Forceval Junior Capsules (Alliance Pharmaceuticals)

1. Name Of The Medicinal Product

Forceval Junior Capsules

2. Qualitative And Quantitative Composition

Each capsule contains:

Vitamin A (as β-Carotene) HSE 1,250.0 iu

Vitamin D2 (Ergocalciferol) HSE 200.0 iu

Vitamin B1 (Thiamine) USP 1.5 mg

Vitamin B2 (Riboflavin) BP 1.0 mg

Vitamin B6 (Pyridoxine) BP 1.0 mg

Vitamin B12 (Cyanocobalamin) PhEur 2.0 mcg

Vitamin C (Ascorbic Acid) BP 25.0 mg

Vitamin E (dl-α-Tocopheryl Acetate) USP 5.0 mg

d-Biotin (Vitamin H) FCC 50.0 mcg

Nicotinamide (Vitamin B3) BP 7.5 mg

Pantothenic Acid (Vitamin B5) USP 2.0 mg

Vitamin K1 (Phytomenadione) BP 25.0 mcg

Folic Acid (Vitamin B Complex) BP 100.0 mcg

Iron BP 5.0 mg

Copper HSE 1.0 mg

Magnesium BP 1.0 mg

Zinc HSE 5.0 mg

Iodine BP 75.0 mcg

Manganese HSE 1.25 mg

Selenium BP 25.0 mcg

Chromium HSE 50.0 mcg

Molybdenum HSE 50.0 mcg

3. Pharmaceutical Form

Small, opaque, brown, oval, soft gelatin capsule printed in white with 571.

4. Clinical Particulars

4.1 Therapeutic Indications

1. As a therapeutic nutritional adjunct where the intake of vitamins and minerals is suboptimal, e.g. in the presence of organic disease such as malignancy and immune deficiency syndromes, such as AIDS.

2. As a therapeutic nutritional adjunct in conditions where the absorption of vitamins and minerals is suboptimal, e.g. malabsorption, inflammatory bowel disease and fistulae, short bowel syndrome and Crohn's disease, and where concurrent medication decreases vitamin and mineral absorption.

3. As a therapeutic nutritional adjunct in convalescence from illness, e.g. where anorexia or cachexia exists and following chemo- or radio-therapy.

4. As a therapeutic nutritional adjunct in convalescence from surgery, e.g. where nutritional intake continues to be inadequate.

5. As a therapeutic nutritional adjunct for patients on special or restricted diets, e.g. in renal diets and where several food groups are restricted in therapeutic weight reducing diets.

6. As a therapeutic nutritional adjunct where food intolerance exists, e.g. exclusion diets.

7. As an adjunct in synthetic diets, e.g. in phenylketonuria, galactosaemia and ketogenic diets.

4.2 Posology And Method Of Administration

Children over 5 years of age

2 capsules per day or as recommended by the doctor.

Do not exceed the stated dose.

Adults and the Elderly

Not recommended - use Forceval Capsules.

4.3 Contraindications

Haemochromatosis and other iron storage disorders.

4.4 Special Warnings And Precautions For Use

Forceval Junior Capsules should be used as a vitamin and mineral source in conjunction with an energy-providing diet suitable for individual patient requirements. No other vitamins, minerals or supplements with or without vitamin A should be taken with this preparation except under medical supervision.

Do not exceed the stated dose. Keep out of the reach of children.

The label will state:

Important warning: Contains iron. Keep out of the reach and sight of children, as overdose may be fatal.

This warning will appear on the front of pack, enclosed in a rectangle, in which there is no other information of any kind.

This medicine contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

Evidence from Randomised Control Trials suggests that high doses (20-30 mg/day) b-carotene intake may increase the risk of lung cancer in current smokers and those previously exposed to asbestos. This high-risk population should consider the potential risks and benefits of Forceval Junior Capsules, which contain 4.5mg per recommended daily dose, before use.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Vitamin K may interact with anticoagulants such as phenindione, warfarin and nicoumalone inhibiting their effect. Folic acid can reduce the plasma concentration of phenytoin. Oral iron and zinc sulphate reduce the absorption of tetracyclines.

4.6 Pregnancy And Lactation

Forceval Junior Capsules can be given to pregnant and lactating women, provided the product is administered with the approval of their clinician.

4.7 Effects On Ability To Drive And Use Machines

None anticipated.

4.8 Undesirable Effects

No undesirable effects due to Forceval Junior therapy have been reported and none can be expected if the dosage schedule is adhered to.

4.9 Overdose

No cases of overdosage due to Forceval Junior therapy have been reported. Any symptoms which may be observed due to ingestion of large quantities of Forceval Junior capsules will be due to the fat soluble vitamin content. If iron overdosage is suspected, symptoms may include nausea, vomiting, diarrhoea, abdominal pain, haematemesis, rectal bleeding, lethargy and circulatory collapse. Hyperglycaemia and metabolic acidosis may also occur. Treatment should be implemented immediately. In severe cases, after a latent phase, relapse may occur after 24 - 48 hours, manifest by hypotension coma and hepatocellular necrosis and renal failure.

Treatment

The following steps are recommended to minimise or prevent further absorption of the medication:

1. Administer an emetic.

2. Gastric lavage may be necessary to remove drug already released into the stomach. This should be undertaken using desferrioxamine solution (2 g/l). Desferrioxamine 5 g in 50-100 ml water should be introduced into the stomach following gastric emptying. Keep the patient under constant surveillance to detect possible aspiration of vomitus; maintain suction apparatus and standby emergency oxygen in case of need.

3. A drink of mannitol or sorbitol should be given to induce small bowel emptying.

4. Severe poisoning: in the presence of shock and/or coma with high serum iron levels >142 μmol/l) immediate supportive measures plus i.v. infusion of desferrioxamine should be instituted. The recommended dose of desferrioxamine is 5 mg/kg/h by slow i.v. infusion up to a maximum of 80 mg/kg/24 hours. Warning: hypotension may occur if the infusion rate is too rapid.

5. Less severe poisoning: i.m. desferrioxamine 50 mg/kg up to a maximum dose of 4 g should be given.

6. Serum iron levels should be monitored throughout.

7. Any fluid or electrolyte imbalance should be corrected.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

The following account summarises the pharmacological effects of the vitamins and minerals in Forceval Junior Capsules and describes the conditions caused by deficiency of these.

Vitamin A

Vitamin A plays an important role in the visual process. It is isomerised to the 11-cis isomer and subsequently bound to the opsin to form the photoreceptor for vision under subdued light. One of the earliest symptoms of deficiency is night blindness which may develop into the more serious condition xerophthalmia. Vitamin A also participates in the formation and maintenance of the integrity of epithelial tissues and mucous membranes. Deficiency may cause skin changes resulting in a dry rough skin with lowered resistance to minor skin infections. Deficiency of Vitamin A, usually accompanied by protein-energy malnutrition, is linked with a frequency of infection and with defective immunological defence mechanisms.

Vitamin D

Vitamin D is required for the absorption of calcium and phosphate from the gastro-intestinal tract and for their transport. Its involvement in the control of calcium metabolism and hence the normal calcification of bones is well documented. Deficiency of Vitamin D in children may result in the development of rickets.

Vitamin B₁ (Thiamine)

Thiamine (as the coenzyme, thiamine pyrophosphate) is associated with carbohydrate metabolism. Thiamine pyrophosphate also acts as a co

Vitamin B₂ (Riboflavine)

Riboflavine is phosphorylated to flavine mononucleotide and flavine adenine dinucleotide which act as co-enzymes in the respiratory chain and in oxidative phosphorylation. Riboflavine deficiency presents with ocular symptoms, as well as lesions on the lips and at angles of the mouth.

Vitamin B₆ (Pyridoxine)

Pyridoxine, once absorbed, is rapidly converted to the co-enzymes pyridoxal phosphate and pyridoxamine phosphate which play an essential role in protein metabolism. Convulsions and hypochromic anaemia have occurred in infants deficient in pyridoxine.

