Sandostatin LAR

1. Name Of The Medicinal Product

Sandostatin^® LAR^® 10 mg, 20 mg or 30 mg powder and solvent for suspension for injection

2. Qualitative And Quantitative Composition

The active substance is octreotide* free peptide, 10 mg, 20 mg or 30 mg nominally 4.15% of fill weight equivalent to 4.65% of octreotide acetate.

Following suspension of the powder (microspheres) with the supplied vehicle solution, Sandostatin LAR suspension contains less than 1mmol (23mg) of sodium per dose, i.e. essentially “sodium-free”.

For a full list of excipients see section 6.1.

* INN rec.

3. Pharmaceutical Form

Powder and solvent for suspension for injection.

Powder: white to off-white powder.

Solvent for suspension for injection: clear, colourless solution.

Sandostatin LAR is a long-acting depot injection form of octreotide. Powder (microspheres for suspension for injection) to be suspended in a vehicle immediately prior to i.m. injection.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of patients with acromegaly:

For symptomatic control and reduction of growth hormone and IGF-1 levels in patients with acromegaly

• who are adequately controlled on s.c. treatment with Sandostatin; in whom surgery or radiotherapy is inappropriate or ineffective, or in the interim period until radiotherapy becomes fully effective.

• in short term treatment (3-12 months) prior to pituitary surgery (see also Section 5.1 Pharmacological properties).

Treatment of patients with advanced neuroendocrine tumours of the midgut; or of unknown primary origin where non-midgut sites of origin have been excluded.

Relief of symptoms associated with functional gastroenteropancreatic endocrine tumours including:

• Carcinoid tumours with features of carcinoid syndrome

• VIPomas

• Glucagonomas

in patients whose symptoms are adequately controlled on s.c. treatment with Sandostatin.

Currently data does not support the use of Sandostatin as antitumour therapy in patients with pancreatic neuroendocrine tumours.

4.2 Posology And Method Of Administration

Sandostatin LAR may only be administered by deep intragluteal injection. The site of repeat intragluteal injections should be alternated between the left and right gluteal muscle (see 6.6 Instructions for use/handling).

Acromegaly

For patients who have not received prior treatment with subcutaneous Sandostatin, a test dose of s.c. Sandostatin (50-100mcg) is recommended to assess any adverse reaction to octreotide prior to initiating treatment with Sandostatin LAR.

For de novo patients who have received a test dose and for patients who are adequately controlled with s.c. Sandostatin, treatment should be started with 20mg Sandostatin LAR intramuscularly at 4-week intervals for 3 months. Treatment with Sandostatin LAR can be started on the day after the last dose of s.c. Sandostatin. Subsequent dosage adjustment should be based on serum growth hormone (GH) and insulin-like growth factor l (IGF 1)/somatomedin C concentrations and clinical symptoms.

For patients in whom clinical symptoms and biochemical parameters (GH; IGF 1) are not fully controlled (GH concentrations still above 2.5μg/L{5mU/L}), the dose may be increased to 30mg every 4 weeks.

For patients whose GH concentrations are consistently below 1μg/L (2mU/L), whose IGF 1 serum concentrations have normalised, and in whom most reversible signs/symptoms of acromegaly have disappeared after 3 months of treatment with 20mg, the dose may be reduced to 10mg every 4 weeks. However, in this group of patients serum GH and IGF 1 concentrations, and clinical signs/symptoms should be monitored particularly closely.

For patients on a stable dose of Sandostatin LAR, assessment of GH and IGF should be made every 12 months. Six-monthly monitoring may be necessary in those patients whose clinical and biochemical control is less adequate.

In order to permit successful endocrine testing of the completeness of tumour removal 5-6 weeks post surgery, the last injection of Sandostatin LAR should be administered at least 3-4 weeks prior to surgery.

Treatment of patients with advanced neuroendocrine tumours of the midgut; or of unknown primary origin where non-midgut sites of origin have been excluded

The recommended dose of Sandostatin LAR is 30mg administered every 4 weeks (see section 5.1 Pharmacodynamic properties). Treatment with Sandostatin LAR for tumour control should be continued in the absence of tumour progression.

Relief of symptoms associated with functional gastroenteropancreatic endocrine tumours.

After adequate control has been established with Sandostatin s.c., treatment should be started with 20mg Sandostatin LAR intramuscularly at 4-week intervals. Treatment with Sandostatin s.c. should be continued at the previously effective dosage for 2 weeks after the first injection of Sandostatin LAR. Response should be assessed after 3 months of treatment.

For patients in whom symptoms are only partially controlled after 3 months of treatment, the dose may be increased to 30mg Sandostatin LAR every 4 weeks.

For patients in whom symptoms and biological markers are well controlled after 3 months of treatment, the dose may be reduced to 10mg Sandostatin LAR every 4 weeks.

For days when symptoms associated with gastroenteropancreatic tumours may increase during treatment with Sandostatin LAR, additional administration of s.c. Sandostatin is recommended at the dose used prior to the Sandostatin LAR treatment.

Use in patients with impaired renal function

Impaired renal function did not affect the total exposure (AUC; area under the curve) to octreotide when administered s.c. as Sandostatin. Therefore, no dose adjustment of Sandostatin LAR is necessary.

Use in patients with impaired hepatic function

In a study with Sandostatin administered s.c. and i.v. it was shown that the elimination capacity may be reduced in patients with liver cirrhosis, but not in patients with fatty liver disease. In certain cases patients with liver impairment may require dose adjustment.

Use in elderly patients

In a study with Sandostatin administered s.c., no dose adjustment was necessary in patients

Use in children

There is very limited experience with use of Sandostatin LAR in children.

4.3 Contraindications

Known hypersensitivity to octreotide or to any of the excipients.

4.4 Special Warnings And Precautions For Use

General

As GH-secreting pituitary tumours may sometimes expand, causing serious complications (eg. visual field defects), it is essential that all patients be carefully monitored. If evidence of tumour expansion appears, alternative procedures are advisable.

The therapeutic benefits of a reduction in growth hormone (GH) levels and normalisation of insulin-like growth factor 1 (IGF-1) concentration in female acromegalic patients could potentially restore fertility. Female patients of child-bearing potential should be advised to use adequate contraception if necessary during treatment with octreotide (see also section 4.6 Pregnancy and lactation).

Thyroid function (TSH and thyroid hormone levels) should be monitored in patients receiving prolonged treatment with octreotide.

Cardiovascular related events

Uncommon cases of bradycardia have been reported. Dose adjustments of drugs such as beta-blockers, calcium channel blockers, or agents to control fluid and electrolyte balance, may be necessary.

Gallbladder and related events

The incidence of gallstone formation with Sandostatin treatment is estimated to be between 15-30%. Long term exposure to Sandostatin LAR of patients with acromegaly or gastroenteropancreatic tumours suggests that treatment with Sandostatin LAR does not increase the incidence of gallstone formation, compared with s.c. treatment. Ultrasonic examination of the gallbladder before and at about 6 monthly intervals during Sandostatin LAR therapy is however recommended. If gallstones do occur, they are usually asymptomatic; symptomatic stones should be treated either by dissolution therapy with bile acids or by surgery.

Glucose metabolism

Because of its inhibitory action on growth hormone, glucagon and insulin release, Sandostatin LAR may affect glucose regulation. Post prandial glucose tolerance may be impaired. As reported for patients treated with s.c. Sandostatin, in some instances a state of persistent hyperglycaemia may be induced as a result of chronic administration. Hypoglycaemia has also been observed.

In patients with concomitant Type I diabetes mellitus, Sandostatin LAR is likely to affect glucose regulation, and insulin requirements may be reduced. In non diabetics and Type II diabetics with partially intact insulin reserves, Sandostatin s.c. administration may result in increases in post-prandial glycaemia. It is therefore recommended to monitor glucose tolerance and antidiabetic treatment in patients receiving Sandostatin LAR.

In patients with insulinomas, octreotide, because of its greater relative potency in inhibiting the secretion of GH and glucagon than that of insulin, and because of the shorter duration of the inhibitory action on insulin, may increase the depth and prolong the duration of hypoglycaemia. These patients should be closely monitored.

