Pamidronate Disodium 3mg/Ml Concentrate For Solution For Infusion
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Pamidronate Disodium 3mg/ml Concentrate for Solution for Infusion
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml of concentrate for solution for infusion contains 3mg pamidronate disodium. 1 vial of 5ml of sterile concentrate contains 15mg of pamidronate disodium.
For excipients, see section 6.1
3 PHARMACEUTICAL FORM
Concentrate for solution for infusion.
The concentrate is a clear and colourless solution, free from visible particles.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of conditions associated with increased osteoclast activity:
• Tumour-induced hypercalcaemia.
• Osteolytic lesions and bone pain in patients with bone metastases associated with breast cancer and multiple myeloma.
• Paget’s disease of bone.
4.2 Posology and method of administration
Pamidronate disodium must never be given as a bolus injection (See Section “4.4 Special warnings and special precautions for use”). The concentrate must be diluted before use (see below) and must be infused slowly.
For information concerning compatibility with infusion solutions, refer to Section “6.6 Instructions for use and handling”. The infusion rate should never exceed 60mg/hour (1mg/min), and the concentration of pamidronate disodium in the infusion solution should not exceed 60mg/250ml. In patients with established or suspected renal impairment (e.g. those with tumour-induced hypercalcaemia or multiple myeloma) it is recommended that the infusion rate does not exceed 20mg/hour (see also "Patients with renal impairment”). In order to minimise local reactions at the infusion site, the cannula should be inserted carefully into a relatively large vein.
Until further experience is gained, pamidronate disodium is only recommended for use in adult patients.
Tumour-induced hypercalcaemia:
Patient must be adequately rehydrated with 0.9% w/v sodium chloride solution before or during treatment.
The total dose of pamidronate disodium to be used for a treatment course depends on the patient's initial serum calcium levels. The following guidelines are derived from clinical data on uncorrected calcium values. However, doses within the ranges given are also applicable for calcium values corrected for serum protein or albumin in rehydrated patients.
|
Initial serum calcium |
Recommended total | |
|
(mmol/L) |
(mg %) |
dose (mg) |
|
up to 3.0 |
up to 12.0 |
15 - 30 |
|
3.0 - 3.5 |
12.0 - 14.0 |
30 - 60 |
|
3.5 - 4.0 |
14.0 - 16.0 |
60 - 90 |
|
> 4.0 |
> 16.0 |
90 |
The total dose of pamidronate disodium may be administered either in a single infusion or in multiple infusions over 2-4 consecutive days. The maximum dose per treatment course is 90mg for both initial and repeated courses.
A significant decrease in serum calcium is generally observed 24-48 hours after administration of pamidronate disodium, and normalisation is usually achieved within 3 to 7 days. If normocalcaemia is not achieved within this time, a further dose may be given. The duration of the response may vary from patient to patient, and treatment can be repeated whenever hypercalcaemia recurs. Clinical experience to date suggests that pamidronate disodium may become less effective as the number of treatment increases.
Osteolytic lesions and bone pain in bone metastases associated with breast cancer: The recommended dose is 90mg every 4 weeks. This dose may also be administered at 3 weekly intervals to coincide with chemotherapy if desired.
Osteolytic lesions and bone pain in Multiple myeloma: The recommended dose is 90mg every 4 weeks.
Paget's disease of Bone:
The recommended treatment course consists of a total dose of 180mg administered in unit doses of either 30mg once a week for 6 consecutive weeks, or 60mg every other week over 6 weeks. Experience to date suggests that any mild and transient unwanted effects (see Section “4.8 Undesirable Effects”) tend to occur after the first dose. For this reason if unit doses of 60mg are used it is recommended that treatment be started with an initial dose of 30mg followed by 60mg every other week (i.e. total dose 210mg). Each dose of 30 or 60mg should be diluted in 125 or 250 ml 0.9% w/v sodium chloride solution respectively, and the infusion rate should not exceed 60mg/hour (1mg/min).This regimen or increased dose levels according to disease severity, up to a maximum total dose of 360mg (in divided doses of 60mg) can be repeated every 6 months until remission of disease is achieved, and if relapse occurs.
