction of ≥50% from baseline.) At two years, 78.7% (p = 0.002) and 65.6% of patients were classified as responders, respectively in the 150 mg arm per month and in that of 2.5 mg per day.
Based on the results of study BM16549, Bonviva 150 mg once monthly is expected to be at least as effective as 2.5 mg ibandronic acid daily in preventing fractures.
Ibandronic acid 2.5 mg per day
In the initial three-year, randomized, double-blind, placebo-controlled fracture study (MF4411), a statistically significant and clinically relevant reduction in the incidence of new vertebral fractures was demonstrated from radiological, morphometric and clinical points of view. (Table 3) In this study, ibandronic acid was evaluated at oral doses of 2.5 mg per day and 20 mg according to an exploratory intermittent dosing regimen. Ibandronic acid was taken 60 minutes before morning food and drink (post-intake fasting period). The study enrolled women between the ages of 55 and 80, postmenopausal for at least 5 years, with lumbar spine BMD 2 to 5 SD below the mean pre-menopausal T-score. in at least one vertebra (L1-L4) and which had one to four prevalent vertebral fractures. All patients received 500 mg of calcium and 400 IU of vitamin D per day. Efficacy was evaluated in 2,928 patients. 2.5 mg ibandronic acid administered once daily showed a statistically significant and clinically relevant reduction in the incidence of new vertebral fractures. This regimen reduced the incidence of new radiologically appreciable vertebral fractures by 62% (p = 0.0001) over the three-year study duration. A relative risk reduction of 61% was observed after 2 years (p = 0, 0006). A statistically significant difference was not reached after 1 year of treatment (p = 0.056). The anti-fracture effect was constant throughout the duration of the study. There was no indication of a reduction in the effect over time.
The incidence of clinical vertebral fractures was also significantly reduced by 49% (p = 0.011). The strong effect on vertebral fractures was also reflected in a statistically significant reduction in stature loss compared to placebo (p
Table 3: Results from the 3-year fracture study MF4411 (%, 95% CI)
The effect of ibandronic acid treatment was further evaluated with a subpopulation analysis of patients who had a lumbar spine BMD T-score below -2.5 at baseline. The reduction in the risk of vertebral fractures was strongly consistent with that observed in the global population.
Table 4: Results from the MF4411 3-year fracture study (%, 95% CI) in patients who had a lumbar spine BMD T-score below -2.5 at baseline.
No reduction in non-vertebral fractures was observed in the general population of study MF4411; however, daily ibandronic acid was shown to be effective in a high-risk subpopulation (femoral neck BMD T-score
Daily treatment with 2.5 mg resulted in a progressive increase in vertebral and non-vertebral skeletal BMD.
At three years, the lumbar spine BMD increase compared to placebo was 5.3% and 6.5% from baseline. The hip increases from baseline were 2.8% at the level of the femoral neck, 3.4% at the level of the hip as a whole and 5.5% at the level of the trochanter.
Biochemical markers of bone turnover (such as urinary CTX and serum osteocalcin) showed the expected pattern of suppression at premenopausal levels and reached a maximum of suppression over a period of 3-6 months.
A clinically significant 50% reduction in biochemical markers of bone resorption was observed as early as one month after initiation of treatment with ibandronic acid 2.5 mg.
After discontinuation of treatment, there is a return to pre-treatment pathological values of elevated bone resorption associated with postmenopausal osteoporosis.
Histological analysis of bone biopsies after two and three years of treatment in postmenopausal women showed that the bone formed has normal characteristics and that there is no evidence of a mineralization defect.
Pediatric population (see sections 4.2 and 5.2)
Bonviva has not been studied in the pediatric population, therefore no efficacy and safety data are available for this patient population.
05.2 Pharmacokinetic properties
The main pharmacological effects of ibandronic acid on bone are not directly related to actual plasma concentrations, as demonstrated by various animal and human studies.
Absorption
Absorption of ibandronic acid from the upper gastrointestinal tract is rapid following oral administration and plasma concentrations increase dose proportionally up to oral intake of 50 mg, with more than proportional increases for higher doses. The maximum observed plasma concentrations have been reached. in 0.5-2 hours (median 1 hour) fasting and the absolute bioavailability was approximately 0.6%. The extent of absorption is compromised by the simultaneous intake of food or drink (apart from water ) Bioavailability is reduced by approximately 90% when ibandronic acid is administered with a standard breakfast, compared to bioavailability found in fasted subjects. There is no significant reduction in bioavailability if ibandronic acid is taken 60 minutes before morning food and drink. Both the bioavailability and the increase in BMD are reduced if food or drink is consumed less than 60 minutes after ingestion of ibandronic acid.
Distribution
After initial systemic exposure, ibandronic acid rapidly binds to bone or is excreted in the urine. In humans, the apparent terminal volume of distribution is at least 90 l and the percentage of the dose reaching bone is estimated to be 40-50% of the circulating dose. Protein binding in human plasma is approximately 85% - 87% (determined in vitro at therapeutic drug concentrations) and therefore there is a low potential for drug interactions due to displacement.
Biotransformation
There is no evidence that ibandronic acid is metabolised in animals or humans.
