Lysodren

mitotane

Dosage Form: tablet
Lysodren®

(mitotane tablets, USP)

Warnings

Lysodren (mitotane tablets, USP) should be administered under the supervision of a qualified physician experienced in the uses of cancer chemotherapeutic agents. Lysodren should be temporarily discontinued immediately following shock or severe trauma since adrenal suppression is its prime action. Exogenous steroids should be administered in such circumstances, since the depressed adrenal may not immediately start to secrete steroids.

Lysodren Description

Lysodren® (mitotane tablets, USP) is an oral chemotherapeutic agent. It is best known by its trivial name, o,p′-DDD, and is chemically, 1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl) ethane. The chemical structure is shown below:

Lysodren is a white granular solid composed of clear colorless crystals. It is tasteless and has a slight pleasant aromatic odor. It is soluble in ethanol, isooctane, and carbon tetrachloride. It has a molecular weight of 320.05.

Inactive ingredients in Lysodren tablets are: avicel, Polyethylene Glycol 3350, silicon dioxide, and starch.

Lysodren is available as 500 mg scored tablets for oral administration.

Lysodren - Clinical Pharmacology

Lysodren can best be described as an adrenal cytotoxic agent, although it can cause adrenal inhibition, apparently without cellular destruction. Its biochemical mechanism of action is unknown. Data are available to suggest that the drug modifies the peripheral metabolism of steroids as well as directly suppressing the adrenal cortex. The administration of Lysodren alters the extra-adrenal metabolism of cortisol in man; leading to a reduction in measurable 17-hydroxy corticosteroids, even though plasma levels of corticosteroids do not fall. The drug apparently causes increased formation of 6-β-hydroxycortisol.

Data in adrenal carcinoma patients indicate that about 40% of oral Lysodren is absorbed and approximately 10% of the administered dose is recovered in the urine as a water-soluble metabolite. A variable amount of metabolite (1%-17%) is excreted in the bile and the balance is apparently stored in the tissues.

Following discontinuation of Lysodren, the plasma terminal half-life has ranged from 18 to 159 days. In most patients blood levels become undetectable after 6 to 9 weeks. Autopsy data have provided evidence that Lysodren is found in most tissues of the body; however, fat tissues are the primary site of storage. Lysodren is converted to a water-soluble metabolite.

No unchanged Lysodren has been found in urine or bile.

Indications and Usage for Lysodren

Lysodren is indicated in the treatment of inoperable adrenal cortical carcinoma of both functional and nonfunctional types.

Contraindications

Lysodren (mitotane tablets, USP) should not be given to individuals who have demonstrated a previous hypersensitivity to it.

Warnings

Lysodren should be temporarily discontinued immediately following shock or severe trauma, since adrenal suppression is its prime action. Exogenous steroids should be administered in such circumstances, since the depressed adrenal may not immediately start to secrete steroids.

Lysodren should be administered with care to patients with liver disease other than metastatic lesions from the adrenal cortex, since the metabolism of Lysodren may be interfered with and the drug may accumulate.

All possible tumor tissues should be surgically removed from large metastatic masses before Lysodren administration is instituted. This is necessary to minimize the possibility of infarction and hemorrhage in the tumor due to a rapid cytotoxic effect of the drug.

Long-term continuous administration of high doses of Lysodren may lead to brain damage and impairment of function. Behavioral and neurological assessments should be made at regular intervals when continuous Lysodren treatment exceeds 2 years.

A substantial percentage of the patients treated show signs of adrenal insufficiency. It therefore appears necessary to watch for and institute steroid replacement in those patients. However, some investigators have recommended that steroid replacement therapy be administered concomitantly with Lysodren. It has been shown that the metabolism of exogenous steroids is modified and consequently somewhat higher doses than normal replacement therapy may be required.

Precautions

General

Adrenal insufficiency may develop in patients treated with Lysodren, and adrenal steroid replacement should be considered for these patients.

Since sedation, lethargy, vertigo, and other CNS side effects can occur, ambulatory patients should be cautioned about driving, operating machinery, and other hazardous pursuits requiring mental and physical alertness.

Drug Interactions

Lysodren has been reported to accelerate the metabolism of warfarin by the mechanism of hepatic microsomal enzyme induction, leading to an increase in dosage requirements for warfarin. Therefore, physicians should closely monitor patients for a change in anticoagulant dosage requirements when administering Lysodren to patients on coumarin-type anticoagulants. In addition, Lysodren should be given with caution to patients receiving other drugs susceptible to the influence of hepatic enzyme induction.

Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic and mutagenic potentials of Lysodren (mitotane tablets, USP) are unknown. However, the mechanism of action of this compound suggests that it probably has less carcinogenic potential than other cytotoxic chemotherapeutic drugs.