Patients with renal impairment:
Until further experience is gained a maximum infusion rate of 20mg/hour is recommended in renal impaired patients.
Pamidronate disodium should not be administered to patients with severe renal impairment (creatinine clearance < 30 mL/min) unless in cases of life-threatening tumour-induced hypercalcaemia where the benefit outweighs the potential risk. Because there is only limited clinical experience in patients with severe renal impairment no dose recommendations for this patient population can be made (see Section 4.4 “Special warnings and special precautions for use” and Section 5.2 “Pharmacokinetic properties”).
As with other i.v. bisphosphonates, renal monitoring is recommended, for instance, measurement of serum creatinine prior to each dose of Pamidronate disodium . In patients receiving Pamidronate disodium for bone metastases or multiple myeloma who show evidence of deterioration in renal function, Pamidronate disodium treatment should be withheld until renal function returns to within 10% of the baseline value. This recommendation is based on a clinical study, in which renal deterioration was defined as follows:
• For patients with normal baseline creatinine, increase of 0.5mg/dL.
• For patients with abnormal baseline creatinine, increase of 1.0mg/dL.
A pharmacokinetic study conducted in patients with cancer and normal or impaired renal function indicates that the dose adjustment is not necessary in mild (creatinine clearance 61-90 mL/min) to moderate renal impairment (creatinine clearance 30-60 mL/min). In such patients, the infusion rate should not exceed 90 mg/4h (approximately 20-22 mg/h).
Patients with hepatic impairment:
Although patients with hepatic impairment exhibited higher mean AUC and Cmax values compared to patients with normal hepatic function, this is not perceived being clinically relevant. As pamidronate is still rapidly cleared from the plasma almost entirely into the bone and as is administered on a monthly basis for chronic treatment, drug accumulation is not expected. Therefore no dose adjustment is necessary in patients with mild to moderate abnormal hepatic function (see Section 5.2 Pharmacokinetic properties “Hepatic impairment”).
Clinical data in patients with severe hepatic impairment is not available. Pamidronate disodium should be administered to this patient population with caution.
Children:
There is no clinical experience of pamidronate disodium in children. Therefore until further experience is gained, Pamidronate disodium is only recommended for use in adult patients.
4.3 Contraindications
Known hypersensitivity to pamidronate disodium or to other Bisphosphonates, or to any of the excipients of Pamidronate disodium.
in pregnancy (see also section 4.6)
in breast feeding women (see also section 4.6)
4.4 Special warnings and precautions for use General
Pamidronate disodium must never be given as a bolus injection, but should always be diluted and given as a slow intravenous infusion (see Section 4.2 Posology and method of administration).
Patients must be assessed prior to administration of Pamidronate disodium to assure that they are appropriately hydrated. This is especially important for patients receiving diuretic therapy.
Convulsions have been precipitated in some patients with tumour-induced hypercalcaemia due to the electrolyte changes associated with this condition and its effective treatment
Standard hypocalcaemia-related metabolic parameters including serum electrolyte, calcium and phosphate should be monitored following initiation of therapy with Pamidronate disodium . Patients who have undergone thyroid surgery may be particularly susceptible to developing hypocalcaemia due to relative hypoparathyroidism.
In patients with cardiac disease, especially in the elderly, additional saline overload may precipitate cardiac failure (left ventricular failure or congestive heart failure). Fever (influenza-like symptoms) may also contribute to this deterioration.
Pamidronate disodium should be given under the supervision of a physician with the facilities to monitor the clinical and biochemical effects.
Renal Insufficiency
Bisphosphonates, including Pamidronate disodium , have been associated with renal toxicity manifested as deterioration of renal function and potential renal failure. Renal deterioration, progression to renal failure and dialysis have been reported in patients after the initial dose or a single dose of Pamidronate disodium . Deterioration of renal function (including renal failure) has also been reported following long-term treatment with Pamidronate disodium in patients with multiple myeloma.
Pamidronate disodium is excreted intact primarily via the kidney (see Section 5.2 Pharmacokinetic properties), thus the risk of renal adverse reactions may be greater in patients with impaired renal function.