Elimination
The absorbed fraction of ibandronic acid is removed from the circulation by bone absorption (estimated to be 40-50% in postmenopausal women) and the remainder is eliminated unchanged by the kidney. The unabsorbed fraction of ibandronic acid is eliminated unchanged in the faeces.
The range of apparent half-lives observed is wide, the apparent terminal half-life is generally in the range of 10-72 hours. Since the calculated values largely depend on the duration of the study, the posology used and the sensitivity of the test, the actual terminal half-life is likely to be considerably longer, as is the case with other bisphosphonates. Initial plasma levels fall rapidly, reaching 10% of peak values within 3 and 8 hours of intravenous or oral administration, respectively.
Total clearance of ibandronic acid is low with mean values between 84 and 160 ml / min. Renal clearance (approximately 60 ml / min in healthy postmenopausal women) constitutes 50-60% of the total clearance and is correlated creatinine clearance. The difference between apparent and total renal clearance is thought to reflect bone uptake.
The secretory pathway does not appear to include known acid or basic transport systems involved in the excretion of other active substances. Furthermore, ibandronic acid does not inhibit the major human hepatic P450 isoenzymes and does not induce the hepatic cytochrome P450 system in the rat.
Pharmacokinetics in special clinical situations
Sex
The bioavailability and pharmacokinetics of ibandronic acid are similar in men and women.
Race
There is no evidence of clinically relevant inter-ethnic differences between Asians and Caucasians in the availability of ibandronic acid. Limited data are available on patients of African descent.
Patients with renal insufficiency
Renal clearance of ibandronic acid in patients with varying degrees of renal insufficiency is linearly related to creatinine clearance.
No dose adjustments are required for patients with mild to moderate renal impairment (creatinine clearance equal to or greater than 30 mL / min), as demonstrated in study BM16549 in which the majority of patients had mild to moderate renal impairment.
Subjects with severe renal impairment (creatinine clearance less than 30 ml / min) who took an oral daily dose of ibandronic acid of 10 mg for 21 days had plasma concentrations 2-3 times higher than subjects with normal renal function. and the total clearance of ibandronic acid was 44 ml / min. After intravenous administration of 0.5 mg, the total, renal and non-renal clearances decreased by 67%, 77% and 50%, respectively, in subjects with insufficiency severe renal impairment; however no reduction in tolerability associated with increased exposure was observed. Due to limited clinical experience, the use of Bonviva is not recommended in patients with severe renal impairment (see sections 4.2 and 4.4). The pharmacokinetics of ibandronic acid have not been evaluated in patients with end-stage renal disease not undergoing hemodialysis. The pharmacokinetics of ibandronic acid in these patients are unknown and ibandronic acid should not be used in these cases.
Patients with hepatic insufficiency (see section 4.2)
There are no pharmacokinetic data for ibandronic acid in patients with hepatic insufficiency. The liver does not play a significant role in the elimination of ibandronic acid, which is not metabolised but is eliminated by renal excretion and bone uptake. Therefore no dosage adjustments are necessary in patients with hepatic insufficiency.
Elderly population (see section 4.2)
In a multivariate analysis, age was not an independent factor for any of the pharmacokinetic parameters studied. As renal function decreases with age, this is the only factor to consider (see section on renal insufficiency).
Pediatric population (see sections 4.2 and 5.1)
There are no data on the use of Bonviva in these age groups.
05.3 Preclinical safety data
Toxic effects, eg signs of renal damage, were observed in dogs only at exposures considered significantly in excess of the maximum human exposure, suggesting little clinical relevance.
Mutagenicity / Carcinogenicity
No signs of carcinogenic potential were observed. Tests for genotoxicity revealed no evidence of genetic activity of ibandronic acid.
Reproductive toxicity
There is no evidence of a direct fetal toxic or teratogenic effect of ibandronic acid in orally treated rats and rabbits and no developmental adverse events occurred in the F1 offspring of rats with an extrapolated exposure at least 35 times higher than the exposure in rats. "man. In reproduction studies conducted in rats using oral administration, the effects on fertility consisted of increased preimplantation loss at a dose of 1 mg / kg / day or higher. In reproduction studies conducted in rats using intravenous administration, ibandronic acid decreased sperm counts at doses of 0.3 and 1 mg / kg / day and decreased fertility in males at doses of 1 mg / kg / day. day and in females at a dose of 1.2 mg / kg / day Adverse effects of ibandronic acid in reproductive toxicity studies in rats were those observed with bisphosphonates as a drug class. Among them, a reduced number of implantation sites, interference with natural birth (dystocia) and an increase in visceral alterations (reno-pelvic-ureteral syndrome).
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Core of the tablet
Lactose monohydrate
Povidone
Microcrystalline cellulose
Crospovidone
Stearic acid
Anhydrous colloidal silica
Tablet coating
Hypromellose
Titanium dioxide (E171)
Talc
Macrogol 6000
06.2 Incompatibility
Not relevant.
06.3 Period of validity
5 years.
06.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package
Bonviva 150 mg film-coated tablets are supplied in blisters (PVC / PVDC, sealed with aluminum foil) containing 1 or 3 tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations. The release of medicinal products into the environment must be minimized.
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 / 1/03/265/003
036899019
EU / 1/03/265/004
036899021
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 23 February 2004
Date of most recent renewal: December 18, 2013
10.0 DATE OF REVISION OF THE TEXT
December 2013