Vitamin B₁₂ (Cyanocobalamin)

Vitamin B₁₂ is present in the body mainly as methylcobalamin and as adenosylcobalamin and hydroxocobalamin. These act as co-enzymes in the trans methylation of homocysteine to methionine; in the isomerisation of methylmalonyl co₁₂ interferes with haemopoiesis and produces megaloblastic anaemia.

Vitamin C (Ascorbic Acid)

Vitamin C cannot be synthesised by man therefore a dietary source is necessary. It acts as a cofactor in numerous biological processes including the hydroxylation of proline to hydroxyproline. In deficiency, the formation of collagen is, therefore, impaired. Ascorbic acid is important in the hydroxylation of dopamine to noradrenaline and in hydroxylations occurring in steroid synthesis in the adrenals. It is a reducing agent in tyrosine metabolism and by acting as an electron donor in the conversion of folic acid to tetrahydrofolic acid is indirectly involved in the synthesis of purine and thymine. Vitamin C is also necessary for the incorporation of iron into ferritin. Vitamin C increases the phagocytic function of leucocytes; it possesses anti-inflammatory activity and it promotes wound healing. Deficiency can produce scurvy. Features include swollen inflamed gums, petechial haemorrhages and subcutaneous bruising. The deficiency of collagen leads to development of thin watery ground substances in which blood vessels are insecurely fixed and readily ruptured. The supportive components of bone and cartilage are also deficient causing bones to fracture easily and teeth to become loose. Anaemia commonly occurs probably due to Vitamin C's role in iron metabolism.

Vitamin E

Vitamin E deficiency has been linked to disorders such as cystic fibrosis where fat absorbtion is impaired. It is essential for the normal function of the muscular system and the blood.

Nicotinamide

The biochemical functions of nicotinamide as NAD and NADP (nicotinamide adenine dinucleotide phosphate) include the degradation and synthesis of fatty acids, carbohydrates and amino acids as well as hydrogen transfer. Deficiency produces pellagra and mental neurological changes.

Pantothenic Acid

Pantothenic acid is incorporated into co-enzyme A and is involved in metabolic pathways involving acetylation which includes detoxification of drug molecules and biosynthesis of cholesterol, steroid hormones, mucopolysaccharides and acetylcholine. CoA has an essential function in lipid metabolism.

Vitamin K1 (Phytomenadione)

Phytomenadione is a provitamin; following activation it exerts Vitamin K effects. Vitamin K is essential for the formation of prothrombin (Factor II) and other clotting factors (Factors VII, IX and X) in the liver. Deficiency of Vitamin K produces hypoprothrombinaemia, in which the clotting time of the blood is prolonged and spontaneous haemorrhage may occur.

Folic Acid

Folic acid is reduced in the body to tetrahydrofolate which is a co-enzyme for various metabolic processes, including the synthesis of purine and pyrimidine nucleotides and hence in the synthesis of DNA. It is also involved in some amino acid conversion and in the formation and utilisation of formate. Deficiency of folic acid leads to megaloblastic anaemia.

Vitamin H (d-Biotin)

Biotin is a co-enzyme for carboxylation during the metabolism of proteins and carbohydrates.

Selenium

Selenium is an essential trace element, deficiency of which has been reported in man. It is thought to be involved in the functioning of membranes and the synthesis of amino acids. Deficiency of selenium in the diet of experimental animals produces fatty liver followed by necrosis.

Iron

Iron, as a constituent of haemoglobin, plays an essential role in oxygen transport. It is also present in the muscle protein myoglobin and in the liver. Deficiency of iron leads to anaemia.

Copper (Copper Sulphate)

Traces of copper are essential to the body as constituents of enzyme systems involved in oxidation reactions.

Magnesium (Magnesium Sulphate)

Magnesium is essential to the body as a constituent of skeletal structures and in maintaining cell integrity and fluid balance. It is utilised in many of the functions in which calcium is concerned but often exerts the opposite effect. Some enzymes require the magnesium ion as a co-factor.

Zinc (Zinc Sulphate)

Zinc is a constituent of many enzymes and is, therefore, essential to the body. It is present with insulin in the pancreas. It plays a role in DNA synthesis and cell division. Reported effects of deficiency include delayed puberty and hypogonadal dwarfism.

Manganese (Manganese Sulphate)

Manganese is a constituent of enzyme systems including those involved in lipid synthesis, the tricarboxylic acid cycle and purine and pyrimidine metabolism. It is bound to arginase of the liver and activates many enzymes.

Iodine (Potassium Iodide)

Iodine is an essential constituent of the thyroid hormones.

Chromium (Chromium Amino Acid Chelate 10%)

Chromium is an essential trace element involved in carbohydrate metabolism.

Molybdenum (Sodium Molybdate)

Molybdenum is an essential trace element although there have been no reports of deficiency states in man. Molybdenum salts have been used to treat copper poisoning in sheep.

5.2 Pharmacokinetic Properties

The following account describes the absorption and fate of each of the active constituents of Forceval Junior Capsules.

Vitamin A

Except when liver function is impaired, Vitamin A is readily absorbed. β

Vitamin D

The metabolism of ergocalciferol is similar to that of cholecalciferol. Cholecalciferol is absorbed from the gastro-intestinal tract into the circulation. In the liver, it is hydroxylated to 25-hydroxycholecalciferol, is subject to entero-hepatic circulation and is further hydroxylated to 1,25

Vitamin B₁ (Thiamine)

Thiamine is absorbed from the gastro-intestinal tract and is widely distributed to most body tissues. Amounts in excess of the body's requirements are not stored but excreted in the urine as unchanged thiamine or its metabolites.

Vitamin B₂ (Riboflavine)

Riboflavine is absorbed from the gastro-intestinal tract and in the circulation is bound to plasma proteins. It is widely distributed. Little is stored and excess amounts are excreted in the urine. In the body riboflavine is converted to flavine mononucleotide (FMN) and then to flavine adenine dinucleotide (FAD).

Vitamin B₆ (Pyridoxine)

Pyridoxine is absorbed from the gastro-intestinal tract and converted to the active pyridoxal phosphate which is bound to plasma proteins. It is excreted in the urine as 4

Vitamin B₁₂ (Cyanocobalamin)

Cyanocobalamin is absorbed from the gastro-intestinal tract and is extensively bound to specific plasma proteins. Vitamin B₁₂ is taken up by the intestinal mucosa and held there for 2

Vitamin C (Ascorbic Acid)

Ascorbic acid is readily absorbed from the gastro-intestinal tract and is widely distributed in the body tissues. Ascorbic acid in excess of the body's needs is rapidly eliminated in the urine.

Vitamin E

Vitamin E is absorbed from the gastro-intestinal tract. Most appears in the lymph and is then widely distributed to all tissues. Most of a dose is slowly excreted in the bile and the remainder is eliminated in the urine as glucuronides of tocopheronic acid or other metabolites.

Nicotinamide (Nicotinic Acid Amide)

Nicotinamide is absorbed from the gastro-intestinal tract, is widely distributed in the body tissues and has a short half-life.

Calcium Pantothenate

Pantothenic acid is readily absorbed from the gastro-intestinal tract and is widely distributed in the body tissues. About 70% of pantothenic acid is excreted unchanged in the urine and about 30% in the faeces.

Vitamin K1 (Phytomenadione)

Phytomenadione is absorbed from the gastro-intestinal tract. It is rapidly metabolised and excreted and is not significantly stored in the body.

Folic Acid

Folic acid is absorbed mainly from the proximal part of the small intestine. Folate polyglutamates are considered to be deconjugated to monoglutamates during absorption. Folic acid rapidly appears in the blood where it is extensively bound to plasma proteins. Some folic acid is distributed in body tissues, some is excreted as folate in the urine and some is stored in the liver as folate.

Vitamin H (d-Biotin)

Following absorption, biotin is stored in the liver, kidney and pancreas.

Selenium

Although it has been established that selenium is essential to human life, very little information is available on its function and metabolism.

Ferrous Fumarate (Iron)

Iron is absorbed chiefly in the duodenum and jejunum. Absorption is aided by the acid secretion of the stomach and if the iron is in the ferrous state as in ferrous fumarate. In iron deficiency, absorption is increased and, conversely, it is decreased in iron overload. Iron is stored as ferritin.