Due to the risk of clinically significant deterioration in renal function which may progress to renal failure, single doses of Pamidronate disodium should not exceed 90mg, and the recommended infusion time should be observed (See Section 4.2. Posology and method of administration).
As with other i.v. bisphosphonates renal monitoring is recommended, for instance, measurement of serum creatinine prior to each dose of Pamidronate disodium.
Patients treated with Pamidronate disodium for bone metastases or multiple myeloma should have the dose withheld if renal function has deteriorated (see Section 4.2. Posology and method of administration).
Pamidronate disodium should not be administered to patients with severe renal impairment (creatinine clearance < 30 mL/min) unless in cases of life-threatening tumour-induced hypercalcaemia where the benefit outweighs the potential risk. (See section 4.2 Posology and method of administration “Renal impairment”). Because there is only limited pharmacokinetic data with severe renal impairment no dose recommendations for this patient population can be made (See Section 4.2 “Posology and method of administration” and Section 5.2 “Pharmacokinetic properties”). Pamidronate disodium should not be given with other bisphosphonates because their combined effects have not been investigated.
There is very little experience of the use of Pamidronate disodium in patients receiving haemodialysis.
Hepatic Insufficiency
As there are no clinical data available in patients with severe hepatic insufficiency, no specific recommendations can be given for this patient population (see Sections 4.2 Posology and method of administration and 5.2 Pharmacokinetic properties).
Calcium and Vitamin D Supplementation
In the absence of hypercalcaemia, patients with predominantly lytic bone metastases or multiple myeloma, who are at risk of calcium or Vitamin D deficiency (e.g. through malabsorption or lack of exposure to sunlight) and patients with Paget's disease of the bone should take oral calcium and vitamin D supplementation in order to minimise the potential risk of hypocalcaemia.
Osteonecrosis of the jaw
Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with bisphosphonates, including Pamidronate disodium . Many of these patients were also receiving chemotherapy and corticosteroids. Many had signs of local infection including osteomyelitis.
Post-marketing experience and the literature suggest a greater frequency of reports of ONJ based on tumour type (advanced breast cancer, multiple myeloma), and dental status (dental extraction, periodontal disease, local trauma including poorly fitting dentures).
A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, corticosteroids, poor oral hygiene).
While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw. Clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment .
Musculoskeletal Pain
In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates. This category of drugs includes Pamidronate disodium (pamidronate disodium for infusion). The time to onset of symptoms varied from one day to several months after starting the drug with the majority occurring within a few days. Most patients had relief or improvement of symptoms after stopping treatment. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.
4.5 Interaction with other medicinal products and other forms of interaction
Pamidronate disodium should not be co-administered with other bisphosphonates because their combined effects have not been investigated.
Pamidronate disodium has been administered concomitantly with commonly used anticancer agents without interactions occurring.
Pamidronate disodium has been used in combination with calcitonin in patients with severe hypercalcaemia, resulting in a synergistic effect producing a more rapid fall in serum calcium.
Caution is warranted when Pamidronate disodium is used with other potentially nephrotoxic drugs.
In multiple myeloma patients, the risk of renal dysfunction may be increased when Pamidronate disodium is used in combination with thalidomide.
Since pamidronate disodium binds to bone, it could in theory interfere with bone scintigraphy examinations.
4.6 Fertility, pregnancy and lactation
Pregnancy:
Studies in animals have shown reproductive toxicity (see Section 5.3 Preclinical safety data). Dystocia was observed in the rats. In rats, prolonged parturition and reduced survival rate of pups were probably caused by a decrease in maternal serum calcium levels. In pregnant rats, pamidronate disodium has been shown to cross the placental barrier and accumulate in foetal bone in a manner similar to that observed in adult animals.
There is insufficient clinical experience to support the use of pamidronate disodium in pregnant women. Therefore, pamidronate disodium should not be administered during pregnancy except in cases of life-threatening hypercalcaemia.
Lactation:
It is not known whether pamidronate disodium is excreted in human milk. A study in lactating rats has shown that pamidronate disodium will pass into the milk. Mothers treated with pamidronate disodium should therefore not breast-feed their infants.