Pregnancy

Pregnancy Category C

Animal reproduction studies have not been conducted with Lysodren. It is also not known whether Lysodren can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Lysodren should be given to a pregnant woman only if clearly needed.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from mitotane, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of Lysodren did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between 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.

Adverse Reactions

A very high percentage of patients treated with Lysodren have shown at least one type of side effect. The main types of adverse reactions consist of the following:

1. Gastrointestinal disturbances, which consist of anorexia, nausea or vomiting, and in some cases diarrhea, occur in about 80% of the patients.


2. Central nervous system side effects occur in 40% of the patients. These consist primarily of depression as manifested by lethargy and somnolence (25%), and dizziness or vertigo (15%).


3. Skin toxicity has been observed in about 15% of the cases. These skin changes consist primarily of transient skin rashes which do not seem to be dose related. In some instances, this side effect subsided while the patients were maintained on the drug without a change of dose. Infrequently occurring side effects involve the eye (visual blurring, diplopia, lens opacity, toxic retinopathy); the genitourinary system (hematuria, hemorrhagic cystitis, and albuminuria); cardiovascular system (hypertension, orthostatic hypotension, and flushing); and some miscellaneous effects including generalized aching, hyperpyrexia, and lowered protein bound iodine (PBI).

Overdosage

No proven antidotes have been established for Lysodren overdosage.

Lysodren Dosage and Administration

The recommended treatment schedule is to start the patient at 2 g to 6 g of Lysodren per day in divided doses, either 3 or 4 times a day. Doses are usually increased incrementally to 9 g to 10 g per day. If severe side effects appear, the dose should be reduced until the maximum tolerated dose is achieved. If the patient can tolerate higher doses and improved clinical response appears possible, the dose should be increased until adverse reactions interfere. Experience has shown that the maximum tolerated dose (MTD) will vary from 2 g to 16 g per day, but has usually been 9 g to 10 g per day. The highest doses used in the studies to date were 18 g to 19 g per day.

Treatment should be instituted in the hospital until a stable dosage regimen is achieved.

Treatment should be continued as long as clinical benefits are observed. Maintenance of clinical status or slowing of growth of metastatic lesions can be considered clinical benefits if they can clearly be shown to have occurred.

If no clinical benefits are observed after 3 months at the maximum tolerated dose, the case would generally be considered a clinical failure. However, 10% of the patients who showed a measurable response required more than 3 months at the MTD. Early diagnosis and prompt institution of treatment improve the probability of a positive clinical response. Clinical effectiveness can be shown by reduction in tumor mass; reduction in pain, weakness or anorexia; and reduction of symptoms and signs due to excessive steroid production.

A number of patients have been treated intermittently with treatment being restarted when severe symptoms have reappeared. Patients often do not respond after the third or fourth such course. Experience accumulated to date suggests that continuous treatment with the maximum possible dosage of Lysodren is the best approach.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-4

To minimize the risk of dermal exposure, always wear impervious gloves when handling bottles containing Lysodren tablets. Lysodren tablets should not be crushed. Personnel should avoid exposure to crushed and/or broken tablets. If contact with broken tablets occurs, wash immediately and thoroughly. More information is available in the references listed below.

How is Lysodren Supplied

Lysodren® (mitotane tablets, USP)

NDC 0015-3080-60—500 mg Tablets, bottle of 100

STORAGE

Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature].

REFERENCES

1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.


2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html


3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006;63:1172-1193.


4. Polovich M, White JM, Kelleher LO, eds. 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd ed.) Pittsburgh, PA: Oncology Nursing Society.

Manufactured for:

Bristol-Myers Squibb Company

Princeton, New Jersey 08543 USA

Made in Italy

1050972A4

Rev June 2010

----------------------------------------------

REPRESENTATIVE PACKAGING

See How Supplied section for a complete list of available packages of Lysodren.

NDC 0015-3080-60

100 TABLETS

Lysodren® (mitotane tablets, USP)

EACH TABLET CONTAINS 500 mg

Rx only

Bristol-Myers Squibb

Lysodren  mitotane  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0015-3080 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength mitotane (mitotane) mitotane 500 mg

Inactive Ingredients Ingredient Name Strength cellulose, microcrystalline   polyethylene glycol 3350   silicon dioxide

Product Characteristics Color white Score 2 pieces Shape ROUND Size 13mm Flavor Imprint Code BL;L1 Contains

Packaging # NDC Package Description Multilevel Packaging 1 0015-3080-60 100 TABLET In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA016885	06/01/2009

Labeler - E.R. Squibb & Sons, L.L.C. (006370092)

Revised: 06/2010E.R. Squibb & Sons, L.L.C.

