Texpami

Package leaflet: Information for the user

TEXPAMI 30 mg/10 ml solution for infusion, 60 mg/10 ml solution for infusion, 90 mg/10 ml solution for infusion

Pamidronate disodium
Generic medicine
Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or nurse.
• If you experience any side effects, including those not listed in this leaflet, tell your doctor or nurse. See section 4.

Contents of this leaflet:

1. What TEXPAMI is and what it is used for
2. What you need to know before you use TEXPAMI
3. How to use TEXPAMI
4. Possible side effects
5. How to store TEXPAMI
6. Contents of the pack and other information

1. What TEXPAMI is and what it is used for

TEXPAMI contains the active substance pamidronate disodium, which belongs to a group of medicines called bisphosphonates that are used to prevent bone tissue loss.
Pamidronate is indicated for the treatment of bone diseases associated with tumours (bone metastases, predominantly lytic, multiple myeloma, tumour-induced osteolysis with hypercalcaemia).

2. What you need to know before using TEXPAMI

You must not be given TEXPAMI

• if you are allergic to disodium pamidronate, to other medicines in the same group (bisphosphonates), or to any of the other ingredients of this medicine (listed in section 6);
• if you are pregnant or breastfeeding (see section “Pregnancy and breastfeeding”);
• if the person to receive this medicine is a child.

Warnings and precautions
Talk to your doctor before receiving TEXPAMI:

• if you have or have had pain, swelling or numbness in the jaw, a feeling of heaviness in the jaw, or loose teeth. Your doctor may recommend a dental examination before starting treatment with TEXPAMI.
• if you are undergoing dental treatment or are scheduled to have dental surgery, inform your dentist that you are being treated with TEXPAMI and inform your doctor about the dental treatment.
• while being treated with TEXPAMI, you must maintain good oral hygiene (including regular tooth brushing) and undergo routine dental check-ups.

Contact your doctor and dentist immediately if you experience any problems with your mouth or teeth, such as loose teeth, pain or swelling, failure of wounds to heal, or discharge, as these could be signs of a condition called osteonecrosis of the jaw.
Patients undergoing chemotherapy and/or radiotherapy, taking steroids, undergoing dental surgery, not receiving routine dental care, suffering from gingivitis, who are smokers, or who have previously been treated with a bisphosphonate (used to treat or prevent bone disorders) may have an increased risk of developing osteonecrosis of the jaw.

During treatment with TEXPAMI:

• avoid certain tests called scintigraphy scans, as this medicine may interfere with the agents used in these procedures.
• you will need to undergo tests to monitor calcium levels and other substances in your blood (monitoring of serum electrolytes, calcium, and phosphates).

TEXPAMI will be administered to you with particular caution if:

• you have undergone surgery on the thyroid gland: because you may develop low levels of calcium in the blood (hypocalcemia due to hypoparathyroidism).
• you suffer from heart conditions (left ventricular insufficiency or congestive heart failure): because treatment with this medicine could worsen your condition.
• you have kidney problems (renal insufficiency): this medicine may cause worsening of kidney function. If you are at risk of developing kidney problems, you will undergo periodic monitoring of kidney function.
• you have tumors associated with high levels of calcium in the blood: because you may develop seizures.

During treatment with TEXPAMI, you may experience:

• low levels of calcium in the blood. In this case, your doctor may need to give you calcium or vitamin D supplements (especially if you have lytic bone metastases or multiple myeloma);
• bone, muscle, and joint pain;
• femoral bone fractures. Inform your doctor if you experience any pain in your thigh, hip, or groin.

Other medicines and TEXPAMI
Tell your doctor or nurse if you are taking, have recently taken, or might take any other medicines.
Administration of TEXPAMI together with other medicines of the same type (bisphosphonates) is not recommended, as their combined effect has not yet been studied.
Pay particular attention and inform your doctor if:

• you are taking calcitonin (a medicine used to treat bone mass loss and elevated blood calcium levels) and have severe hypercalcemia;
• you are taking nephrotoxic medicines, especially if you have cancer (multiple myeloma);
• you are receiving treatment with thalidomide;
• you are taking anti-angiogenic medicines.

Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, are planning a pregnancy, or are breastfeeding, consult your doctor or nurse before receiving this medicine.
Do not use TEXPAMI during pregnancy unless absolutely necessary and under strict medical supervision.
Do not use TEXPAMI if you are breastfeeding.

Driving and using machines
After receiving TEXPAMI, in rare cases you may experience drowsiness or dizziness. If this occurs, avoid driving and using machinery.

3. How to use TEXPAMI

This medicine will be administered to you by specialized healthcare personnel. If you have any doubts, consult your doctor or nurse.
After dilution, this medicine must be administered to you as a slow intravenous infusion (into a vein).
Your doctor will determine the dose based on your age, body weight, and your overall health condition.

If you use more TEXPAMI than you should
Since this medicine will be administered by specialized personnel, it is unlikely that you will receive an excessive dose.
However, an overdose of this medicine may lead to decreased calcium levels in the blood (hypocalcaemia), which may manifest as loss of sensation (paraesthesia), muscle cramps and spasms (tetany), and reduced blood pressure (hypotension).
If you think you have been given too much of this medicine, contact your doctor or nurse immediately.

If you have any doubts about how to use this medicine, consult your doctor or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Very common (may affect more than 1 in 10 people)

• fever and flu-like symptoms, sometimes accompanied by malaise, chills, fatigue and hot flushes;
• decrease in blood calcium and phosphate levels (hypocalcaemia, hypophosphataemia).

Common (may affect up to 1 in 10 people)

• decrease in the number of certain white blood cells in the blood (lymphocytopenia);
• decrease in haemoglobin in the blood (anaemia);
• decrease in the number of platelets in the blood (thrombocytopenia);
• decrease in blood calcium levels (symptomatic hypocalcaemia) with tingling and muscle cramps (paraesthesiae, tetany);
• insomnia;
• drowsiness;
• headache;
• skin irritation (rash);
• nausea, vomiting, loss of appetite (anorexia), abdominal pain, diarrhoea, constipation, inflammation of the stomach (gastritis);
• eye inflammations (conjunctivitis);
• generalised pain, temporary bone pain, joint pain (arthralgia) and muscle pain (myalgia);
• pain, redness, swelling and hardening at the infusion site, vein inflammation, phlebitis and formation of blood clots (thrombophlebitis);
• increased blood pressure (hypertension);
• reduced potassium levels in the blood (hypokalaemia);
• reduced magnesium levels in the blood (hypomagnesaemia);
• increased creatinine levels in the blood (increased creatininaemia).

Uncommon (may affect up to 1 in 100 people):

• recurrent stomach pain and/or discomfort (dyspepsia);
• eye inflammations (uveitis including iritis and iridocyclitis);
• muscle cramps;
• osteonecrosis;
• involuntary muscle contractions (seizures), agitation, dizziness, tendency to continuous sleep and reduced responsiveness (lethargy);
• serious kidney problems (acute renal failure);
• decreased blood pressure (hypotension);
• itching;
• serious breathing problems (bronchospasm, dyspnoea, Quincke's oedema);
• allergic reactions, including anaphylactoid reactions;
• changes in liver function test parameters, increased serum urea.

Rare (may affect up to 1 in 1,000 people):

• serious kidney problems (focal segmental glomerulosclerosis, nephrotic syndrome).

Very rare (may affect up to 1 in 10,000 people):

• recurrence of infection caused by the herpes virus (herpes simplex or herpes zoster);
• decrease in the number of white blood cells in the blood (leucopenia);
• eye inflammations (scleritis, episcleritis), vision disorders (xanthopsia);
• serious heart problems (congestive heart failure with fluid accumulation (oedema));
• serious heart problems: left ventricular failure with fluid accumulation (oedema) and serious breathing problems (dyspnoea);
• acute respiratory distress syndrome, interstitial lung disease;
• worsening of existing kidney problems, presence of blood in the urine (haematuria), renal tubular disorder, tubulo-interstitial nephritis, glomerulonephropathy;
• confusion, visual hallucinations;
• increased levels of potassium and sodium in the blood (hyperkalaemia and hypernatraemia);
• liver problems, increased blood nitrogen levels;
• severe allergic reactions (anaphylactic shock).