Copper Sulphate (Copper)

Copper is absorbed from the gastro-intestinal tract and its major route of excretion is in the bile.

Magnesium Sulphate (Magnesium)

Magnesium salts are poorly absorbed from the gastro-intestinal tract; however, sufficient magnesium will normally be absorbed to replace deficiency states. It is excreted in both the urine and the faeces but excretion in the urine is reduced in deficiency states.

Zinc Sulphate (Zinc)

Zinc is poorly absorbed from the gastro-intestinal tract. It is widely distributed throughout the body. It is excreted in the faeces with traces appearing in the urine.

Manganese Sulphate (Manganese)

Manganese salts are poorly absorbed.

Potassium Iodide (Iodine)

Iodides are absorbed and stored in the thyroid gland as thyroglobulin. Iodides are excreted in the urine with smaller amounts appearing in the faeces, saliva and sweat.

Chromium Amino Acid Chelate 10% (Chromium)

Although it has been established that chromium is essential to human life, little information is available on its function and metabolism.

Sodium Molybdate (Molybdenum)

Although it has been established that molybdenum is essential to human life, little information is available on its function and metabolism.

5.3 Preclinical Safety Data

There are no pre-clinical 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

Soya Bean Oil BP

Soya Lecithin HSE

Fat Mix HSE

Purified Water PhEur

Gelatin BP

Glycerine BP

Black Iron Oxide Pigment (E172) HSE

Red Iron Oxide Pigment (E172) HSE

Sorbitol Solution 70% BP

6.2 Incompatibilities

No major incompatibilities are known.

6.3 Shelf Life

24 months, as packaged for sale.

6.4 Special Precautions For Storage

Store in a cool dry place at a temperature not exceeding 25°C.

Protect from light.

6.5 Nature And Contents Of Container

The product is presented in press-thru blister packs, each blister strip containing 10 Forceval Junior capsules. The blister strip is composed of PVC/PVdC with a printed aluminium foil lidding. The foil is printed (red on gold) with the name and PL number of the product, the number of vitamins and minerals per capsule and the daily dose.

The product is available in packs of 30, 60 or 120 capsules.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Alliance Pharmaceuticals Ltd

Avonbridge House

2 Bath Road

Chippenham

Wiltshire

SN15 2BB

United Kingdom

8. Marketing Authorisation Number(S)

PL 16853/0080

9. Date Of First Authorisation/Renewal Of The Authorisation

18^th April 2005

10. Date Of Revision Of The Text

April 2005

Skelaxin

metaxalone

Dosage Form: tablet
Skelaxin®

(Metaxalone) Tablets

Skelaxin Description

Skelaxin® (metaxalone) is available as an 800 mg oval, scored pink tablet.

Chemically, metaxalone is 5-[(3,5- dimethylphenoxy) methyl]-2-oxazolidinone. The empirical formula is C12H15NO3, which corresponds to a molecular weight of 221.25. The structural formula is:

Metaxalone is a white to almost white, odorless crystalline powder freely soluble in chloroform, soluble in methanol and in 96% ethanol, but practically insoluble in ether or water.

Each tablet contains 800 mg metaxalone and the following inactive ingredients: alginic acid, ammonium calcium alginate, B-Rose Liquid, corn starch, and magnesium stearate.

Skelaxin - Clinical Pharmacology

Mechanism of Action

The mechanism of action of metaxalone in humans has not been established, but may be due to general central nervous system depression. Metaxalone has no direct action on the contractile mechanism of striated muscle, the motor end plate, or the nerve fiber.

Pharmacokinetics

The pharmacokinetics of metaxalone have been evaluated in healthy adult volunteers after single dose administration of Skelaxin under fasted and fed conditions at doses ranging from 400 mg to 800 mg.

Absorption

Peak plasma concentrations of metaxalone occur approximately 3 hours after a 400 mg oral dose under fasted conditions. Thereafter, metaxalone concentrations decline log-linearly with a terminal half-life of 9.0 ± 4.8 hours. Doubling the dose of Skelaxin from 400 mg to 800 mg results in a roughly proportional increase in metaxalone exposure as indicated by peak plasma concentrations (Cmax) and area under the curve (AUC). Dose proportionality at doses above 800 mg has not been studied. The absolute bioavailability of metaxalone is not known.

The single-dose pharmacokinetic parameters of metaxalone in two groups of healthy volunteers are shown in Table 1.

Table 1: Mean (%CV) Metaxalone Pharmacokinetic Parameters

Dose (mg)	Cmax (ng/mL)	Tmax (h)	AUC∞ (ng•h/mL)	t½(h)	CL/F (L/h)
4001	983 (53)	3.3 (35)	7479 (51)	9.0 (53)	68 (50)
8002	1816 (43)	3.0 (39)	15044 (46)	8.0 (58)	66 (51)
1Subjects received 1x400 mg tablet under fasted conditions (N=42) 2Subjects received 2x400 mg tablets under fasted conditions (N=59)

Food Effects

A randomized, two-way, crossover study was conducted in 42 healthy volunteers (31 males, 11 females) administered one 400 mg Skelaxin tablet under fasted conditions and following a standard high-fat breakfast. Subjects ranged in age from 18 to 48 years (mean age = 23.5 ± 5.7 years). Compared to fasted conditions, the presence of a high fat meal at the time of drug administration increased Cmax by 177.5% and increased AUC (AUC0-t, AUC∞) by 123.5% and 115.4%, respectively. Time-to-peak concentration (Tmax) was also delayed (4.3 h versus 3.3 h) and terminal half-life was decreased (2.4 h versus 9.0 h) under fed conditions compared to fasted.

In a second food effect study of similar design, two 400 mg Skelaxin tablets (800 mg) were administered to healthy volunteers (N=59, 37 males, 22 females), ranging in age from 18-50 years (mean age = 25.6± 8.7 years). Compared to fasted conditions, the presence of a high fat meal at the time of drug administration increased Cmax by 193.6% and increased AUC (AUC0-t, AUC∞) by 146.4% and 142.2%, respectively. Time-to-peak concentration (Tmax) was also delayed (4.9 h versus 3.0 h) and terminal half-life was decreased (4.2 h versus 8.0 h) under fed conditions compared to fasted conditions. Similar food effect results were observed in the above study when one Skelaxin 800 mg tablet was administered in place of two Skelaxin 400 mg tablets. The increase in metaxalone exposure coinciding with a reduction in half-life may be attributed to more complete absorption of metaxalone in the presence of a high fat meal (Figure 1).

Distribution, Metabolism, and Excretion

Although plasma protein binding and absolute bioavailability of metaxalone are not known, the apparent volume of distribution (V/F ~ 800 L) and lipophilicity (log P = 2.42) of metaxalone suggest that the drug is extensively distributed in the tissues. Metaxalone is metabolized by the liver and excreted in the urine as unidentified metabolites.  Hepatic Cytochrome P450 enzymes play a role in the metabolism of metaxalone.  Specifically, CYP1A2, CYP2D6, CYP2E1, and CYP3A4 and, to a lesser extent, CYP2C8, CYP2C9, and CYP2C19 appear to metabolize metaxalone.

Metaxalone does not significantly inhibit major CYP enzymes such as CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. Metaxalone does not significantly induce major CYP enzymes such as CYP1A2, CYP2B6, and CYP3A4 in vitro.

Pharmacokinetics in Special Populations

Age:

The effects of age on the pharmacokinetics of metaxalone were determined following single administration of two 400 mg tablets (800 mg) under fasted and fed conditions. The results were analyzed separately, as well as in combination with the results from three other studies. Using the combined data, the results indicate that the pharmacokinetics of metaxalone are significantly more affected by age under fasted conditions than under fed conditions, with bioavailability under fasted conditions increasing with age.

The bioavailability of metaxalone under fasted and fed conditions in three groups of healthy volunteers of varying age is shown in Table 2.