Nutrition

Octreotide may alter absorption of dietary fats in some patients.

Depressed vitamin B₁₂ levels and abnormal Schilling's tests have been observed in some patients receiving octreotide therapy. Monitoring of vitamin B₁₂ levels is recommended during therapy with Sandostatin LAR in patients who have a history of vitamin B₁₂ deprivation.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Octreotide has been found to reduce the intestinal absorption of cyclosporin and to delay that of cimetidine.

Concomitant administration of octreotide and bromocriptine increases the bioavailability of bromocriptine.

Limited published data indicate that somatostatin analogs might decrease the metabolic clearance of compounds known to be metabolized by cytochrome P450 enzymes, which may be due to the suppression of growth hormone. Since it cannot be excluded that octreotide may have this effect, caution should be exercised during co-administration of octreotide and drugs mainly metabolized by CYP3A4, which have a low therapeutic index (e.g. carbamazepine, digoxin, warfarin and terfenadine).

4.6 Pregnancy And Lactation

Pregnancy

Sandostatin should only be prescribed to pregnant women under compelling circumstances (see also section 4.4 Special warnings and precautions for use).

There are no adequate and well-controlled studies in pregnant women. In the post-marketing experience, data on a limited number of exposed pregnancies have been reported in patients with acromegaly, however, in half of the cases the pregnancy outcomes are unknown. Most women were exposed to octreotide during the first trimester of pregnancy at doses ranging from 100-300 micrograms/day of Sandostatin s.c. or 20-30 mg/month of Sandostatin LAR. In approximately two-thirds of the cases with known outcome, the women elected to continue octreotide therapy during their pregnancies. In most of the cases with known outcome, normal newborns were reported, but also several spontaneous abortions during the first trimester, and a few induced abortions.

There were no cases of congenital anomalies or malformations due to octreotide usage in the cases that reported pregnancy outcomes.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development apart from some transient retardation of physiological growth (see section 5.3 Preclinical safety data).

Lactation

Patients should not breastfeed during Sandostatin treatment. It is unknown whether octreotide is excreted in human breast milk. Animal studies have shown excretion of octreotide in breast milk.

4.7 Effects On Ability To Drive And Use Machines

No data exist on the effects of Sandostatin LAR on the ability to drive and use machines.

4.8 Undesirable Effects

The most frequent adverse reactions reported during octreotide therapy include gastrointestinal disorders, nervous system disorders, hepatobiliary disorders and metabolism and nutritional disorders.

The most commonly reported adverse reactions in clinical trials with octreotide administration were diarrhoea, abdominal pain, nausea, flatulence, headache, cholelithiasis, hyperglycaemia and constipation. Other commonly reported adverse reactions were dizziness, localised pain, bilary sludge, thyroid dysfunction (e.g., decreased thyroid stimulating hormone [TSH], decreased Total T4, and decreased Free T4), loose stools, impaired glucose tolerance, vomiting, asthenia and hypoglycaemia.

In rare instances, gastrointestinal side-effects may resemble acute intestinal obstruction, with progressive abdominal distension, severe epigastric pain, abdominal tenderness and guarding.

Although measured faecal fat excretion may increase, there is no evidence to date that long-term treatment with octreotide has led to nutritional deficiency due to malabsorption.

In very rare instances, acute pancreatitis has been reported within the first hours or days of s.c. Sandostatin treatment and resolved on withdrawal of the drug. In addition, cholelithiasis-induced pancreatitis has been reported for patients on long-term s.c. Sandostatin treatment.

In both acromegalic and carcinoid syndrome patients ECG changes were observed such as QT prolongation, axis shifts, early repolarisation, low voltage, R/S transition, early R wave progression, and non-specific ST-T wave changes. The relationship of these events to octreotide acetate is not established because many of these patients have underlying cardiac diseases (see section 4.4 Special warnings and precautions for use).

The following adverse drug reactions, listed in Table 1, have been accumulated from clinical studies with octreotide:

Adverse drug reactions (Table 1) are ranked under heading of frequency, the most frequent first, using the following convention: 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), including isolated reports. Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.

Table 1 Adverse drug reactions reported in clinical trials

Endocrine disorders
Common:	Hypothyroidism, thyroid dysfunction (e.g., decreased TSH, decreased Total T4, and decreased Free T4).
Metabolism and nutrition disorders
Very common: Common: Uncommon:	Hyperglycaemia. Hypoglycaemia, impaired glucose tolerance, anorexia. Dehydration.
Cardiac disorders
Common: Uncommon:	Bradycardia. Tachycardia.
Respiratory disorders Common:	Dyspnoea.
Gastrointestinal disorders
Very common:	Diarrhoea, abdominal pain, nausea, constipation, flatulence.
Common:	Dyspepsia, vomiting, abdominal bloating, steatorrhoea, loose stools, discolouration of faeces.
Nervous system disorders Very common: Common:	Headache. Dizziness.
Hepatobiliary disorders
Very common:	Cholelithiasis.
Common:	Cholecystitis, biliary sludge, hyperbilirubinaemia.
Skin and subcutaneous tissue disorders
Common:	Pruritus, rash, alopecia.
General disorders and administration site
Very common:	Injection site localised pain.
Investigations Common:	Elevated transaminase levels.

Post-marketing

Spontaneously reported adverse reactions presented in Table 2, are reported voluntarily and it is not always possible to reliably establish frequency or a causal relationship to drug exposure.

Table 2 Adverse drug reactions derived from spontaneous reports

Immune disorders	Anaphylaxis, allergy/hypersensitivity reactions.
Skin and subcutaneous tissue disorders	Urticaria.
Hepatobiliary disorders	Acute pancreatitis, acute hepatitis without cholestasis, cholestatic hepatitis, cholestasis, jaundice, cholestatic jaundice.
Cardiac disorders	Arrhythmias.
Investigations	Increased alkaline phosphatase levels, increased gamma glutamyl transferase levels.

4.9 Overdose

A limited number of accidental overdoses of Sandostatin LAR have been reported. The doses ranged from 100mg to 163mg/month of Sandostatin LAR. The only adverse event reported was hot flushes.

Cancer patients receiving doses of Sandostatin LAR up to 60 mg/month and up to 90mg/2 weeks have been reported. These doses were in general well tolerated; however, the following adverse events have been reported: frequent urination, fatigue, depression, anxiety and lack of concentration.

The management of overdosage is symptomatic.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Octreotide is a synthetic octapeptide derivative of naturally occurring somatostatin with similar pharmacological effects, but with a considerably prolonged duration of action. It inhibits pathologically increased secretion of GH and of peptides and serotonin produced within the gastroenteropancreatic (GEP) endocrine system.

In animals, octreotide is a more potent inhibitor of GH, glucagon and insulin release than somatostatin, with greater selectivity for GH and glucagon suppression.

In healthy subjects octreotide, like somatostatin, has been shown to inhibit

• release of GH stimulated by arginine, exercise and insulin-induced hypoglycaemia;

• post-prandial release of insulin, glucagon, gastrin, other peptides of the GEP system, and arginine-stimulated release of insulin and glucagon;

• thyrotropin-releasing hormone (TRH)-stimulated release of thyroid- stimulating hormone (TSH).

Unlike somatostatin, octreotide inhibits GH preferentially over insulin and its administration is not followed by rebound hypersecretion of hormones (i.e. GH in patients with acromegaly).

In patients with acromegaly, Sandostatin LAR, a galenical formulation of octreotide suitable for repeated administration at intervals of 4 weeks, delivers consistent and therapeutic octreotide serum concentrations thus consistently lowering GH and normalising IGF 1 serum concentrations in the majority of patients. In most patients, Sandostatin LAR markedly reduces the clinical symptoms of the disease, such as headache, perspiration, paraesthesia, fatigue, osteoarthralgia and carpal tunnel syndrome.

In individual patients with GH-secreting pituitary adenoma, Sandostatin LAR was reported to lead to shrinkage of the tumour mass (prior to surgery). However, progression to surgery should not be delayed. Further tumour shrinkage cannot be expected as a feature of continued long term treatment.