Contact your doctor if you experience ear pain, ear discharge and/or ear infection. These episodes could be signs of bone damage in the ear.

Unusual fractures of the femur may rarely occur, particularly in patients who have been treated for a long time for osteoporosis. Contact your doctor if you experience pain, weakness or discomfort in the thigh, hip or groin, as this could be an early sign of a possible femoral fracture.

Not known (frequency cannot be estimated from the available data):

• Mouth, tooth and/or jaw pain, swelling or failure of wounds in the mouth or jaw to heal, discharge, numbness or a feeling of heaviness in the jaw, or tooth instability. These could be signs of bone damage affecting the jaw (osteonecrosis). Contact your doctor and dentist immediately if you experience any of these symptoms while being treated with Texpami or after stopping treatment.
• Orbital inflammation
• Heart problems (atrial fibrillation)

Reporting of side effects

If you get any side effects, including ones not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system at http://www.agenziafarmaco.gov.it/content/come-segnalare-una-sospetta-reazione-avversa. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store TEXPAMI

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the packaging after “Expiry” or
“Expires”. The expiry date refers to the last day of that month.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What TEXPAMI 30 mg/10 ml infusion solution contains
The active substance is pamidronate disodium: 10 ml of solution contain 30 mg (3 mg/ml) of pamidronate disodium.
The other components are: mannitol, phosphoric acid, water for injections.

What TEXPAMI 60 mg/10 ml infusion solution contains
The active substance is pamidronate disodium: 10 ml of solution contain 60 mg (6 mg/ml) of pamidronate disodium.
The other components are: mannitol, phosphoric acid, water for injections.

What TEXPAMI 90 mg/10 ml infusion solution contains
The active substance is pamidronate disodium: 10 ml of solution contain 90 mg (9 mg/ml) of pamidronate disodium.
The other components are: mannitol, phosphoric acid, water for injections.

Description of the appearance of TEXPAMI and contents of the pack
Pack containing 2 vials of 30 mg/10 ml;
Pack containing 1 vial of 60 mg/10 ml;
Pack containing 1 vial of 90 mg/10 ml.

Marketing Authorization Holder
PHARMATEX ITALIA S.R.L. - Via San Paolo 1 - 20121 Milano
Manufacturers
FISIOPHARMA S.r.l. - Nucleo industriale 84020 - Palomonte (SA) Italy
HIKMA ITALIA S.p.A. - Viale Certosa 10 - 27100 Pavia Italy
……

The following information is intended exclusively for physicians or healthcare professionals

CLINICAL INFORMATION
Warnings and precautions
Texpami must not be administered as a bolus injection, since high local concentrations may cause infusion site reactions. Pamidronate disodium must be diluted and administered by slow intravenous infusion (see section 4.2 of the Summary of Product Characteristics).

Before administration of Texpami, patients should be assessed to ensure they are adequately hydrated. This is particularly important for patients receiving diuretic therapy.

Metabolic parameters related to hypercalcemia, including serum electrolytes, calcium, and phosphate levels, should be closely monitored once pamidronate therapy has been initiated.

Fractures
Atypical subtrochanteric and diaphyseal femoral fractures have been reported primarily in patients receiving long-term bisphosphonate therapy for osteoporosis. These fractures, which are short transverse or oblique in nature, may occur anywhere along the femur from just below the lesser trochanter to above the supracondylar line. Such fractures may occur spontaneously or following minimal trauma. Some patients report thigh or groin pain, often associated with imaging findings suggestive of stress fractures, weeks or months before a complete femoral fracture occurs. These fractures are often bilateral; therefore, in patients treated with bisphosphonates who experience 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, discontinuation of bisphosphonate therapy should be considered pending individual benefit-risk assessment.

Osteonecrosis of the external auditory canal
Osteonecrosis of the external auditory canal has been reported in association with bisphosphonate use, predominantly during long-term therapy. Possible risk factors for osteonecrosis of the external auditory canal include steroid use, chemotherapy, and/or local risk factors such as infection or trauma. The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving bisphosphonates who present with ear symptoms, including chronic ear infections.