Table 2: Mean (%CV) Pharmacokinetic Parameters Following Single Administration of Two 400 mg Skelaxin Tablets (800 mg) under Fasted and Fed Conditions

	Younger Volunteers		Older Volunteers
Age (years)	25.6 ± 8.7		39.3 ± 10.8		71.5 ± 5.0
N	59		21		23
Food	Fasted	Fed	Fasted	Fed	Fasted	Fed
Cmax (ng/mL)	1816 (43)	3510 (41)	2719 (46)	2915 (55)	3168 (43)	3680 (59)
Tmax (h)	3.0 (39)	4.9 (48)	3.0 (40)	8.7 (91)	2.6 (30)	6.5 (67)
AUC0-t (ng·h/mL)	14531 (47)	20683 (41)	19836 (40)	20482 (37)	23797 (45)	24340 (48)
AUC∞ (ng·h/mL)	15045 (46)	20833 (41)	20490 (39)	20815 (37)	24194 (44)	24704 (47)

Gender:

The effect of gender on the pharmacokinetics of metaxalone was assessed in an open label study, in which 48 healthy adult volunteers (24 males, 24 females) were administered two Skelaxin 400 mg tablets (800 mg) under fasted conditions. The bioavailability of metaxalone was significantly higher in females compared to males as evidenced by Cmax (2115 ng/mL versus 1335 ng/mL) and AUC∞ (17884 ng·h/mL versus 10328 ng·h/mL). The mean half-life was 11.1 hours in females and 7.6 hours in males. The apparent volume of distribution of metaxalone was approximately 22% higher in males than in females, but not significantly different when adjusted for body weight. Similar findings were also seen when the previously described combined dataset was used in the analysis.

Hepatic/Renal Insufficiency:

The impact of hepatic and renal disease on the pharmacokinetics of metaxalone has not been determined. In the absence of such information, Skelaxin should be used with caution in patients with hepatic and/or renal impairment.

Indications and Usage for Skelaxin

Skelaxin (metaxalone) is indicated as an adjunct to rest, physical therapy, and other measures for the relief of discomforts associated with acute, painful musculoskeletal conditions. The mode of action of this drug has not been clearly identified, but may be related to its sedative properties. Metaxalone does not directly relax tense skeletal muscles in man.

Contraindications

Known hypersensitivity to any components of this product.

Known tendency to drug induced, hemolytic, or other anemias.

Significantly impaired renal or hepatic function.

Warnings

Skelaxin may enhance the effects of alcohol and other CNS depressants.

Precautions

Metaxalone should be administered with great care to patients with pre-existing liver damage. Serial liver function studies should be performed in these patients.

False-positive Benedict’s tests, due to an unknown reducing substance, have been noted. A glucose-specific test will differentiate findings.

Taking Skelaxin with food may enhance general CNS depression; elderly patients may be especially susceptible to this CNS effect. (See CLINICAL PHARMACOLOGY:Pharmacokinetics and PRECAUTIONS: Information for Patients ).

Information for Patients

Skelaxin may impair mental and/or physical abilities required for performance of hazardous tasks, such as operating machinery or driving a motor vehicle, especially when used with alcohol or other CNS depressants.

Drug Interactions

The sedative effects of Skelaxin and other CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricyclic antidepressants) may be additive.  Therefore, caution should be exercised with patients who take more than one of these CNS depressants simultaneously.

Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of metaxalone has not been determined.

Pregnancy

Reproduction studies in rats have not revealed evidence of impaired fertility or harm to the fetus due to metaxalone. Post marketing experience has not revealed evidence of fetal injury, but such experience cannot exclude the possibility of infrequent or subtle damage to the human fetus. Safe use of metaxalone has not been established with regard to possible adverse effects upon fetal development. Therefore, metaxalone tablets should not be used in women who are or may become pregnant and particularly during early pregnancy unless, in the judgement of the physician, the potential benefits outweigh the possible hazards.

Nursing Mothers

It is not known whether this drug is secreted in human milk. As a general rule, nursing should not be undertaken while a patient is on a drug since many drugs are excreted in human milk.

Pediatric Use

Safety and effectiveness in children 12 years of age and below have not been established.

Adverse Reactions

The most frequent reactions to metaxalone include:

CNS: drowsiness, dizziness, headache, and nervousness or “irritability”;

Digestive: nausea, vomiting, gastrointestinal upset.

Other adverse reactions are:

Immune System: hypersensitivity reaction, rash with or without pruritus;

Hematologic: leukopenia; hemolytic anemia;

Hepatobiliary: jaundice.

Though rare, anaphylactoid reactions have been reported with metaxalone.

Overdosage

Deaths by deliberate or accidental overdose have occurred with metaxalone, particularly in combination with antidepressants, and have been reported with this class of drug in combination with alcohol.

When determining the LD50 in rats and mice, progressive sedation, hypnosis, and finally respiratory failure were noted as the dosage increased. In dogs, no LD50 could be determined as the higher doses produced an emetic action in 15 to 30 minutes.

Treatment - Gastric lavage and supportive therapy. Consultation with a regional poison control center is recommended.

Skelaxin Dosage and Administration

The recommended dose for adults and children over 12 years of age is one 800 mg tablet three to four times a day.

How is Skelaxin Supplied

Skelaxin (metaxalone) is available as an 800 mg oval, scored pink tablet inscribed with 8667 on the scored side and “S” on the other. Available in bottles of 100 (NDC 60793-136-01) and in bottles of 500 (NDC 60793-136-05).

Store at Controlled Room Temperature, between 15°C and 30°C (59°F and 86°F).

Rx Only

Prescribing Information as of April 2008.

Distributed by: King Pharmaceuticals, Inc., Bristol, TN 37620

Manufactured by: Corepharma LLC, Middlesex, NJ 08846

LabelGraphic1

Skelaxin  metaxalone  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 60793-136 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength METAXALONE (METAXALONE) METAXALONE 800 mg

Inactive Ingredients Ingredient Name Strength No Inactive Ingredients Found

Product Characteristics Color PINK Score 2 pieces Shape OVAL Size 20mm Flavor Imprint Code 8667;S Contains

Packaging # NDC Package Description Multilevel Packaging 1 60793-136-01 100  In 1 BOTTLE None 2 60793-136-05 500  In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA013217	08/30/2002

Labeler - King Pharmaceuticals, Inc. (809587413)

Revised: 09/2011King Pharmaceuticals, Inc.

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Isodine

Isodine may be available in the countries listed below.

Ingredient matches for Isodine

Povidone Iodine

Povidone-Iodine is reported as an ingredient of Isodine in the following countries:

• Colombia


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International Drug Name Search

Chloroprocaine

Dosage Form: injection, solution
Chloroprocaine

Hydrochloride

Injection, USP

Rx only

Chloroprocaine Description

Chloroprocaine Hydrochloride Injection, USP is a sterile, nonpyrogenic, isotonic, isobaric solution. Each milliliter of 2% solution contains 20 mg of Chloroprocaine hydrochloride; 4 mg sodium chloride; with 1.8 mg sodium metabisulfite added in water for injection. Each milliliter of 3% solution contains 30 mg of Chloroprocaine hydrochloride; 2.1 mg sodium chloride; with 1.8 mg sodium metabisulfite added in water for injection. May contain hydrochloric acid and/or sodium hydroxide for pH adjustment. It contains no bacteriostat, antimicrobial agent or added buffer. Discard unused portion.

It is intended for production of local anesthesia by nerve block, infiltration, caudal or other epidural blocks.

Chloroprocaine Hydrochloride Injection has a pH of 3.1 (2.7 to 4.0).

Sodium Chloride, USP is chemically designated NaCl, a white crystalline compound freely soluble in water.

Chloroprocaine Hydrochloride Injection is identified chemically as 2-(diethylamino) ethyl 4‑amino-2 chlorobenzoate monohydrochloride. Its molecular Formula is: C13H19ClN2O2•HCl and the molecular weight is 307.22. It has the following structural formula:

Chloroprocaine - Clinical Pharmacology

Chloroprocaine, like other local anesthetics, blocks the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone.

Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems. At blood concentrations achieved with normal therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block and ultimately to cardiac arrest. In addition, with toxic blood concentrations myocardial contractility may be depressed and peripheral vasodilation may occur, leading to decreased cardiac output and arterial blood pressure.