For patients with functional tumours of the gastroenteropancreatic endocrine system, treatment with Sandostatin LAR provides continuous control of symptoms related to the underlying disease. The effect of octreotide in different types of gastroenteropancreatic tumours are as follows:

Carcinoid tumours: Administration of octreotide may result in improvement of symptoms, particularly of flushing and diarrhoea. In many cases, this is accompanied by a falling plasma serotonin and reduced urinary excretion of 5-hydroxyindole acetic acid.

VIPomas: The biochemical characteristics of these tumours is overproduction of vasoactive intestinal peptide (VIP). In most cases, administration of octreotide results in alleviation of the severe secretory diarrhoea typical of the condition, with consequent improvement in quality of life. This is accompanied by an improvement in associated electrolyte abnormalities, e.g. hypokalaemia, enabling enteral and parenteral fluid and electrolyte supplementation to be withdrawn. Clinical improvement is usually accompanied by a reduction in plasma VIP levels, which may fall into the normal reference range.

Glucagonomas: Administration of octreotide results in most cases in substantial improvement of the necrolytic migratory rash which is characteristic of the condition. The effect of octreotide on the state of mild diabetes mellitus which frequently occurs is not marked and, in general, does not result in a reduction of requirements for insulin or oral hypoglycaemic agents. Octreotide produces improvement of diarrhoea, and hence weight gain, in those patients affected. Although administration of octreotide often leads to an immediate reduction in plasma glucagon levels, this decrease is generally not maintained over a prolonged period of administration, despite continued symptomatic improvement.

Treatment of patients with advanced neuroendocrine tumours of the midgut; or of unknown primary origin where non-midgut sites of origin have been excluded

A Phase III, randomised, double-blind, placebo-controlled study (PROMID) demonstrated that Sandostatin LAR inhibits tumour growth in patients with advanced neuroendocrine tumours of the midgut. 85 patients were randomised to receive Sandostatin LAR 30 mg every 4 weeks (n = 42) or placebo (n = 43) for 18 months, or until tumour progression or death.

Main inclusion criteria were: treatment naïve; histologically confirmed; locally inoperable or metastatic well-differentiated; functionally active or inactive neuroendocrine tumours/carcinomas; with primary tumour located in the midgut or unknown origin believed to be of midgut origin if a primary within the pancreas, chest, or elsewhere was excluded.

The primary endpoint was time to tumour progression or tumour-related death (TTP).

In the conservative ITT (cITT) analysis population reported by the PROMID study group (Rinke et al., 2009) 26 and 40 progressions or tumour-related deaths were observed in the Sandostatin LAR and placebo groups, respectively (HR=0.34; 95% CI, 0.20 to 0.59; p-value =0.000072; Fig 1). Median time to tumour progression was 14.3 months (95% CI, 11.0 to 28.8 months) in the Sandostatin LAR group and 6.0 months (95% CI, 3.7 to 9.4 months) in the placebo group. Treatment effect was similar in patients with functionally active (HR = 0.23; 95% CI, 0.09 to 0.57) and inactive tumours (HR = 0.25; 95% CI, 0.10 to 0.59). After 6 months of treatment, stable disease was observed in 66 % of patients in the Sandostatin LAR group and 37 % of patients in the placebo group.

The observed TTP benefit was confirmed by a supportive post-hoc analysis performed by Novartis on the ITT analysis population based on 61 events of tumour progressions or tumour-related deaths (25, including one tumour related death, in the Sandostatin LAR arm and 36 in the placebo arm). Median TTP in this post-hoc ITT analysis was 11.3 months (95% CI, 6.7-14.3) in the Sandostatin LAR group and 5.6 months (95% CI, 3.5-6.2) in the placebo group, (HR 0.41, 95% CI, 0.24 to 0.70; p-value=0.0008). This significant delay of progression was consistently observed in the subsets according to functional status, with hazard ratios of 0.41 (95% CI, 0.18 to 0.95) and 0.41 (95% CI, 0.20 to 0.82) in functionally active and inactive tumours, respectively.

Figure 1 Kaplan-Meier estimates of TTP comparing Sandostatin LAR with placebo (conservative ITT population)

Table 1 TTP results by analysis populations

	TTP Events	Median TTP months [95% C.I.]	HR [95% C.I.] p-value *
Sandostatin LAR	Placebo	Sandostatin LAR	Placebo
cITT	26	40	14.3 [95% CI, 11.0 to 28.8]	6.0 [95% CI, 3.7 to 9.4]	0.34 [95% CI, 0.20 to 0.59] P=0.000072
NVS ITT	25	36	11.3 [95% CI, 6.7 to 14.3]	5.6 [95% CI, 3.5 to 6.2]	0.41 [95% CI, 0.24 to 0.7] P=0.0008
HR=hazard ratio; TTP=time to tumor progression; ITT=intention to treat; cITT=conservative ITT; NVS ITT: supportive post-hoc analysis conducted by Novartis *Logrank test stratified by functional activity

Based on the significant clinical benefit of Sandostatin LAR observed in this pre-planned interim analysis the recruitment was stopped.

The safety of Sandostatin LAR in this trial was consistent with its established safety profile.

5.2 Pharmacokinetic Properties

After single i.m. injections of Sandostatin LAR, the octreotide concentration reaches a transient initial peak within 1 hour after administration, followed by a progressive decrease to a low undetectable octreotide level within 24 hours. After this peak on day 1, octreotide remains at sub-therapeutic levels in the majority of the patients for the following 7 days.

Thereafter, octreotide concentrations increase again, reach plateau concentrations at around day 14 and remain relatively constant during the following 3 to 4 weeks. The peak level during day 1 is lower than levels during the plateau phase, and no more than 0.5% of the total drug release occurs during day 1. After about day 42, the octreotide concentration decreases slowly, concomitant with the terminal degradation phase of the polymer matrix of the dosage form.

In patients with acromegaly, mean plateau octreotide concentrations after single doses of 10mg, 20mg and 30mg of Sandostatin LAR amount to 358ng/L, 926ng/L and 1710ng/L, respectively. Steady-state serum octreotide concentrations, reached after 3 injections at 4-week intervals, are higher by a factor of approximately 1.6 to 1.8 and amount to 1557ng/L, and 2384ng/L after multiple injections of 20mg and 30mg of Sandostatin LAR, respectively.

In patients with carcinoid tumours, the mean (and median) steady-state serum concentrations of octreotide after multiple injections of 10mg, 20mg and 30mg of Sandostatin LAR given a 4-week intervals also increase linearly with dose and were 1231 (894) ng/L, 2620 (2270) ng/L, and 3928 (3010) ng/L respectively.

No accumulation of octreotide beyond that expected from overlapping release profiles occurred over a duration of up to 28 monthly injections of Sandostatin LAR.

The pharmacokinetic profile of octreotide after injection of Sandostatin LAR reflects the release profile from the polymer matrix and its biodegradation. Once released into the systemic circulation, octreotide distributes according to its known pharmacokinetic properties, as described for s.c. administration. The volume of distribution of octreotide at steady state is 0.27 L/kg and the total body clearance is 160 ml/min. Plasma protein binding amounts to 65% and essentially no drug is bound to blood cells.

5.3 Preclinical Safety Data

Acute toxicity

Acute toxicity studies of octreotide in mice revealed LD₅₀ values of 72mg/kg by the i.v. route and of 470mg/kg by the s.c. route. The acute i.v. LD₅₀ value of octreotide in rats was determined at 18mg/kg. Octreotide acetate was well tolerated by dogs receiving up to 1mg/kg body weight by i.v. bolus injection.

Repeated dose toxicity

In a repeat dose study performed in rats by i.m. injection of 2.5mg Sandostatin LAR in 50mg microspheres every 4 weeks for 21 weeks, with necropsy at 26 weeks, no drug-related necropsy findings were observed. The only histopathological findings considered to be of significance were at the injection site in treated and control animals, where the microspheres had provoked a reversible granulomatous myositis. After a single i.m. injection of Sandostatin LAR in rats and rabbits, biodegradation of microspheres was complete by day 75 after injection in both species.