4.7 Effects on ability to drive and use machines
Patients should be warned that in rare cases somnolence and/or dizziness may occur following pamidronate disodium infusion, in which case they should not drive, operate potentially dangerous machinery, or engage in other activities that may be hazardous because of decreased alertness.
4.8 Undesirable effects
The most common adverse reactions are asymptomatic hypocalcaemia and fever (an increase in body temperature of 1-2°C), typically occurring within the first 48 hours of infusion. Fever usually resolves spontaneously and does not require treatment.
The frequency is defined using the following conventions:
Very common (>1/10)
Common (>1/100, <1/10)
Uncommon (>1/1,000 <1/100)
Rare (>1/10,000, <1/1,000)
Very rare (<1/10,000)
Not known (cannot be estimated from the available data).
|
VERY COMMON (>1/10) |
COMMON (>1/100, <1/10) |
UNCOMMON (>1/1000, <1/100) |
RARE (>1/10,000, <1/1000) |
VERY RARE (<1/10,000) | |
|
Infections and infestations |
Reactivation of herpes simplex and herpes zoster | ||||
|
Blood and the lymphatic system disorders |
Lymphocytopenia Thrombocytop enia , Anaemia |
Leukopenia | |||
|
Immune system disorders |
Allergic reactions including anaphylactoid reactions, bronchospasm/ dyspnoe, Quincke’s (angioneurotic oedema) |
Anaphylactic shock | |||
|
Metabolism and nutrition disorders |
Asymptomatic hypocalcaemia Anorexia | ||||
|
Psychiatric disorders |
Visual hallucinations Confusion |
|
VERY COMMON (>1/10) |
COMMON (>1/100, <1/10) |
UNCOMMON (>1/1000, <1/100) |
RARE (>1/10,000, <1/1000) |
VERY RARE (<1/10,000) | |
|
Nervous system disorders |
Symptomatic hypocalcaemia (paraesthesia, tetany), Headache, Insomnia, Somnolence |
Agitation Dizziness Seizures, lethargy | |||
|
Eye disorders |
Conjunctivitis |
Uveitis (iritis, iridocyclitis) |
Scleritis Episcleritis Xanthopsia | ||
|
Cardio vascular disorders |
Hypertension |
Hypotension |
left ventricular failure (dyspnoea, pulmonary oedema), congestive heart failure (oedema) due to fluid overload. | ||
|
Gastrointestin al disorders |
Nausea Vomiting Abdominal pain Diarrhoea Constipation Gastritis |
Dyspepsia | |||
|
Skin and subcutaneous tissue disorders |
Rash |
Pruritus | |||
|
Musculoskele tal, connective tissue and bone disorders |
Transient bone pain Arthralgia Myalgia Generalised pain |
Muscle cramps |
|
VERY COMMON (>1/10) |
COMMON (>1/100, <1/10) |
UNCOMMON (>1/1000, <1/100) |
RARE (>1/10,000, <1/1000) |
VERY RARE (<1/10,000) | |
|
Renal and urinary disorders |
Acute renal failure |
focal segmental glomerulosclerosi s including the collapsing variant, nephrotic syndrome |
Haematuria deterioration of preexisting renal disease | ||
|
General disorders and administratio n site conditions |
Fever and influenza-like symptoms, sometimes accompanied by malaise, rigor, fatigue and flushes Reactions at the infusion site: pain, redness, swelling, induration, phlebitis, thrombophlebitis. | ||||
|
Investigations |
hypocalcaemia 5 hypophosphat aemia |
hypomagnesaemia , hypokalaemia, increase in serum creatinine |
abnormal liver function tests, increase in serum urea |
hyperkalaemi a, , hypernatraem ia |
Many of the adverse drug reactions may have been related to the underlying disease.