Osteonecrosis of the jaw/mandible (ONJ)
Osteonecrosis of the jaw/mandible (ONJ) has been reported with uncommon frequency in clinical trials and post-marketing in patients receiving pamidronate. Initiation of treatment or a new treatment cycle should be delayed in patients with open soft tissue lesions of the oral cavity that have not healed, except in cases of medical emergency.

A dental examination with appropriate preventive dentistry and an individual benefit-risk assessment should be recommended before starting bisphosphonate therapy in patients with concomitant risk factors.

The following risk factors should be considered when evaluating an individual's risk of developing ONJ:

• Potency of the bisphosphonate (higher risk with highly potent compounds), route of administration (higher risk with parenteral administration), and cumulative bisphosphonate dose
• Cancer, comorbid conditions (e.g., anemia, coagulopathies, infection), smoking
• Concomitant therapies: chemotherapy, angiogenesis inhibitors (see section 4.5 of the Summary of Product Characteristics), head and neck radiotherapy, corticosteroids
• History of dental disease, poor oral hygiene, periodontal disease, invasive dental procedures (e.g., tooth extractions), and ill-fitting dental prostheses

All patients should be encouraged to maintain good oral hygiene, undergo regular dental check-ups, and promptly report any oral symptoms such as tooth mobility, pain, swelling, or non-healing of sores or discharge during treatment with Texpami. Invasive dental procedures should be performed only after careful evaluation during treatment and should be avoided around the time of pamidronate administration. In patients who develop osteonecrosis of the jaw/mandible while receiving bisphosphonate therapy, dental surgical intervention may worsen the condition. For patients requiring dental procedures, there are no available data suggesting that discontinuation of bisphosphonate therapy reduces the risk of osteonecrosis of the jaw/mandible. Management of patients who develop ONJ should be planned in close collaboration between the treating physician and a dentist or oral surgeon experienced in ONJ. Temporary discontinuation of pamidronate therapy should be considered until the condition resolves and contributing risk factors are mitigated, if possible.

Renal impairment
Bisphosphonates, including Texpami, have been associated with renal toxicity, manifesting as worsening renal function and potential renal failure. Deterioration of renal function, progression to renal failure, and dialysis have been reported in patients after the initial or a single dose of pamidronate. Worsening renal function (including renal failure) has also been reported following long-term treatment with pamidronate in patients with multiple myeloma.

Pamidronate is excreted unchanged primarily via the kidney; therefore, the risk of renal adverse events may be higher in patients with impaired renal function. Due to the risk of clinically significant deterioration in renal function that may lead to renal failure, single doses of pamidronate should not exceed 90 mg, and the recommended infusion time must be observed.

As with other intravenously administered bisphosphonates, monitoring of renal function (e.g., measurement of serum creatinine) is recommended before each dose of pamidronate.

Patients receiving frequent pamidronate infusions over prolonged periods, especially those with pre-existing renal disease or predisposition to renal failure (e.g., patients with multiple myeloma and/or tumor-induced hypercalcemia), should have routine clinical and laboratory parameters related to renal function assessed before each dose of pamidronate.

In patients receiving pamidronate for bone metastases or multiple myeloma who show deterioration in renal function, administration of pamidronate should be suspended.

Pamidronate disodium must not be administered concurrently with other bisphosphonates, as their combined effect has not been studied.

In some patients with tumors associated with hypercalcemia, electrolyte imbalances—possibly exacerbated by treatment—may precipitate seizures.

Hepatic impairment
Since clinical data are not available in patients with severe hepatic impairment, specific recommendations cannot be provided for this patient population.

Calcium and vitamin D supplementation
In the absence of hypercalcemia, patients with predominantly lytic bone metastases or multiple myeloma, who are at potential risk of calcium or vitamin D deficiency, should receive oral supplementation with calcium and vitamin D to reduce the risk of hypocalcemia.

Musculoskeletal pain
During post-marketing experience, severe and occasionally disabling bone, joint, and/or muscle pain has been reported in patients receiving bisphosphonates. These reports have been infrequent. This drug class includes Texpami (pamidronate sodium for infusion). The onset of symptoms after starting treatment has varied from one day to several months. Most patients experienced symptom relief after discontinuation of therapy. A subset of patients experienced symptom recurrence when rechallenged with the same or another bisphosphonate.