Mutagenicity

Octreotide and/or its metabolites were devoid of mutagenic potential when investigated in vitro in validated bacterial and mammalian cell test systems. Increased frequencies of chromosomal changes were observed in V79 Chinese hamster cells in vitro, albeit at high and cytotoxic concentrations only. Chromosomal aberrations were however not increased in human lymphocytes incubated with octreotide acetate in vitro. In vivo, no clastogenic activity was observed in the bone marrow of mice treated with octreotide i.v. (micronucleus test) and no evidence of genotoxicity was obtained in male mice using a DNA repair assay of sperm heads. The microspheres were devoid of mutagenic potential when tested in a validated in vitro bacterial assay.

Carcinogenicity/chronic toxicity

In studies in rats in which s.c. Sandostatin at daily doses up to 1.25mg/kg body weight were administered, fibrosarcomas were observed, predominantly in a number of male animals, at the s.c. injection site after 52, 104 and 113/116 weeks. Local tumours occurred also in the control rats, however development of these tumours was attributed to disordered fibroplasia produced by sustained irritant effects at the injection sites, enhanced by the acidic lactic acid/mannitol vehicle. This non-specific tissue reaction appeared to be particular to rats.

Neoplastic lesions were observed neither in mice receiving daily s.c. injections of Sandostatin at doses up to 2mg/kg for 98 weeks, nor in dogs which were treated with daily s.c. doses of the drug for 52 weeks.

The 116-week carcinogenicity study in rats with s.c. Sandostatin also revealed uterine endometrial adenocarcinomas, their incidence reaching statistical significance at the highest s.c. dose level of 1.25mg/kg per day. The finding was associated with an increased incidence of endometritis, a decreased number of ovarian corpora lutea, a reduction in mammary adenomas and the presence of uterine glandular and luminal dilation, suggesting a state of hormonal imbalance. The available information clearly indicates that the findings of endocrine-mediated tumours in rats are species-specific and are not relevant for the use of the drug in humans.

Reproduction toxicity

Fertility as well as pre-, peri- and post-natal studies in female rats revealed no adverse effects on reproductive performance and development of the offspring, when s.c. doses up to 1mg/kg body weight per day were administered. Some retardation of the physiological growth noted in pups was transient and attributable to GH inhibition brought about by excessive pharmacodynamic activity.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Poly (DL-lactide-co-glycolide); mannitol.

6.2 Incompatibilities

Sandostatin LAR microspheres for injection is to be used as a single dose container, without any dilution with other products. Therefore, no compatibility data with other products have been generated.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

Store at 2 to 8°C, protect from light. Sandostatin LAR can remain at room temperature on the day of injection. However, the suspension must only be prepared immediately prior to i.m. injection.

6.5 Nature And Contents Of Container

The microspheres are packaged in 5ml glass vials (Type I, Ph Eur), with a PTFE-faced rubber stopper and sealed with an aluminium flip-off seal.

6.6 Special Precautions For Disposal And Other Handling

Instructions for i.m. injection of Sandostatin LAR for deep intragluteal injection only

Remove the cap from vial containing Sandostatin LAR. Assure that the powder is settled at the bottom of the vial by lightly tapping the vial. Remove the cap from the vehicle syringe. Attach one of the supplied needles to the vehicle syringe.

Insert needle through centre of rubber stopper of the Sandostatin LAR vial.

Without disturbing the Sandostatin LAR powder, gently inject the vehicle into the vial by running the vehicle down the inside wall of the vial. Do not inject the vehicle directly into the powder. Withdraw any excess air present in the vial.

Do not disturb the vial until the vehicle has wetted the Sandostatin LAR powder for suspension. Once complete wetting (approximately 2-5 minutes) has occurred, the vial should be moderately swirled until a uniform suspension is achieved. Do not vigorously shake the vial.

Immediately draw 2ml of air into the syringe and re-insert the needle through the rubber stopper. Inject the 2ml of air into the vial and then, with the bevel down and the vial tipped at approximately 45 degree angle, slowly draw the entire contents of the vial containing the suspension into the syringe. Immediately change the needle (supplied).

Gently invert the syringe as needed to maintain a uniform suspension. Eliminate air from syringe and disinfect the injection site. Insert needle into right or left gluteus and draw back to ensure that no blood vessel has been penetrated. Immediately inject i.m. by deep intragluteal injection.

Sandostatin LAR must be given only by intragluteal injection, never i.v. If a blood vessel has been penetrated, select another injection site.

Special precautions for disposal

Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

Novartis Pharmaceuticals UK Limited

(Trading as Sandoz Pharmaceuticals)

Frimley Business Park

Frimley

Camberley

Surrey

GU16 7SR

United Kingdom

8. Marketing Authorisation Number(S)

Sandostatin LAR 10mg:	PL 00101/0511
Sandostatin LAR 20mg:	PL 00101/0512
Sandostatin LAR 30mg:	PL 00101/0513

9. Date Of First Authorisation/Renewal Of The Authorisation

07 June 2007

10. Date Of Revision Of The Text

13 July 2011

LEGAL CATEGORY:

POM

Chloroxylenol/Pramoxine Drops

Pronunciation: klor-oh-ZYE-le-nole/pra-MOX-een
Generic Name: Chloroxylenol/Pramoxine
Brand Name: Examples include PramOtic and Uni-Otic

Chloroxylenol/Pramoxine Drops are used for:

Treating certain infections of the outer ear canal. It is also used to control itching caused by these infections. It may also be used for other conditions as determined by your doctor.

Chloroxylenol/Pramoxine Drops are an antibacterial and anesthetic combination. It works by killing sensitive bacteria or fungi and temporarily relieving ear pain.

Do NOT use Chloroxylenol/Pramoxine Drops if:

• you are allergic to any ingredient in Chloroxylenol/Pramoxine Drops


• your eardrum is perforated

Contact your doctor or health care provider right away if any of these apply to you.

Before using Chloroxylenol/Pramoxine Drops:

Some medical conditions may interact with Chloroxylenol/Pramoxine Drops. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have other ear problems

Some MEDICINES MAY INTERACT with Chloroxylenol/Pramoxine Drops. Because little, if any, of Chloroxylenol/Pramoxine Drops are absorbed into the blood, the risk of it interacting with another medicine is low.

Ask your health care provider if Chloroxylenol/Pramoxine Drops may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Chloroxylenol/Pramoxine Drops:

Use Chloroxylenol/Pramoxine Drops as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Chloroxylenol/Pramoxine Drops are only for the ear. Do not get it in your eyes, nose, or mouth. If you get Chloroxylenol/Pramoxine Drops in any of these areas, flush thoroughly with cool water.


• Thoroughly clean and dry the outer ear before using Chloroxylenol/Pramoxine Drops.


• Lie down or tilt your head so that the affected ear faces up. For adults, gently pull the earlobe up and back to straighten the ear canal. For children, gently pull the earlobe down and back to straighten the ear canal. Drop the medicine into the ear canal. Keep the ear facing up for 5 minutes so the medicine can run to the bottom of the ear canal. A clean cotton plug may be gently inserted into the ear canal to prevent medicine from leaking out. Repeat, if necessary, in the other ear.


• To prevent germs from contaminating your medicine, do not touch the applicator to any surface, including the ear. Keep the container tightly closed.


• Wash your hands immediately after using Chloroxylenol/Pramoxine Drops.


• Using Chloroxylenol/Pramoxine Drops at the same times each day will help you remember to use it.


• To clear up your infection completely, use Chloroxylenol/Pramoxine Drops for the full course of treatment. Keep using it even if you feel better in a few days.


• If you miss a dose of Chloroxylenol/Pramoxine Drops, use it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not use 2 doses at once.

Ask your health care provider any questions you may have about how to use Chloroxylenol/Pramoxine Drops.

Important safety information:

• Do NOT use more than the recommended dose or use for longer than 10 days without checking with your doctor.


• Do not use Chloroxylenol/Pramoxine Drops for other conditions than the one for which it was prescribed. Do not use it for other ear problems without first checking with your doctor.