Following systemic absorption, toxic blood concentrations of local anesthetics can produce central nervous system stimulation, depression, or both. Apparent central stimulation may be manifested as restlessness, tremors and shivering, which may progress to convulsions. Depression and coma may occur, possibly progressing ultimately to respiratory arrest.

However, the local anesthetics have a primary depressant effect on the medulla and on higher centers. The depressed stage may occur without a prior stage of central nervous system stimulation.

Pharmacokinetics

The rate of systemic absorption of local anesthetic drugs is dependent upon the total dose and concentration of drug administered, the route of administration, the vascularity of the administration site, and the presence or absence of epinephrine in the anesthetic injection. Epinephrine usually reduces the rate of absorption and plasma concentration of local anesthetics and is sometimes added to local anesthetic injections in order to prolong the duration of action.

The onset of action with Chloroprocaine is rapid (usually within 6 to 12 minutes), and the duration of anesthesia, depending upon the amount used and the route of administration, may be up to 60 minutes.

Local anesthetics appear to cross the placenta by passive diffusion. However, the rate and degree of diffusion varies considerably among the different drugs as governed by: (1) the degree of plasma protein binding, (2) the degree of ionization, and (3) the degree of lipid solubility. Fetal/maternal ratios of local anesthetics appear to be inversely related to the degree of plasma protein binding, since only the free, unbound drug is available for placental transfer. Thus, drugs with the highest protein binding capacity may have the lowest fetal/maternal ratios. The extent of placental transfer is also determined by the degree of ionization and lipid solubility of the drug. Lipid soluble, nonionized drugs readily enter the fetal blood from the maternal circulation.

Depending upon the route of administration, local anesthetics are distributed to some extent to all body tissues with high concentrations found in highly perfused organs such as the liver, lungs, heart and brain.

Various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presence of hepatic or renal disease, addition of epinephrine, factors affecting urinary pH, renal blood flow, the route of administration, and the age of the patient. The in vitro plasma half-life of Chloroprocaine in adults is 21 ± 2 seconds for males and 25 ± 1 seconds for females. The in vitro plasma half-life in neonates is 43 ± 2 seconds.

Chloroprocaine is rapidly metabolized in plasma by hydrolysis of the ester linkage by pseudocholinesterase. The hydrolysis of Chloroprocaine results in the production of ß-diethyl-aminoethanol and 2-chloro-4-aminobenzoic acid, which inhibits the action of the sulfonamides (see PRECAUTIONS).

The kidney is the main excretory organ for most local anesthetics and their metabolites. Urinary excretion is affected by urinary perfusion and factors affecting urinary pH.

Indications and Usage for Chloroprocaine

Chloroprocaine Hydrochloride Injection in single-dose containers without preservative and without EDTA, is indicated for the production of local anesthesia by infiltration, peripheral and central nerve block, including lumbar and caudal epidural blocks.

Chloroprocaine Hydrochloride Injection is not to be used for subarachnoid administration.

Contraindications

Chloroprocaine Hydrochloride Injection is contraindicated in patients hypersensitive (allergic) to drugs of the PABA ester group.

Lumbar and caudal epidural anesthesia should be used with extreme caution in persons with the following conditions: existing neurological disease, spinal deformities, septicemia and severe hypertension.

Warnings

LOCAL ANESTHETICS SHOULD ONLY BE EMPLOYED BY CLINICIANS WHO ARE WELL VERSED IN DIAGNOSIS AND MANAGEMENT OF DOSE-RELATED TOXICITY AND OTHER ACUTE EMERGENCIES WHICH MIGHT ARISE FROM THE BLOCK TO BE EMPLOYED, AND THEN ONLY AFTER ENSURING THE IMMEDIATE AVAILABILITY OF OXYGEN, OTHER RESUSCITATIVE DRUGS, CARDIOPULMONARY RESUSCITATIVE EQUIPMENT, AND THE PERSONNEL RESOURCES NEEDED FOR PROPER MANAGEMENT OF TOXIC REACTIONS AND RELATED EMERGENCIES (See also ADVERSE REACTIONS and PRECAUTIONS.) DELAY IN PROPER MANAGEMENT OF DOSE-RELATED TOXICITY, UNDERVENTILATION FROM ANY CAUSE AND/OR ALTERED SENSITIVITY MAY LEAD TO THE DEVELOPMENT OF ACIDOSIS, CARDIAC ARREST AND, POSSIBLY, DEATH.

Chloroprocaine Hydrochloride Injection, contains no preservative; discard unused injection remaining in vial after initial use.

Intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures is an unapproved use, and there have been post-marketing reports of chondrolysis in patients receiving such infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of gleno-humeral chondrolysis have been described in pediatric and adult patients following intra-articular infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours. There is insufficient information to determine whether shorter infusion periods are not associated with these findings. The time of onset of symptoms, such as joint pain, stiffness and loss of motion can be variable, but may begin as early as the 2nd month after surgery. Currently, there is no effective treatment for chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic procedures and some  required arthroplasty or shoulder replacement.

Vasopressors should not be used in the presence of ergot-type oxytocic drugs, since a severe persistent hypertension may occur.

To avoid intravascular injection, aspiration should be performed before the anesthetic solution is injected. The needle must be repositioned until no blood return can be elicited. However, the absence of blood in the syringe does not guarantee that intravascular injection has been avoided.

Mixtures of local anesthetics are sometimes employed to compensate for the slower onset of one drug and the shorter duration of action of the second drug. Experiments in primates suggest that toxicity is probably additive when mixtures of local anesthetics are employed, but some experiments in rodents suggest synergism. Caution regarding toxic equivalence should be exercised when mixtures of local anesthetics are employed.

Chloroprocaine Hydrochloride Injection contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.

Precautions

General:

The safety and effective use of Chloroprocaine depend on proper dosage, correct technique, adequate precautions and readiness for emergencies. Resuscitative equipment, oxygen and other resuscitative drugs should be available for immediate use. (See WARNINGS and ADVERSE REACTIONS). The lowest dosage that results in effective anesthesia should be used to avoid high plasma levels and serious adverse effects. Injections should be made slowly, with frequent aspirations before and during the injection to avoid intravascular injection. Syringe aspirations should also be performed before and during each supplemental injection in continuous (intermittent) catheter techniques. During the administration of epidural anesthesia, it is recommended that a test dose be administered (3 mL of 3% or 5 mL of 2% Chloroprocaine Hydrochloride Injection) initially and that the patient be monitored for central nervous system toxicity and cardiovascular toxicity, as well as for signs of unintended intrathecal administration, before proceeding. When clinical conditions permit, consideration should be given to employing a Chloroprocaine solution that contains epinephrine for the test dose because circulatory changes characteristic of epinephrine may also serve as a warning sign of unintended intravascular injection. An intravascular injection is still possible even if aspirations for blood are negative. With the use of continuous catheter techniques, it is recommended that a fraction of each supplemental dose be administered as a test dose in order to verify proper location of the catheter.

Injection of repeated doses of local anesthetics may cause significant increases in plasma levels with each repeated dose due to slow accumulation of the drug or its metabolites. Tolerance to elevated blood levels varies with the physical condition of the patient. Debilitated, elderly patients, acutely ill patients, and children should be given reduced doses commensurate with their age and physical status. Local anesthetics should also be used with caution in patients with hypotension or heart block.

Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs and the patient’s state of consciousness should be accomplished after each local anesthetic injection. It should be kept in mind at such times that restlessness, anxiety, tinnitus, dizziness, blurred vision, tremors, depression or drowsiness may be early warning signs of central nervous system toxicity.

Local anesthetic injections containing a vasoconstrictor should be used cautiously and in carefully circumscribed quantities in areas of the body supplied by end arteries or having otherwise compromised blood supply. Patients with peripheral vascular disease and those with hypertensive vascular disease may exhibit exaggerated vasoconstrictor response. Ischemic injury or necrosis may result.