More Lysodren resources

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

• Lysodren Concise Consumer Information (Cerner Multum)


• Lysodren MedFacts Consumer Leaflet (Wolters Kluwer)


• Lysodren Monograph (AHFS DI)


• Lysodren Advanced Consumer (Micromedex) - Includes Dosage Information


• Mitotane Professional Patient Advice (Wolters Kluwer)

Compare Lysodren with other medications

• Adrenal Cortical Carcinoma

MXL capsules 30 mg, 60 mg, 90 mg, 120 mg, 150 mg, 200 mg

1. Name Of The Medicinal Product

MXL 30 mg, 60 mg, 90 mg, 120 mg, 150 mg, 200 mg prolonged release capsules.

2. Qualitative And Quantitative Composition

Capsules containing morphine sulphate 30 mg, 60 mg, 90 mg, 120 mg, 150 mg, 200 mg.

For excipients, see 6.1.

3. Pharmaceutical Form

Capsules, prolonged release

Hard gelatin capsules containing white to off white multiparticulates.

MXL capsules 30 mg are size 4, light blue capsules marked MS OD30.

MXL capsules 60 mg are size 3, brown capsules marked MS OD60.

MXL capsules 90 mg are size 2, pink capsules marked MS OD90.

MXL capsules 120 mg are size 1, olive capsules marked MS OD120.

MXL capsules 150 mg are size 1, blue capsules marked MS OD150.

MXL capsules 200 mg are size 0, rust capsules marked MS OD200

4. Clinical Particulars

4.1 Therapeutic Indications

The prolonged relief of severe and intractable pain.

4.2 Posology And Method Of Administration

Route of administration

Oral.

The capsules may be swallowed whole or opened and the contents sprinkled on to soft cold food. The capsules and contents should not be crushed or chewed. MXL capsules should be used at 24-hourly intervals. The dosage is dependent upon the severity of the pain, the patient's age and previous history of analgesic requirements.

Adults and elderly

Patients presenting with severe uncontrolled pain, who are not currently receiving opioids, should have their dose requirements calculated through the use of immediate release morphine, where possible, before conversion to MXL capsules.

Patients presenting in pain, who are currently receiving weaker opioids should be started on:

a) 60 mg MXL capsule once-daily if they weigh over 70 kg.

b) 30 mg MXL capsule once-daily if they weigh under 70 kg, are frail or elderly.

Increasing severity of pain will require an increased dosage of MXL capsules using 30 mg, 60 mg, 90 mg, 120 mg, 150 mg or 200 mg alone or in combination to achieve pain relief. Higher doses should be made, where appropriate in 30% - 50% increments as required. The correct dosage for any individual patient is that which controls the pain with no or tolerable side effects for a full 24 hours.

Patients receiving MXL capsules in place of parenteral morphine should be given a sufficiently increased dosage to compensate for any reduction in analgesic effects associated with oral administration. Usually such increased requirement is of the order of 100%. In such patients individual dose adjustments are required.

Children aged 1 year and above

The use of MXL capsules in children has not been extensively evaluated.

For severe and intractable pain in cancer a starting dose in the range of 0.4 to 1.6 mg morphine per kg bodyweight daily is recommended. Doses should be titrated in the normal way as for adults.

4.3 Contraindications

Hypersensitivity to any of the constituents.

Respiratory depression, head injury, paralytic ileus, acute abdomen,delayed gastric emptying, obstructive airways disease, known morphine sensitivity, acute hepatic disease, concurrent administration of monoamine oxidase inhibitors (MAOIs) or within two weeks of discontinuation of their use. Not recommended during pregnancy or for pre-operative use or for the first 24 hours post-operatively. Children under one year of age.

4.4 Special Warnings And Precautions For Use

As with all narcotics, a reduction in dosage may be advisable in the elderly, in hypothyroidism, in renal and chronic hepatic disease. Use with caution in patients with impaired respiratory function, convulsive disorders, acute alcoholism, delirium tremens, raised intracranial pressure, hypotension with hypovolaemia, severe cor pulmonale, opioid dependent patients, patients with a history of substance abuse, diseases of the biliary tract, pancreatitis, inflammatory bowel disorders, prostatic hypertrophy and adrenocortical insufficiency. MXL capsules should not be used where there is a possibility of paralytic ileus occurring. Should paralytic ileus be suspected or occur during use, MXL capsules should be discontinued immediately. As with all morphine preparations, patients who are to undergo cordotomy or other pain relieving surgical procedures should not receive MXL capsules for 24 hours prior to surgery. If further treatment with MXL capsules is then indicated the dosage should be adjusted to the new post-operative requirement.

It is not possible to ensure bio-equivalence between different brands of controlled release morphine products. Therefore, it should be emphasised that patients, once titrated to an effective dose should not be changed from MXL capsules to other slow, sustained or controlled release morphine or other potent narcotic analgesic preparations without retitration and clinical assessment.