When the effects of zoledronic acid (4 mg) and pamidronate (90 mg) were compared in one clinical trial, the number of atrial fibrillation adverse events was higher in the pamidronate group (12/556, 2.2%) than in the zoledronic acid group (3/563, 0.5%). Previously, it has been observed in a clinical trial, investigating patients with postmenopausal osteoporosis, that zoledronic acid treated patients (5 mg) had an increased risk of atrial fibrillation serious adverse events compared to placebo (1.3% compared to 0.6%). The mechanism behind the increased incidence of atrial fibrillation in association with zoledronic acid and pamidronate treatment is unknown.
Postmarketing experience:
The following adverse reactions have been reported during post-approval use of pamidronate disodium. Because these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Cases of osteonecrosis (primarily of the jaw) have been reported predominantly in cancer patients treated with bisphosphonates including pamidronate disodium (uncommon). Many of these patients had signs of local infection including osteomyelitis and the majority of the reports refer to cancer patients following tooth extractions or other dental surgeries. Osteonecrosis of the jaw has multiple well documented risk factors including a diagnosis of cancer, concomitant therapies (e.g. chemotherapy, radiotherapy, corticosteroids) and co-morbid conditions (e.g. anaemia, coagulopathies, infection, pre-existing oral disease). Although causality has not been determined, it is prudent to avoid dental surgery as recovery may be prolonged (see section 4.4 Special warnings and precautions for use). Data suggest a greater frequency of reports of ONJ based on tumour type (advanced breast cancer, multiple myeloma).
4.9 Overdose
Patients who have received doses higher than those recommended should be carefully monitored. In the event of clinically significant hypocalcaemia with paraesthesia, tetany and hypotension, reversal may be achieved with an infusion of calcium gluconate.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
ATC code: M05B A03
The active substance pamidronate disodium is a potent inhibitor of osteoclastic bone resorption. It binds strongly to hydroxyapatite crystals and inhibits the formation and dissolution of these crystals in vitro. Inhibition of osteoclastic bone resorption in vivo may be at least partly due to binding of the drug to the bone mineral.
Pamidronate disodium suppresses the accession of osteoclast precursors onto the bone. However, the local and direct antiresorptive effect of bone-bound bisphosphonate appears to be the predominant mode of action in vitro and in vivo.
Experimental studies have demonstrated that pamidronate disodium inhibits tumour-induced osteolysis when given prior to or at the time of inoculation or transplantation with tumour cells. Biochemical changes reflecting the inhibitory effect of pamidronate disodium on tumour-induced hypercalcaemia are characterised by a decrease in serum calcium and phosphate and secondarily by decreases in urinary excretion of calcium, phosphate, and hydroxyproline.
Hypercalcaemia can lead to depletion in the volume of extracellular fluid and a reduction in the glomerular filtration rate (GFR). By controlling hypercalcaemia, pamidronate disodium improves GFR and lowers elevated serum creatinine levels in most patients.
Clinical trials in patients with breast cancer and predominantly lytic bone metastases or with multiple myeloma showed that pamidronate disodium prevented or delayed skeletal-related events (hypercalcaemia, fractures, radiation therapy, surgery to bone, spinal cord compression) and decreased bone pain.
Paget's disease of bone, which is characterised by local areas of increased bone resorption and formation with qualitative changes in bone remodelling, responds well to treatment with pamidronate disodium. Clinical and biochemical remission of the disease has been demonstrated by bone scintigraphy, decreases in urinary hydroxyproline and serum alkaline phosphatase, and by symptomatic improvement.
5.2 Pharmacokinetic properties
Pamidronate disodium has a strong affinity for calcified tissues, and total elimination of pamidronate disodium from the body is not observed within the time frame of experimental studies. Calcified tissues are therefore regarded as site of "apparent elimination".
Absorption. Pamidronate disodium is given by intravenous infusion. By definition, absorption is complete at the end of the infusion.
Distribution. Plasma concentrations of pamidronate disodium rise rapidly after the start of an infusion and fall rapidly when the infusion is stopped. The apparent halflife in plasma is about 0.8 hours. Apparent steady-state concentrations are therefore achieved with infusions of more than about 2-3 hours' duration. Peak plasma pamidronate disodium concentrations of about 10 nmol/ml are achieved after an intravenous infusion of 60mg given over 1 hour and the apparent plasma clearance is about 180 ml/min.