Since ester-type local anesthetics are hydrolyzed by plasma cholinesterase produced by the liver, Chloroprocaine should be used cautiously in patients with hepatic disease.

Local anesthetics should also be used with caution in patients with impaired cardiovascular function since they may be less able to compensate for functional changes associated with the prolongation of A-V conduction produced by these drugs.

Use in Ophthalmic Surgery:

When local anesthetic injections are employed for retrobulbar block, lack of corneal sensation should not be relied upon to determine whether or not the patient is ready for surgery. This is because complete lack of corneal sensation usually precedes clinically acceptable external ocular muscle akinesia.

Information for Patients:

When appropriate, patients should be informed in advance that they may experience temporary loss of sensation and motor activity, usually in the lower half of the body, following proper administration of epidural anesthesia.

Clinically Significant Drug Interactions:

The administration of local anesthetic solutions containing epinephrine or norepinephrine to patients receiving monoamine oxidase inhibitors, tricyclic antidepressants or phenothiazines may produce severe prolonged hypotension or hypertension. Concurrent use of these agents should generally be avoided. In situations when concurrent therapy is necessary, careful patient monitoring is essential.

Concurrent administration of vasopressor drugs (for the treatment of hypotension related to obstetric blocks) and ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents.

The para-aminobenzoic acid metabolite of Chloroprocaine inhibits the action of sulfonamides. Therefore, Chloroprocaine should not be used in any condition in which a sulfonamide drug is being employed.

Carcinogenesis, Mutagenesis, and Impairment of Fertility:

Long-term studies in animals to evaluate carcinogenic potential and reproduction studies to evaluate mutagenesis or impairment of fertility have not been conducted with Chloroprocaine.

Pregnancy Category C:

Animal reproduction studies have not been conducted with Chloroprocaine. It is also not known whether Chloroprocaine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Chloroprocaine should be given to a pregnant woman only if clearly needed. This does not preclude the use of Chloroprocaine at term for the production of obstetrical anesthesia.

Labor and Delivery:

Local anesthetics rapidly cross the placenta, and when used for epidural, paracervical, pudendal or caudal block anesthesia, can cause varying degrees of maternal, fetal and neonatal toxicity.

(See CLINICAL PHARMACOLOGY–Pharmacokinetics).

The incidence and degree of toxicity depend upon the procedure performed, the type and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus and neonate involve alterations of the central nervous system, peripheral vascular tone and cardiac function.

Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. Elevating the patient’s legs and positioning her on her left side will help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously, and electronic fetal monitoring is highly advisable. Epidural, paracervical, or pudendal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts. In one study, paracervical block anesthesia was associated with a decrease in the mean duration of first stage labor and facilitation of cervical dilation. However, epidural anesthesia has also been reported to prolong the second stage of labor by removing the parturient’s reflex urge to bear down or by interfering with motor function. The use of obstetrical anesthesia may increase the need for forceps assistance.

The use of some local anesthetic drug products during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life. The long-term significance of these observations is unknown.

Careful adherence to recommended dosage is of the utmost importance in obstetrical paracervical block. Failure to achieve adequate analgesia with recommended doses should arouse suspicion of intravascular or fetal intracranial injection. Cases compatible with unintended fetal intracranial injection of local anesthetic injection have been reported following intended paracervical or pudendal block or both. Babies so affected present with unexplained neonatal depression at birth which correlates with high local anesthetic serum levels and usually manifest seizures within six hours. Prompt use of supportive measures combined with forced urinary excretion of the local anesthetic has been used successfully to manage this complication.

Case reports of maternal convulsions and cardiovascular collapse following use of some local anesthetics for paracervical block in early pregnancy (as anesthesia for elective abortion) suggest that systemic absorption under these circumstances may be rapid. The recommended maximum dose of each drug should not be exceeded. Injection should be made slowly and with frequent aspiration. Allow a 5-minute interval between sides.

There are no data concerning use of Chloroprocaine for obstetrical paracervical block when toxemia of pregnancy is present or when fetal distress or prematurity is anticipated in advance of the block; such use is, therefore, not recommended. The following information should be considered by clinicians who select Chloroprocaine for obstetrical paracervical block anesthesia: 1) Fetal bradycardia (generally a heart rate of less than 120 per minute for more than 2 minutes) has been noted by electronic monitoring in about 5 to 10 percent of the cases (various studies) where initial total doses of 120 mg to 400 mg of Chloroprocaine were employed. The incidence of bradycardia, within this dose range, might not be dose related. 2) Fetal acidosis has not been demonstrated by blood gas monitoring around the time of bradycardia or afterwards. These data are limited and generally restricted to nontoxemic cases where fetal distress or prematurity was not anticipated in advance of the block. 3) No intact Chloroprocaine and only trace quantities of a hydrolysis product, 2-chloro-4-aminobenzoic acid, have been demonstrated in umbilical cord arterial or venous plasma following properly administered paracervical block with Chloroprocaine. 4) The role of drug factors and non-drug factors associated with fetal bradycardia following paracervical block are unexplained at this time.

Nursing Mothers:

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Chloroprocaine is administered to a nursing woman.

Pediatric Use:

Guidelines for the administration of Chloroprocaine Hydrochloride Injection to children are presented in DOSAGE AND ADMINISTRATION.

Geriatric Use:

Clinical studies of Chloroprocaine Hydrochloride Injection did not include sufficient number of subjects 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

This drug and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Adverse Reactions

Systemic:

The most commonly encountered acute adverse experiences that demand immediate countermeasures are related to the central nervous system and the cardiovascular system. These adverse experiences are generally dose-related and may result from rapid absorption from the injection site, diminished tolerance or from unintentional intravascular injection of the local anesthetic solution. In addition to systemic dose-related toxicity, unintentional subarachnoid injection of drug during the intended performance of caudal or lumbar epidural block or nerve blocks near the vertebral column (especially in the head and neck region) may result in underventilation or apnea (“Total Spinal”). Factors influencing plasma protein binding, such as acidosis, systemic diseases that alter protein production, or competition of other drugs for protein binding sites, may diminish individual tolerance. Plasma cholinesterase deficiency may also account for diminished tolerance to ester-type local anesthetics.

Central Nervous System Reactions:

These are characterized by excitation and/or depression. Restlessness, anxiety, dizziness, tinnitus, blurred vision or tremors may occur, possibly proceeding to convulsions. However, excitement may be transient or absent, with depression being the first manifestation of an adverse reaction. This may quickly be followed by drowsiness merging into unconsciousness and respiratory arrest.

The incidence of convulsions associated with the use of local anesthetics varies with the procedure used and the total dose administered. In a survey of studies of epidural anesthesia, overt toxicity progressing to convulsions occurred in approximately 0.1 percent of local anesthetic administrations.

Cardiovascular System Reactions:

High doses, or unintended intravascular injection, may lead to high plasma levels and related depression of the myocardium, hypotension, bradycardia, ventricular arrhythmias and, possibly, cardiac arrest.

Allergic:

Allergic-type reactions are rare and may occur as a result of sensitivity to the local anesthetic. These reactions are characterized by signs such as urticaria, pruritis, erythema, angioneurotic edema (including laryngeal edema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and possibly, anaphylactoid-type symptomatology (including severe hypotension). Cross sensitivity among members of the ester-type local anesthetic group has been reported. The usefulness of screening for sensitivity has not been definitely established.

Neurologic:

In the practice of caudal or lumbar epidural block, occasional unintentional penetration of the subarachnoid space by the catheter may occur (see PRECAUTIONS). Subsequent adverse observations may depend partially on the amount of drug administered intrathecally. These observations may include spinal block of varying magnitude (including total spinal block), hypotension secondary to spinal block, loss of bladder and bowel control, and loss of perineal sensation and sexual function. Arachnoiditis, persistent motor, sensory and/or autonomic (sphincter control) deficit of some lower spinal segments with slow recovery (several months) or incomplete recovery have been reported in rare instances. (See DOSAGE AND ADMINISTRATION discussion of Caudal and Lumbar Epidural Block). Backache and headache have also been noted following lumbar epidural or caudal block.