• Talk with your doctor before using any other medicines in your ear.


• Be sure to use Chloroxylenol/Pramoxine Drops for the full course of therapy. If you do not, Chloroxylenol/Pramoxine Drops may not clear up your infection completely. The bacteria could also become less sensitive to this or other medicines. This could make the infection harder to treat in the future.


• Long-term or repeated use of Chloroxylenol/Pramoxine Drops may cause a second infection. Tell your doctor if signs of a second infection occur. Your medicine may need to be changed to treat this.


• Chloroxylenol/Pramoxine Drops may cause harm if it is swallowed. If you may have taken it by mouth, contact your poison control center or emergency room right away.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Chloroxylenol/Pramoxine Drops while you are pregnant. It is not known if Chloroxylenol/Pramoxine Drops are found in breast milk. If you are or will be breast-feeding while you use Chloroxylenol/Pramoxine Drops, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Chloroxylenol/Pramoxine Drops:

All medicines may cause side effects, but many people have no, or minor, side effects. No COMMON side effects have been reported with Chloroxylenol/Pramoxine Drops. Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue).

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Chloroxylenol/Pramoxine side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.

Proper storage of Chloroxylenol/Pramoxine Drops:

Store Chloroxylenol/Pramoxine Drops at room temperature, between 59 and 86 degrees F (15 and 30 degrees C), in the original container. Store away from heat and light. Keep Chloroxylenol/Pramoxine Drops out of the reach of children and away from pets.

General information:

• If you have any questions about Chloroxylenol/Pramoxine Drops, please talk with your doctor, pharmacist, or other health care provider.


• Chloroxylenol/Pramoxine Drops are to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Chloroxylenol/Pramoxine Drops. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Chloroxylenol/Pramoxine resources

• Chloroxylenol/Pramoxine Side Effects (in more detail)
• Chloroxylenol/Pramoxine Dosage
• Chloroxylenol/Pramoxine Use in Pregnancy & Breastfeeding
• Chloroxylenol/Pramoxine Support Group
• 0 Reviews for Chloroxylenol/Pramoxine - Add your own review/rating

Compare Chloroxylenol/Pramoxine with other medications

• Otitis Externa

Hypertensive Retinopathy Medications

There are currently no drugs listed for "Hypertensive Retinopathy".

Definition of Hypertensive Retinopathy: Hypertensive retinopathy involves damage to the retina caused by high blood pressure.

Learn more about Hypertensive Retinopathy

Medical Encyclopedia:

• Hypertensive retinopathy

Drug List:

Liquid PedvaxHIB

Generic Name: haemophilus b conjugate (PRP-OMP) vaccine (hem OFF il us B KON ju gate)

Brand Names: Liquid PedvaxHIB

What is haemophilus B conjugate (PRP-OMP) vaccine?

Haemophilus B is a type of influenza (flu) caused by bacteria.

Haemophilus B bacteria can infect the lungs or throat, and can also spread to the blood, bones, joints, brain, or spinal cord. It can cause breathing problems or meningitis, and these infections can be fatal.

Haemophilus B disease can spread from one person to another through small droplets of saliva that are expelled into the air when an infected person coughs or sneezes. The bacteria can also be passed through contact with objects the infected person has touched, such as a door handle, or other surface. The bacteria can also be passed through kissing, or sharing a drinking glass or eating utensil with an infected person.

Haemophilus B conjugate vaccine is used to prevent infection caused by haemophilus B bacteria. The vaccine will not protect against other types of influenza.

Haemophilus B conjugate vaccine works by exposing your child to a small dose of the bacteria or a protein from the bacteria, which causes the body to develop immunity to the disease. This vaccine will not treat an active infection that has already developed in the body.

Haemophilus B conjugate vaccine is for use in children between the ages of 2 months and 6 years old.

Like any vaccine, haemophilus B conjugate vaccine may not provide protection from disease in every person.

What is the most important information I should know about this vaccine?

The haemophilus B conjugate vaccine is given in a series of shots. The first shot may be given when the child is at least 2 months old. Booster shots may be given at 12 to 15 months of age.

Your child's individual booster schedule may be different from these guidelines. Follow your doctor's instructions or the schedule recommended by the health department of the state you live in.

Be sure your child receives all recommended doses of this vaccine. If your child does not receive the full series of vaccines, he or she may not be fully protected against the disease.

Your child can still receive a vaccine if he or she has a cold or fever. In the case of a more severe illness with a fever or any type of infection, wait until the child gets better before receiving this vaccine.

Your child should not receive a booster vaccine if he or she had a life-threatening allergic reaction after the first shot.

Keep track of any and all side effects your child has after receiving this vaccine. When the child receives a booster dose, you will need to tell the doctor if the previous shots caused any side effects.

Becoming infected with haemophilus B is much more dangerous to your child's health than receiving the vaccine to protect against it. Like any medicine, this vaccine can cause side effects, but the risk of serious side effects is extremely low.

What should I discuss with my healthcare provider before receiving haemophilus B conjugate (PRP-OMP) vaccine?

Your child should not receive this vaccine if he or she has ever had an allergic reaction to a haemophilus B or a meningococcal vaccine, or if the child has received cancer chemotherapy or radiation treatment in the past 3 months..

Before receiving haemophilus B conjugate vaccine, tell your child's doctor if the child is allergic to any drugs, or has:

• 
  

  a bleeding or blood clotting disorder such as hemophilia or easy bruising;

  
  


• 
  

  a history of seizures;

  
  


• 
  

  a neurologic disorder or disease affecting the brain (or if this was a reaction to a previous vaccine);

  
  


• 
  

  an allergy to latex rubber;

  
  


• 
  

  a weak immune system caused by disease, bone marrow transplant, or by using certain medicines or receiving cancer treatments; or

  
  


• 
  

  if the child is taking a blood thinner such as warfarin (Coumadin).

  
  

FDA pregnancy category C. This vaccine may be harmful to an unborn baby and should not be given to a pregnant woman. Haemophilus B conjugate vaccine should not be given to a woman who is breast-feeding a baby.

How is this vaccine given?

This vaccine is given as an injection (shot) into a muscle. Your child will receive this injection in a doctor's office or other clinic setting.

Haemophilus B conjugate vaccine is given to children between the ages of 2 months and 6 years old. It may also be given to an older child with a medical conditions such as HIV or AIDS, sickle cell disease, or who is receiving cancer treatments or a bone marrow transfusion.

The haemophilus B conjugate vaccine is given in a series of shots. The first shot may be given when the child is at least 2 months old. Booster shots may be given at 12 to 15 months of age.

Your child's individual booster schedule may be different from these guidelines. Follow your doctor's instructions or the schedule recommended by the health department of the state you live in.

Your child can still receive a vaccine if he or she has a cold or fever. In the case of a more severe illness with a fever or any type of infection, wait until the child gets better before receiving this vaccine.

Your doctor may recommend treating fever and pain with an aspirin-free pain reliever such as acetaminophen (Tylenol) or ibuprofen (Motrin, Advil, and others) when the shot is given and for the next 24 hours. Follow the label directions or your doctor's instructions about how much of this medicine to give your child.

It is especially important to prevent fever from occurring in a child who has a seizure disorder such as epilepsy.

What happens if I miss a dose?

Contact your doctor if you will miss a booster dose or if you get behind schedule. The next dose should be given as soon as possible. There is no need to start over.

Be sure your child receives all recommended doses of this vaccine. If your child does not receive the full series of vaccines, he or she may not be fully protected against the disease.

What happens if I overdose?

An overdose of this vaccine is not likely to occur.

What should I avoid before or after receiving this vaccine?

There are no restrictions on food, beverages, or activity before or after receiving this vaccine unless your child's doctor has told you otherwise.

This vaccine side effects

Keep track of any and all side effects your child has after receiving this vaccine. When the child receives another haemophilus B vaccine in the future, you will need to tell the child's doctor if the first shot caused any side effects.