DOSAGE AND METHOD OF ADMINISTRATION
Texpami must never be administered as a bolus injection, but must be diluted in a calcium-free infusion solution (e.g., 0.9% sodium chloride) and infused slowly.

The infusion rate must not exceed 60 mg/hour (1 mg/min), and the concentration of Texpami in the infusion solution must not exceed 90 mg/250 mL. Typically, a 90 mg dose should be administered as a 250 mL infusion over 2 hours. However, in patients with multiple myeloma or tumor-induced hypercalcemia, a dose of 90 mg should not exceed an infusion volume of 500 mL over 4 hours.

In patients with confirmed or suspected renal dysfunction (multiple myeloma or tumor-induced hypercalcemia), the infusion rate should not exceed 20 mg/hour.

To minimize the risk of infusion site reactions, the cannula should be carefully inserted into a relatively large vein.

Use in adults and elderly
Dosage may vary depending on the patient's clinical condition:

• Predominantly lytic bone metastases and multiple myeloma: The recommended dose of Texpami is 90 mg administered as a single infusion every 4 weeks. In patients with bone metastases receiving chemotherapy every 3 weeks, Texpami at a dose of 90 mg may also be administered every 3 weeks.
• Malignant osteolysis with hypercalcemia:

Prior to or during treatment with Texpami, rehydration with saline solution is recommended.
The total dose of Texpami to be used depends on the patient's initial serum calcium levels.

The following table provides guidance based on clinical data for uncorrected serum calcium values; the same dose range may be used for serum calcium values corrected for serum proteins or albumin in rehydrated patients:

The total dose of Texpami may be administered either as a single infusion or as multiple infusions over 2–4 consecutive days. The maximum dose per treatment cycle is 90 mg, both for initial and repeated administrations. A significant decrease in serum calcium levels is generally observed within 24–48 hours after Texpami administration, with normalization typically achieved within 3–7 days. If normocalcemia is not reached within this time frame, an additional dose may be administered.

The duration of response may vary from patient to patient, and treatment may be repeated if hypercalcemia recurs.

Clinical experience to date suggests that Texpami may decrease in efficacy with increasing numbers of treatments.

Renal impairment
Texpami must not be administered to patients with severe renal impairment (creatinine clearance < 30 ml/min), except in cases of life-threatening oncologic hypercalcemia where the benefit of treatment outweighs the potential risk.

As with other intravenous bisphosphonates, renal monitoring is recommended; for example, serum creatinine should be determined before each dose of Texpami. In patients being treated for bone metastases or multiple myeloma who show signs of worsening renal function, Texpami treatment should be suspended until renal function returns to within 10% of baseline value. This recommendation is based on the results of a clinical study in which worsening renal function was defined as follows:

• In patients with normal baseline creatinine values, an increase of 0.5 mg/dl;
• In patients with abnormal baseline creatinine values, an increase of 1.0 mg/dl.

Results from a pharmacokinetic study conducted in tumor patients with normal or impaired renal function indicate that dosage adjustment is not required in patients with mild (creatinine clearance 61–90 ml/min) to moderate (creatinine clearance 30–60 ml/min) renal impairment. In these patients, the infusion rate must not exceed 90 mg/4 h (approximately 20–22 mg/h).

Hepatic impairment
A pharmacokinetic study has shown that no dose adjustment is necessary in patients with mild to moderate hepatic impairment. Pamidronate has not been studied in patients with severe hepatic impairment.

Children
There is no clinical experience regarding the use of Texpami in children.

Instructions for use
Before administration, the solution must be diluted with an infusion solution (0.9% sodium chloride or 5% glucose) that does not contain calcium.

Overdose
Patients receiving doses higher than those recommended should be closely monitored. If hypocalcemia occurs with symptoms such as paresthesia, tetany, or hypotension, treatment may be administered by infusion of calcium gluconate.

Incompatibilities
Texpami must not be added to infusion solutions containing calcium, as it may form insoluble complexes with bivalent cations.

For further information, consult the Summary of Product Characteristics.