Overdosage

Acute emergencies from local anesthetics are generally related to high plasma levels encountered during therapeutic use of local anesthetics or to unintended subarachnoid injection of local anesthetic solution (see ADVERSE REACTIONS, WARNINGS, and PRECAUTIONS).

In mice, the intravenous LD50 of Chloroprocaine HCl is 97 mg/kg and the subcutaneous LD50 of Chloroprocaine HCl is 950 mg/kg.

Management of Local Anesthetic Emergencies:

The first consideration is prevention, best accomplished by careful and constant monitoring of cardiovascular and respiratory vital signs and the patient’s state of consciousness after each local anesthetic injection. At the first sign of change, oxygen should be administered.

The first step in the management of convulsions, as well as underventilation or apnea due to unintentional subarachnoid injection of drug solution, consists of immediate attention to the maintenance of a patent airway and assisted or controlled ventilation with oxygen and a delivery system capable of permitting immediate positive airway pressure by mask. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated, keeping in mind that drugs used to treat convulsions sometimes depress the circulation when administered intravenously. Should convulsions persist despite adequate respiratory support, and if the status of the circulation permits, small increments of an ultra-short acting barbiturate (such as thiopental or thiamylal) or a benzodiazepine (such as diazepam) may be administered intravenously; the clinician should be familiar, prior to the use of local anesthetics, with these anticonvulsant drugs. Supportive treatment of circulatory depression may require administration of intravenous fluids and, when appropriate, a vasopressor dictated by the clinical situation (such as ephedrine to enhance myocardial contractile force).

If not treated immediately, both convulsions and cardiovascular depression can result in hypoxia, acidosis, bradycardia, arrhythmias and cardiac arrest. Underventilation or apnea due to unintentional subarachnoid injection of local anesthetic solution may produce these same signs and also lead to cardiac arrest if ventilatory support is not instituted. If cardiac arrest should occur, standard cardiopulmonary resuscitative measures should be instituted. Recovery has been reported after prolonged resuscitative efforts.

Endotracheal intubation, employing drugs and techniques familiar to the clinician, may be indicated, after initial administration of oxygen by mask, if difficulty is encountered in the maintenance of a patent airway or if prolonged ventilatory support (assisted or controlled) is indicated.

Chloroprocaine Dosage and Administration

Chloroprocaine may be administered as a single injection or continuously through an indwelling catheter. As with all local anesthetics, the dose administered varies with the anesthetic procedure, the vascularity of the tissues, the depth of anesthesia and degree of muscle relaxation required, the duration of anesthesia desired, and the physical condition of the patient. The smallest dose and concentration required to produce the desired result should be used. Dosage should be reduced for children, elderly and debilitated patients and patients with cardiac and/or liver disease. The maximum single recommended doses of Chloroprocaine in adults are: without epinephrine, 11 mg/kg, not to exceed a maximum total dose of 800 mg; with epinephrine (1:200,000), 14 mg/kg, not to exceed a maximum total dose of 1000 mg. For specific techniques and procedures, refer to standard textbooks.

There have been adverse event reports of chondrolysis in patients receiving intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures.  Chloroprocaine is not approved for this use (see WARNINGS and DOSAGE AND ADMINISTRATION).

Caudal and Lumbar Epidural Block:

In order to guard against adverse experiences sometimes noted following unintended penetration of the subarachnoid space, the following procedure modifications are recommended:

1. Use an adequate test dose (3 mL of 3% or 5 mL of 2% Chloroprocaine Hydrochloride Injection) prior to induction of complete block. This test dose should be repeated if the patient is moved in such a fashion as to have displaced the epidural catheter. Allow adequate time for onset of anesthesia following administration of each test dose. 2. Avoid the rapid injection of a large volume of local anesthetic injection through the catheter. Consider fractional doses, when feasible. 3. In the event of the known injection of a large volume of local anesthetic injection into the subarachnoid space, after suitable resuscitation and if the catheter is in place, consider attempting the recovery of drug by draining a moderate amount of cerebrospinal fluid (such as 10 mL) through the epidural catheter.

As a guide for some routine procedures, suggested doses are given below:

 1. Infiltration and Peripheral Nerve Block: Chloroprocaine Hydrochloride Injection

Anesthetic Procedure	Solution Concentration %	Volume (mL)	Total Dose (mg)
Mandibular	2	2 – 3	40 – 60
Infraorbital	2	0.5 – 1	10 – 20
Brachial plexus	2	30 – 40	600 – 800
Digital (without epinephrine)	1	3 – 4	30 – 40
Pudendal	2	10 each side	400
Paracervical	1	3 per each of 4 sites	up to 120
(see also PRECAUTIONS)

    2.  Caudal and Lumbar Epidural Block: For caudal anesthesia, the initial dose is 15 to 25 mL of a 2% or 3% solution. Repeated doses may be given at 40 to 60 minute intervals.

For lumbar epidural anesthesia, 2 to 2.5 mL per segment of a 2% or 3% solution can be used. The usual total volume of Chloroprocaine Hydrochloride Injection is from 15 to 25 mL. Repeated doses 2 to 6 mL less than the original dose may be given at 40 to 50 minute intervals.

The above dosages are recommended as a guide for use in the average adult. Maximum dosages of all local anesthetics must be individualized after evaluating the size and physical condition of the patient and the rate of systemic absorption from a particular injection site.

Pediatric Dosage:

It is difficult to recommend a maximum dose of any drug for children, since this varies as a function of age and weight. For children over 3 years of age who have a normal lean body mass and normal body development, the maximum dose is determined by the child’s age and weight and should not exceed 11 mg/kg (5 mg/lb). For example, in a child of 5 years weighing 50 lbs (23 kg), the dose of Chloroprocaine HCl without epinephrine would be 250 mg. Concentrations of 0.5 – 1% are suggested for infiltration and 1 – 1.5% for nerve block. In order to guard against systemic toxicity, the lowest effective concentration and lowest effective dose should be used at all times. Some of the lower concentrations for use in infants and smaller children are not available in pre-packaged containers; it will be necessary to dilute available concentrations with the amount of 0.9% sodium chloride injection necessary to obtain the required final concentration of Chloroprocaine injection.

Preparation of Epinephrine Injections:

To prepare a 1:200,000 epinephrine-Chloroprocaine HCl injection, add 0.15 mL of 1 to 1000 Epinephrine Injection to 30 mL of Chloroprocaine Hydrochloride Injection.

Chloroprocaine is incompatible with caustic alkalis and their carbonates, soaps, silver salts, iodine and iodides.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever injection and container permit. As with other anesthetics having a free aromatic amino group, Chloroprocaine Hydrochloride Injection is slightly photosensitive and may become discolored after prolonged exposure to light. It is recommended that this product be stored in the original outer containers, protected from direct sunlight. Discolored injection should not be administered. If exposed to low temperatures, Chloroprocaine Hydrochloride Injection may deposit crystals of Chloroprocaine HCl which will redissolve with shaking when returned to room temperature. The product should not be used if it contains undissolved (e.g., particulate) material.

How is Chloroprocaine Supplied

Chloroprocaine Hydrochloride Injection, USP is supplied in single-dose containers as follows:

Concentration	NDC No.	Container	Container Size
2%	0409-4169-01	Vial	30 mL
3%	0409-4170-01	Vial	30 mL

Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.]