Becoming infected with haemophilus B is much more dangerous to your child's health than receiving the vaccine to protect against it. Like any medicine, this vaccine can cause side effects, but the risk of serious side effects is extremely low.

Get emergency medical help if your child has any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if your child has any of these serious side effects:

• 
  

  pale skin, severe weakness, dizziness, fast heartbeat;

  
  


• 
  

  extreme drowsiness, fainting;

  
  


• 
  

  fussiness, irritability, crying for an hour or longer;

  
  


• 
  

  seizure (black-out or convulsions); or

  
  


• 
  

  high fever (within a few hours or a few days after the vaccine).

  
  

Less serious side effects include:

• 
  

  redness, pain, swelling, or a lump where the shot was given;

  
  


• 
  

  low fever;

  
  


• 
  

  mild fussiness or crying;

  
  


• 
  

  joint pain, body aches;

  
  


• 
  

  drowsiness; or

  
  


• 
  

  diarrhea.

  
  

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect this vaccine?

Before receiving this vaccine, tell the doctor about all other vaccines your child has recently received.

Also tell the doctor if your child has recently received drugs or treatments that can weaken the immune system, including:

• 
  

  an oral, nasal, inhaled, or injectable steroid medicine;

  
  


• 
  

  medications to treat psoriasis, rheumatoid arthritis, or other autoimmune disorders, such as azathioprine (Imuran), efalizumab (Raptiva), etanercept (Enbrel), leflunomide (Arava), and others; or

  
  


• 
  

  medicines to treat or prevent organ transplant rejection, such as basiliximab (Simulect), cyclosporine (Sandimmune, Neoral, Gengraf), muromonab-CD3 (Orthoclone), mycophenolate mofetil (CellCept), sirolimus (Rapamune), or tacrolimus (Prograf).

  
  

This list is not complete and there may be other drugs not listed that can affect haemophilus B conjugate vaccine. Tell your doctor about all the prescription and over-the-counter medications your child uses. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your child's doctor.

More Liquid PedvaxHIB resources

• Liquid PedvaxHIB Side Effects (in more detail)
• Liquid PedvaxHIB Use in Pregnancy & Breastfeeding
• Liquid PedvaxHIB Drug Interactions
• Liquid PedvaxHIB Support Group
• 0 Reviews for Liquid PedvaxHIB - Add your own review/rating

Compare Liquid PedvaxHIB with other medications

• Haemophilus influenzae Prophylaxis

Where can I get more information?

• Your doctor or pharmacist may have information about haemophilus B conjugate vaccine written for health professionals that you may read. You may also find additional information from your local health department or the Centers for Disease Control and Prevention.

See also: Liquid PedvaxHIB side effects (in more detail)

Stesolid rectal tubes 5 mg

1. Name Of The Medicinal Product

Stesolid® rectal tubes 5 mg.

2. Qualitative And Quantitative Composition

Diazepam 2 mg/ml.

3. Pharmaceutical Form

Enema.

4. Clinical Particulars

4.1 Therapeutic Indications

Diazepam has anticonvulsant, sedative, and muscle relaxant properties. It is used in the treatment of severe anxiety and tension states, as a sedative and premedication, in the control of muscle spasm, and in the management of alcohol withdrawal symptoms.

Stesolid rectal tubes 5 mg may be used in acute severe anxiety and agitation, epileptic and febrile convulsions, tetanus, as a sedative in minor surgical and dental procedures, or in other circumstances in which a rapid effect is required but where intravenous injection is impracticable or undesirable.

Stesolid rectal tubes 5 mg may be of particular value for the immediate treatment of convulsions in infants and children.

4.2 Posology And Method Of Administration

Sensitivity to diazepam varies with age.

Children above 1 year of age:	0.5 mg/kg body weight
Adults:	0.5 mg/kg body weight
Elderly patients:	0.25 mg/kg body weight

A maximum dose of 30 mg diazepam is recommended, unless adequate medical supervision and monitoring are available.

4.3 Contraindications

• Known hypersensitivity to diazepam, benzodiazepines or any of the excipients

• Phobic or obsessional states; chronic psychosis, hyperkinesis (paradoxical reactions may occur)

• Acute pulmonary insufficiency; respiratory depression, acute or chronic severe respiratory insufficiency (ventilatory failure may be exacerbated)

• Myasthenia gravis (condition may be exacerbated)

• Sleep apnoea (condition may be exacerbated)

• Severe hepatic insufficiency (elimination half-life of diazepam may be prolonged)

• Acute porphyria

• Diazepam should not be used as monotherapy in patients with depression or those with anxiety and depression as suicide may be precipitated in such patients.

• Planning a pregnancy (see section 4.6).

• Pregnancy (unless there are compelling reasons – see section 4.6).

4.4 Special Warnings And Precautions For Use

Tolerance

Some loss of efficacy to the hypnotic effects of diazepam may develop after repeated use for a few weeks.

Dependence

Use of benzodiazepines may lead to development of physical and psychic dependence upon these products. The risk of dependence increases with dose and duration of treatment; it is also greater in patients with a history of alcohol or drug abuse.

Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms. These may consist of headaches, muscle pain, extreme anxiety, tension, restlessness, confusion and irritability. In severe cases the following symptoms may occur: derealisation, depersonalisation, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations or epileptic seizures.

As sudden discontinuation of benzodiazepines may result in convulsions, particular care should be taken in patients with epilepsy, other patients who have had a history of seizures or in alcohol dependants.

Rebound insomnia and anxiety: a transient syndrome whereby the symptoms that led to treatment with a benzodiazepine recur in an enhanced form may occur on withdrawal of treatment. It may be accompanied by other reactions including mood changes, anxiety or sleep disturbances and restlessness. Since the risk of withdrawal phenomena/rebound phenomena is greater after abrupt discontinuation of treatment, it is recommended that the dosage is decreased gradually.

Psychiatric and paradoxical reactions

Reactions like restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychosis, inappropriate behaviour and other adverse behavioural effects are known to occur when using benzodiazepines. Should this occur, use of the medicinal product should be discontinued.

They are more likely to occur in children and the elderly.

Amnesia

Diazepam may induce anterograde amnesia. The condition occurs most often several hours after administering the product and therefore to reduce the risk patients should ensure that they will be able to have uninterrupted sleep of 7-8 hours. Anterograde amnesia may occur using therapeutic doses, the risk increases with higher doses.

Specific patient groups

Benzodiazepines should not be given to children without careful assessment of the need to do so; the duration of treatment must be kept to a minimum. Elderly should be given a reduced dose (see posology). Benzodiazepines are not indicated to treat patients with severe hepatic insufficiency as they may precipitate encephalopathy.

Benzodiazepines are not recommended for the primary treatment of psychotic illness.

Benzodiazepines should not be used alone to treat depression or anxiety associated with depression (suicide may be precipitated in such patients).

In common with other benzodiazepines, the use of diazepam may be associated with amnesia and should not be used in cases of loss or bereavement as psychological adjustment may be inhibited.

Stesolid rectal tubes 5 mg should not be used in phobic or obsessional states, as there is insufficient evidence of efficacy and safety in such conditions.

Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse.

Stesolid should not be used concomitantly with disulfiram due to its ethanol content. A reaction may occur as long as two weeks after cessation of disulfram

Stesolid contains 15 mg/ml benzyl alcohol. Benzyl alcohol may cause toxic reactions and anaphylactoid reactions in infants and children up to 3 years old.

Stesolid rectal tubes, contains benzoic acid (E210) and sodium benzoate (E211) and it may be mildly irritating to the skin and mucous membranes.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Not recommended

Alcohol

Diazepam should not be used together with alcohol (enhanced sedative effects: impaired ability to drive/ operate machinery).

Sodium oxybate

Avoid concomitant use (enhanced effects of sodium oxybate).

HIV-protease inhibitors

Avoid concomitant use (increased risk of prolonged sedation) – see below for zidovudine.

Take into account

Centrally acting drugs

Enhancement of the central depressive effect may occur if diazepam is combined with drugs such as neuroleptics, antipsychotics, tranquillisers, antidepressants, hypnotics, analgesics, anaesthetics, barbiturates and sedative antihistamines. The elderly may require special supervision.