In animals and in man, a similar percentage of the dose is retained in the body after each dose of pamidronate disodium. Thus the accumulation of pamidronate disodium in bone is not capacity-limited, and is dependent solely on the total cumulative dose administered.
The percentage of circulating pamidronate disodium bound to plasma proteins is relatively low (about 54 %), and increases when calcium concentrations are pathologically elevated.
Elimination. Pamidronate disodium does not appear to be eliminated by biotransformation. After an intravenous infusion, about 20-55 % of the dose is recovered in the urine within 72 hours as unchanged pamidronate disodium. Within the time frame of experimental studies the remaining fraction of the dose is retained in the body. The percentage of the dose retained in the body is independent of both the dose (range 15-180 mg) and the infusion rate (range 1.25-60mg/h). From the urinary elimination of pamidronate disodium, two decay phases, with apparent halflife of about 1.6 and 27 hours, can be observed. The apparent renal clearance is about 54 ml/min, and there is a tendency for the renal clearance to correlate with creatinine clearance.
Characteristics in patients.
Hepatic and metabolic clearance of pamidronate disodium is insignificant.
Hepatic Impairment:
Impairment of liver function is therefore not expected to influence the pharmacokinetics of pamidronate disodium. Pamidronate disodium thus displays little potential for drug-drug interactions both at the metabolic level and at the level of protein binding (see above). No changes in dosing are recommended for patients with mild to moderate hepatic dysfunction.
Renal Impairment:
A pharmacokinetic study conducted in patients with cancer showed no differences in plasma AUC of pamidronate between patients with normal renal function and patients with mild to moderate renal impairment. In patients with severe renal impairment (creatinine clearance <30mL/min), the AUC of pamidronate was approximately 3 times higher than in patients with normal renal function (creatinine clearance>90mL/min). Because there is only limited pharmacokinetic data with severe renal impairment no dose recommendations for this patient population can be made (See Section 4.2 “Posology and method of administration” and Section 4.4 “Special warnings and special precautions for use”).
5.3 Preclinical safety data
The toxicity of pamidronate disodium is characterised by direct (cytotoxic) effects on organs with a copious blood supply, particularly the kidneys following i.v. exposure. The compound is not mutagenic and does not appear to have carcinogenic potential.
Studies in rats and rabbits determined that pamidronate disodium produces maternal toxicity and embryo/foetal effects when administered at doses of 0.6 to 8.3 times the highest recommended human dose for a single intravenous infusion. The effects include protracted parturition leading to dystocia, and shortened long bones in the foetus. .Animal data suggest that uptake of bisphosphonates into foetal bone is greater than into maternal bone.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Mannitol, sodium hydroxide, phosphoric acid (for pH adjustment), water for injection.
6.2 Incompatibilities
Pamidronate disodium will form complexes with divalent cations and should not be added to calcium-containing intravenous solutions.
6.3 Shelf life
36 months
6.4 Special precautions for storage
Chemical and physical in-use stability in glucose 50mg/ml has been demonstrated for
24 hours at 2-8°C.
From a microbiological point of view, the product should be used immediately.
If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2-8°C, unless dilution has taken place in controlled and validated aseptic conditions.
6.5 Nature and contents of container
5 ml vials made of clear, colourless glass (Type I glass, Ph.Eur.).
The vial closures are made from chlorobutyl rubber, with a PTFE coated surface. The vials are then sealed with tamper proof aluminium caps, and packaged in a carton.
Pack sizes:
1, 2, 4, 5, 6 and 10 vials
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
The concentrate should be further diluted with a calcium-free infusion solution (0.9% w/v Sodium Chloride Intravenous Infusion is recommended) before administration. Do not use if particles are present. Any portion of the contents remaining after use should be discarded.
7 MARKETING AUTHORISATION HOLDER
Tillomed Laboratories Ltd.
3 Howard Road, Eaton Socon
St. Neots, Cambridgeshire PE19 3ET
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 11311/0217
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
21/09/2011
10 DATE OF REVISION OF THE TEXT
21/09/2011