Revised: March, 2010

Printed in USA                            EN-2433

Hospira, Inc., Lake Forest, IL 60045 USA

RL-1392

 

RL-1393

 

Chloroprocaine HYDROCHLORIDE  Chloroprocaine hydrochloride  injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0409-4169 Route of Administration EPIDURAL, INFILTRATION DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Chloroprocaine HYDROCHLORIDE (Chloroprocaine) Chloroprocaine HYDROCHLORIDE 20 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE 4 mg  in 1 mL SODIUM METABISULFITE 1.8 mg  in 1 mL WATER   HYDROCHLORIC ACID   SODIUM HYDROXIDE

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0409-4169-01 25 VIAL In 1 TRAY contains a VIAL, SINGLE-DOSE 1 30 mL In 1 VIAL, SINGLE-DOSE This package is contained within the TRAY (0409-4169-01)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA087447	03/24/2010

Chloroprocaine HYDROCHLORIDE  Chloroprocaine hydrochloride  injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0409-4170 Route of Administration INFILTRATION, EPIDURAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Chloroprocaine HYDROCHLORIDE (Chloroprocaine) Chloroprocaine HYDROCHLORIDE 30 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE 2.1 mg  in 1 mL SODIUM METABISULFITE 1.8 mg  in 1 mL WATER   HYDROCHLORIC ACID   SODIUM HYDROXIDE

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0409-4170-01 25 VIAL In 1 TRAY contains a VIAL, SINGLE-DOSE 1 30 mL In 1 VIAL, SINGLE-DOSE This package is contained within the TRAY (0409-4170-01)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA087446	03/24/2010

Labeler - Hospira, Inc. (141588017)

Revised: 08/2011Hospira, Inc.

More Chloroprocaine resources

• Chloroprocaine Side Effects (in more detail)
• Chloroprocaine Drug Interactions
• Chloroprocaine Support Group
• 0 Reviews for Chloroprocaine - Add your own review/rating

• Chloroprocaine Professional Patient Advice (Wolters Kluwer)

Compare Chloroprocaine with other medications

• Local Anesthesia

Tylenol Infants Plus Cold Drops

Pronunciation: a-SEET-a-MIN-oh-fen/FEN-il-EF-rin
Generic Name: Acetaminophen/Phenylephrine
Brand Name: Tylenol Infants Plus Cold

Tylenol Infants Plus Cold Drops are used for:

Relieving symptoms such as pain and sinus congestion due to colds, upper respiratory infections, and allergies. It may also used for other conditions as determined by your doctor.

Tylenol Infants Plus Cold Drops are an analgesic and decongestant combination. The analgesic works in the brain to help decrease pain. The decongestant works by constricting blood vessels and reducing swelling in the nasal passages, which decreases stuffiness.

Do NOT use Tylenol Infants Plus Cold Drops if:

• you are allergic to any ingredient in Tylenol Infants Plus Cold Drops


• you have severe high blood pressure, severe heart blood vessel disease, rapid heartbeat, or severe heart problems


• you have taken furazolidone or a monoamine oxidase inhibitor (MAOI) (eg, phenelzine) within the last 14 days

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

Before using Tylenol Infants Plus Cold Drops:

Some medical conditions may interact with Tylenol Infants Plus Cold 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 a history of adrenal gland problems (eg, adrenal gland tumor), heart problems, high blood pressure, diabetes, blood vessel problems, stroke, glaucoma, an enlarged prostate or other prostate problems, seizures, an overactive thyroid, severe kidney problems, or liver problems (eg, hepatitis), or if you drink 3 or more drinks with alcohol per day


• if you smoke or have a history of addiction to alcohol

Some MEDICINES MAY INTERACT with Tylenol Infants Plus Cold Drops. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Beta-blockers (eg, propranolol), catechol-O-methyltransferase (COMT) inhibitors (eg, tolcapone), furazolidone, hydantoins (eg, phenytoin), indomethacin, isoniazid, MAOIs (eg, phenelzine), or tricyclic antidepressants (eg, amitriptyline) because may increase the risk of Tylenol Infants Plus Cold Drops's side effects


• Anticoagulants (eg, warfarin), digoxin, or droxidopa because the risk of bleeding, irregular heartbeat, or heart attack may be increased


• Bromocriptine because the risk of its side effects may be increased by Tylenol Infants Plus Cold Drops


• Guanadrel, guanethidine, mecamylamine, methyldopa, or reserpine because their effectiveness may be decreased by Tylenol Infants Plus Cold Drops

This may not be a complete list of all interactions that may occur. Ask your health care provider if Tylenol Infants Plus Cold 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 Tylenol Infants Plus Cold Drops:

Use Tylenol Infants Plus Cold Drops as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Take Tylenol Infants Plus Cold Drops by mouth with or without food.


• Use the dropper that comes with Tylenol Infants Plus Cold Drops to measure your dose. Ask your pharmacist for help if you are unsure of how to measure your dose.


• If you miss a dose of Tylenol Infants Plus Cold Drops, take 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 take 2 doses at once.

Ask your health care provider any questions you may have about how to use Tylenol Infants Plus Cold Drops.

Important safety information:

• Tylenol Infants Plus Cold Drops may cause drowsiness, dizziness, or blurred vision. These effects may be worse if you take it with alcohol or certain medicines. Use Tylenol Infants Plus Cold Drops with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Do not take diet or appetite control medicines while you use Tylenol Infants Plus Cold Drops unless your doctor tells you to.


• Tylenol Infants Plus Cold Drops contains acetaminophen and phenylephrine. Before you start any new medicine, check the label to see if it has acetaminophen or a decongestant (eg, phenylephrine) in it too. If it does or if you are not sure, check with your doctor or pharmacist.


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


• If your symptoms do not get better within 7 days or if they get worse, check with your doctor.


• If you have a sore throat that is severe or lasts for more than 2 days, contact your doctor right away. If you have fever, headache, rash, nausea, or vomiting along with or after a sore throat, contact your doctor right away.


• Tylenol Infants Plus Cold Drops may cause you to become sunburned more easily. Avoid the sun, sunlamps, or tanning booths until you know how you react to Tylenol Infants Plus Cold Drops. Use a sunscreen or wear protective clothing if you must be outside for more than a short time.


• Tylenol Infants Plus Cold Drops may harm your liver. Your risk may be greater if you drink alcohol while you are using Tylenol Infants Plus Cold Drops. Talk to your doctor before you take Tylenol Infants Plus Cold Drops or other fever reducers if you drink more than 3 drinks with alcohol per day.


• Tell your doctor or dentist that you take Tylenol Infants Plus Cold Drops before you receive any medical or dental care, emergency care, or surgery.


• Use Tylenol Infants Plus Cold Drops with caution in the ELDERLY; they may be more sensitive to its effects.


• Caution is advised when using Tylenol Infants Plus Cold Drops in CHILDREN; they may be more sensitive to its effects.


• Different brands of Tylenol Infants Plus Cold Drops may have different dosing instructions for CHILDREN. Follow the dosing instructions on the package labeling. If your doctor has given you instructions, follow those. If you are unsure of the dose to give a child, check with your doctor or pharmacist.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Tylenol Infants Plus Cold Drops while you are pregnant. Tylenol Infants Plus Cold Drops are found in breast milk. Do not breast-feed while taking Tylenol Infants Plus Cold Drops. If you are or will be breast-feeding while you use Tylenol Infants Plus Cold Drops, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Tylenol Infants Plus Cold Drops:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome: Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Constipation; diarrhea; dizziness; excitability; headache; trouble sleeping; upset stomach.

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); dark urine; difficulty urinating or inability to urinate; fast or irregular heartbeat; hallucinations; mood or mental changes; seizures; severe dizziness, lightheadedness, or headache; severe drowsiness; stomach pain; tremor; vision changes; yellowing of skin or eyes.

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: Tylenol Infants Plus Cold 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. Symptoms may include blurred vision; confusion; hallucinations; seizures; severe dizziness, lightheadedness, or headache; severe drowsiness; unusually fast, slow, or irregular heartbeat; vomiting.

Proper storage of Tylenol Infants Plus Cold Drops:

Store Tylenol Infants Plus Cold Drops at room temperature, between 68 and 77 degrees F (20 and 25 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Tylenol Infants Plus Cold Drops out of the reach of children and away from pets.

General information:

• If you have any questions about Tylenol Infants Plus Cold Drops, please talk with your doctor, pharmacist, or other health care provider.


• Tylenol Infants Plus Cold 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 Tylenol Infants Plus Cold 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 Tylenol Infants Plus Cold resources

• Tylenol Infants Plus Cold Side Effects (in more detail)
• Tylenol Infants Plus Cold Use in Pregnancy & Breastfeeding
• Tylenol Infants Plus Cold Drug Interactions
• Tylenol Infants Plus Cold Support Group
• 1 Review for Tylenol Infants Plus Cold - Add your own review/rating

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