Anti-epileptic drugs

Pharmacokinetic studies on potential interactions between diazepam and antiepileptic drugs have produced conflicting results. Both depression and elevation of drug levels, as well as no change, have been reported.

Phenobarbital taken concomitantly may result in an additive CNS effect. Special care should be taken in adjusting the dose in the initial stages of treatment.

Side effects may be more evident with hydantoins or barbiturates.

Diazepam has been reported to be displaced from protein-binding sites by sodium valproate (increased serum levels: increased risk of drowsiness).

Narcotic analgesics

Enhancement of the euphoria may lead to increased psychological dependence.

Other drugs enhancing the sedative effect of diazepam

Cisapride, lofexidine, nabilone, disulfiram and the muscle-relaxants - baclofen and tizanidine.

Compounds that affect hepatic enzymes (particularly cytochrome P450):

• Inhibitors (eg cimetidine: isoniazid: erythromycin: omeprazole: esomeprazole) reduce clearance and may potentiate the action of benzodiazepines.

Itraconazloe, ketoconazole, and to a lesser extent fluconazole and voriconazole are potent inhibitors of the cytochrome P450 isoenzyme CYP3A4 and may increase plasma levels of benzodiapines. The effects of benzodiapines may be increased and prolonged by concomitant use. A dose reduction of the benzodiazepine may be required.

• Inducers (eg rifampicin) may increase clearance of benzodiazepines

Antihypertensives, vasodilators& diuretics:

Enhanced hypotensive effect with ACEinhibitors, alpha-blockers, angiotensin–II receptor antagonists, calcium channel. blockers adrenergic neurone blockers, beta-blockers, moxonidine, nitrates, hydralazine, minoxidil, sodium nitroprusside and diuretics. Enhanced sedative effect with alpha-blockers or moxonidine.

Dopaminergics

Possible antagonism of the effect of levodopa.

Zidivudine

Increased zidovudine clearance by diazepam.

Oestrogen-containing contraceptives

Possible inhibition of hepatic metabolism of diazepam.

Theophylline

Increases metabolism of diazepam which possibly reduces the effect.

Caffeine

Concurrent use may result in reduced sedative and anxiolytic effects of diazepam.

Grapefruit juice

Inhibition of CYP3A4 may increase the plasma concentration of diazepam (possible increased sedation and amnesia). This interaction may of little significance in healthy individuals, but it is not clear is if other factors such as old age or liver cirrhosis increase the risk of adverse effects with concurrent use.

4.6 Pregnancy And Lactation

In animal studies administration of benzodiazepines during gestation has lead to cleft palate, CNS malformation and permanent functional disturbances in the offspring.

There is no evidence as to the safety of diazepam in human pregnancy. It should not be used, especially during the first and last trimesters, unless the benefit is considered to outweigh the potential risk.

In labour, high single doses or repeated low doses have been reported to produce hypotonia, poor sucking, and hyperthermia in the neonate, and irregularities in the foetal heart.

If benzodiazepines are prescribed to a woman of childbearing potential, she should be warned to contact her physician regarding discontinuance of the product if she intends to become or suspects that she is pregnant.

If, for compelling medical reasons, the product is administered during the late phase of pregnancy, or during labour at high doses, effects on neonate, such as hypothermia, hypotonia and moderate respiratory depression, can be expected, due to the pharmacological action of the compound.

Infants born to mothers who took benzodiazepines chronically during the later states of pregnancy may have developed physical dependence and may be at some risk for developing withdrawal symptoms in the postnatal period.

Since benzodiazepines are found in breast milk, benzodiazepines should not be given to breast feeding mothers.

4.7 Effects On Ability To Drive And Use Machines

Sedation, amnesia, impaired muscular function may adversely effect the ability to drive or use machines. If insufficient sleep occurs, the likelihood of impaired alertness may be increased (see also Interactions). Patients should be warned that effects on the central nervous system may persist into the day after administration even after a single dose.

4.8 Undesirable Effects

During the first week of administration or when high doses are used they may have a sedative effect and cause some degree of drowsiness. In such cases there is an advantage in administering half the total daily intake at night, the remainder being given in divided doses during the day.

The elderly and debilitated are particularly sensitive to the effects of central depressant drugs and may experience confusion, especially if organic brain changes are present; the dosage of diazepam should not exceed one-half that recommended for other adults.

Skin and appendages disorders

Allergic reactions (skin rash or itching) occur rarely.

Central and peripheral nervous disorders

Drowsiness, sedation, unsteadiness, ataxia is common (these effects are dose-related and may persist into the following day even after a single dose), light-headedness, headache, vertigo, dystonic effects occur rarely. Impaired motor ability, dizziness, muscle weakness, tremor, slurred speech.

Vision disorders

Visual disturbances occur rarely.

Psychiatric disorders

Libido fluctuations occur rarely. Anterograde amnesia (amnesia may be associated with inappropriate behaviour), concentration difficulties, abnormal psychological reactions, behavioural adverse effects include paradoxical aggressive outbursts, excitement, confusion, restlessness, agitation, irritability, delusions, rages, nightmares, hallucinations, psychoses, inappropriate behaviour, numbed emotions, the uncovering of depression with suicidal tendencies and dependence (see section 4.4). Abuse of benzodiazepines has been reported.

Gastro-intestinal system disorders

Gastrointestinal upsets occur rarely. Increased salivary secretion.

Liver and billiary system disorders

Jaundice occurs rarely.

Endocrine disorders

Gynaecomastia.

Cardio disorders

Hypotension occurs rarely.

Respiratory system disorders

Respiratory depression, apnoea.

Blood disorders

Blood dyscrasias occur rarely.

Urinary system disorders

Urinary retention occurs rarely.

Body as a whole-general disorders

Fatigue, anaphylaxis.

Withdrawal effects

Withdrawal symptoms: Development of dependence is common after regular use, even in therapeutic doses for short periods, particularly in patients with a history of drug or alcohol abuse or marked personality disorders. Discontinuation of the therapy may result in withdrawal or rebound phenomena (see 4.4 Special Warnings and Special Precautions for Use). Symptoms of benzodiazepine withdrawal include anxiety, depression, impaired concentration, insomnia, headache, dizziness, tinnitus, loss of appetite, tremor, perspiration, irritability, perceptual disturbances such as hypersensitivity to physical, visual, and auditory stimuli and abnormal taste, nausea, vomiting, abdominal cramps, palpitations, mild systolic hypertension, tachycardia, and orthostatic hypotension.

Rare and more serious symptoms include muscle twitching, confusional or paranoid psychosis, convulsions, hallucinations, and a state resembling delirium tremens. Broken sleep with vivid dreams and increased REM sleep may persist for some weeks after withdrawal of benzodiazepines.

4.9 Overdose

Features

The symptoms of diazepam overdose are mainly an intensification of the therapeutic effects (ataxia, drowsiness, dysarthria, sedation, muscle weakness, profound sleep, hypotension, bradycardia, nystagmus) or paradoxical excitation. In most cases only observation of vital functions is required.

Extreme overdosage may lead to coma, areflexia, cardiorespiratory depression and apnoea, requiring appropriate countermeasures (ventilation, cardiovascular support). Benzodiazepine respiratory depressant effects are more serious in patients with severe chronic obstructive airways disease. Severe effects in overdose also include rhabdomyolysis and hypothermia.

Management

Maintain a clear airway and adequate ventilation.

Monitoring level of consciousness, respiratory rate, pulse oximetry and blood pressure in symptomatic patients.

Consider arterial blood gas analysis in patients who have a reduced level of consciousness (GCS < 8; AVPU scale P or U) or have reduced oxygen saturations on pulse oximetry.

Correct hypotension by raising the foot of the bed and by giving an appropriate fluid challenge. Where hypotension is thought mainly due to decreased systemic vascular resistance, drugs with alpha-adrenergic activity such as noradrenaline or high dose dopamine (10-30 micrograms/kg/min) may be beneficial. The dose of inotrope should be titrated against blood pressure.

If severe hypotension persists despite the above measures, then central venous pressure monitoring should be considered.

Supportive measures are indicated depending on the patient's clinical state.

Benzodiazepines are not significantly removed from the body by dialysis.

Flumazenil, a benzodiazepine antagonist, is not advised as a routine diagnostic test in patients with reduced conscious level. It may sometimes be used as an alternative to ventilation in children who are naive to benzodiazepines, or in patients with COPD to avoid the need for ventilation. It is not necessary or appropriate in cases of poisoning to fully reverse the benzodiazepine effect. Flumazenil has a short half-life (about an hour) and in this situation an infusion may therefore be required. Flumazenil is contraindicated when patients have ingested multiple medicines, especially after co-ingestion of a benzodiazepine and a tricyclic antidepressant or any other drug that causes seizures. This is because the benzodiazepine may be suppressing seizures induced by the second drug; its antagonism by flumazenil can reveal severe status epilepticus that is very difficult to control.

Contraindications to the use of flumazenil include features suggestive of a tricyclic antidepressant ingestion including a wide QRS, or large pupils. Use in patients postcardiac arrest is also contraindicated.

It should be used with caution in patients with a history of seizures, head injury, or chronic benzodiazepine use.

Occasionally a respirator may be required but generally few problems are encountered, although behavioral changes are likely in children.

If excitation occurs, barbiturates should not be used.

Effects of overdose are more severe when taken with centrally-acting drugs, especially alcohol, and in the absence of supportive measures, may prove fatal.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Diazepam has anticonvulsant, sedative, and muscle relaxant properties.

5.2 Pharmacokinetic Properties

Absorption: Diazepam is quickly absorbed from the rectal mucosa. The maximum serum concentration is reached within 17 minutes. Absorption is 100% compared with that of intravenous injection of diazepam.

5.3 Preclinical Safety Data

Not applicable.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Benzoic acid

Ethanol

Propylene glycol

Sodium benzoate

Benzyl alcohol

Purified water.

6.2 Incompatibilities

None known.

6.3 Shelf Life

30 months at 25°C.

6.4 Special Precautions For Storage

The storage temperature must not exceed 25°C.

6.5 Nature And Contents Of Container

Carton containing sealed low density polyethylene tubes, single packed in aluminium laminated bags.

Package size: 5 x 2.5 ml

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

Administrative Data

7. Marketing Authorisation Holder

Actavis Group PTC ehf.

Reykjavikurvegi 76-78

220 Hafnarfjordur

Iceland

8. Marketing Authorisation Number(S)

PL 30306/0040

9. Date Of First Authorisation/Renewal Of The Authorisation

01/06/2007

10. Date Of Revision Of The Text

22/06/2011

Vicks Cold & Flu Care Medinite Complete Syrup

1. Name Of The Medicinal Product

Vicks Cold & Flu Care Medinite Complete Syrup.

2. Qualitative And Quantitative Composition

ACTIVE INGREDIENTS

	Percentage w/v	Specification
Dextromethorphan HBr	0.050	EP
Doxylamine succinate	0.025	USP
Paracetamol	2.000	EP
Pseudoephidrine HCl	0.200	BP

3. Pharmaceutical Form

Syrup.

4. Clinical Particulars

4.1 Therapeutic Indications

For the treatment of symptoms of the common cold, accompanied by sneezing, headache, bodyache, sore throat, cough and nasal congestion.

4.2 Posology And Method Of Administration

Oral administration.

Adults & Children over 12 years: 30ml in measuring cup at bedtime.

Elderly patients: Adult dose applies.

4.3 Contraindications

Cardiovascular disorders, thyroid disease, diabetes, monoamine oxidase inhibitor therapy, severe hepatic or renal insufficiency. Pregnancy. Hypersensitivity to any of the ingredients.

Not to be used in Children under 12 years of age

4.4 Special Warnings And Precautions For Use

Care is advised in the administration of paracetamol to patients with severe renal or severe hepatic impairment and in those with non-cirrhotic alcoholic liver disease. The hazards of overdose are greater in those with alcoholic liver disease.

Do not exceed the recommended dose.

Patients should be advised not to take other paracetamol-containing products concurrently.

If symptoms persist, consult your doctor.

Keep out of the reach of children.

This preparation should not be administered to children under 10 years except on medical advice.

Contains paracetamol.

May cause drowsiness. If affected do not drive or operate machinery. Avoid alcoholic drink.

If you are under the care of your doctor or are receiving prescribed medication or if you are pregnant, consult your doctor before using this product.

Prolonged use without medical supervision is not advisable.

Contains alcohol.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by cholestyramine.

The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular use of paracetamol with increased risk of bleeding.

Paracetamol may cause a marginal increase in blood levels of chloramphenicol, monoamine oxidase inhibitors, antihypertensives, beta-blockers.

4.6 Pregnancy And Lactation

Epidemiological studies in human pregnancy have shown no effects due to paracetamol used in the recommended dosage. However, paracetamol should be avoided in pregnancy unless considered essential by the physician.

Paracetamol is excreted in breast milk but not in a clinically significant amount. Available published data do not contraindicate breast feeding.

Regarding the product as a whole there is insufficient evidence to assure safe use in pregnancy and lactation.

4.7 Effects On Ability To Drive And Use Machines

May cause drowsiness. Those affected should not drive or operate machinery.

4.8 Undesirable Effects

Adverse effects of paracetamol are rare but hypersensitivity including skin rash may occur. There have been reports of blood dyscrasias including thrombocytopenia and agranulocytosis, and of acute pancreatitis.

4.9 Overdose

4.9.1 Symptoms

Paracetamol:

Symptoms of paracetamol overdosage in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, coma and death. Acute renal failure with acute tubular necrosis may develop even in the absence of severe liver damage. Cardiac arrhythmias have been reported.

Liver damage is likely in adults who have taken 10g or more of paracetamol. It is considered that excess quantities of a toxic metabolite (usually adequately detoxified by glutathione when normal doses of paracetamol are ingested), become irreversibly bound to liver tissue. Other symptoms may include CNS depression, cardiovascular effects and renal damage.

4.9.2 Treatment of overdose

Paracetamol:

Immediate treatment is essential in the management of paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention and any patient who has ingested around 7.5g or more of paracetamol in the preceeding 4 hours should undergo gastric lavage. Administration of oral methionine or intravenous N- acetylcysteine which may have a beneficial effect up to at least 48 hours after the overdose, may be required. General supportive measures must be available.

Treatment of other symptoms is by symptomatic management.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Paracetamol:	Analgesic/antipyretic.
Dextromethorphan HBr:	Anti-tussive.
Doxylamine succinate:	Antihistamine, anticholinergic
Pseudoephidrine hydrochloride:	Sympathomimetic agent - nasal decongestant

.

5.2 Pharmacokinetic Properties

Paracetamol:	Metabolised in the liver and excreted in the urine as glucuronide and sulphate conjugates.
Dextromethorphan HBr:	Metabolised in the liver and excreted as unchanged dextromethorphan and demethylated morphinian compounds.
Doxylamine succinate:	Is believed to to be metabolised in the liver and excreted mainly as metabolites in the urine
Pseudoephidrine hydrochloride:	Is resistant to metabolism by monoamine oxidase and is largely excreted unchanged in the urine

5.3 Preclinical Safety Data

There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Ethanol 96%

Sodium citrate

Citric acid monohydrate

Sodium benzoate

Polyethylene glycol 6000

Sucrose

Glycerol

Anethole

Quinoline yellow (E104)

Indigotin blue (E132)

Water, purified

6.2 Incompatibilities

None known.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

Do not store above 25^oC.

6.5 Nature And Contents Of Container

180 ml clear flint glass bottle with wadless polypropylene screw cap or white polypropylene child resistant closure.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Procter & Gamble (Health & Beauty Care) Limited

The Heights

Brooklands

Weybridge

Surrey

KT13 0XP

8. Marketing Authorisation Number(S)

PL 0129/0029R

9. Date Of First Authorisation/Renewal Of The Authorisation

13th May 1991

10. Date Of Revision Of The Text

June 2009