The major risk of opioid excess is respiratory depression.

The patient may develop tolerance to the drug with chronic use and require progressively higher doses to maintain pain control. Prolonged use of this product may lead to physical dependence and a withdrawal syndrome may occur upon abrupt cessation of therapy. When a patient no longer requires therapy with morphine, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal.

Morphine has an abuse profile similar to other strong agonist opioids. Morphine may be sought and abused by people with latent or manifest addiction disorders. The development of psychological dependence to opioid analgesics in properly managed patients with pain has been reported to be rare. However, data are not available to establish the true incidence of psychological dependence in chronic pain patients. The product should be used with particular care in patients with a history of alcohol and drug abuse.

The controlled release granules must be swallowed whole, and not broken, chewed, dissolved or crushed. The administration of broken, chewed or crushed morphine granules leads to a rapid release and absorption of a potentially fatal dose of morphine (see section 4.9).

Morphine may lower the seizure threshold in patients with a history of epilepsy.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Morphine should be used with caution in patients who are concurrently receiving other central nervous system depressants including sedatives or hypnotics, general anesthetics, phenothiazines, other tranquilizers, muscle relaxants, antihypertensives and alcohol. Interactive effects resulting in respiratory depression, hypotension, profound sedation, or coma may result if these drugs are taken in combination with the usual doses of morphine. Morphine should not be co-administered with monoamine oxidase inhibitors or within two weeks of such therapy.

Mixed agonist/antagonist opioid analgesics (e.g. buprenorphine, nalbuphine, pentazocine) should not be administered to a patient who has received a course of therapy with a pure opioid agonist analgesic.

Cimetidine inhibits the metabolism of morphine.

Plasma concentrations of morphine may be reduced by rifampicin.

Although there are no pharmacokinetic data available for concomitant use of ritonavir with morphine, ritonavir induces the hepatic enzymes responsible for the glucuronidation of morphine, and may possibly decrease plasma concentrations of morphine.

4.6 Pregnancy And Lactation

MXL capsules are not recommended for use in pregnancy and labour due to the risk of neonatal respiratory depression. Administration to nursing mothers is not recommended as morphine is excreted in breast milk. Withdrawal symptoms may be observed in the newborn of mothers undergoing chronic treatment.

4.7 Effects On Ability To Drive And Use Machines

Morphine may modify the patient's reactions to a varying extent depending on the dosage and individual susceptibility. If affected, patients should not drive or operate machinery.

4.8 Undesirable Effects

In normal doses, the commonest side effects of morphine are nausea, vomiting, constipation and drowsiness. With chronic therapy, nausea and vomiting are unusual with MXL capsules but should they occur the capsules can be readily combined with an anti-emetic if required. Constipation may be treated with appropriate laxatives.

Common (incidence of

Undesirable Effects	Common (	Uncommon (
Immune system disorders		Allergic reaction Anaphylactic reaction Anaphylactoid reaction
Psychiatric disorders	Confusion Insomnia Thinking disturbances	Agitation Drug dependence Dysphoria Euphoria Hallucinations Mood altered
Nervous system disorders	Headache Involuntary muscle contractions Myoclonus Somnolence	Convulsions Hypertonia Paraesthesia Syncope Vertigo
Eye disorders		Miosis Visual disturbance
Cardiac disorders		Bradycardia Palpitations Hypertension Tachycardia
Vascular disorders		Facial flushing Hypotension
Respiratory, thoracic and mediastinal disorders	Bronchospasm Cough decreased	Pulmonary oedema Respiratory depression
Gastrointestinal disorders	Abdominal pain Anorexia Constipation Dry mouth Dyspepsia Nausea Vomiting	Gastrointestinal disorders Ileus Taste perversion
Hepatobiliary disorders	Exacerbation of pancreatitis	Biliary pain Increased hepatic enzymes
Skin and subcutaneous tissue disorders	Hyperhidrosis Rash	Urticaria
Renal and urinary disorders		Ureteric spasm Urinary retention

Reproductive system and breast disorders		Amenorrhea Decreased libido Erectile dysfunction
General disorders and administration site conditions	Asthenia Pruritus	Drug tolerance Drug withdrawal syndrome Malaise Peripheral oedema

The effects of morphine have led to its abuse and dependence may develop with regular, inappropriate use. This is not a major concern in the treatment of patients with severe pain.

4.9 Overdose

Signs of morphine toxicity and overdosage are drowsiness, pin-point pupils, skeletal muscle flaccidity, bradycardia, respiratory depression and hypotension. Circulatory failure and deepening coma may occur in more severe cases. Overdosage can result in death. Rhabdomyolysis progressing to renal failure has been reported in opioid overdosage.

Crushing and taking the contents of a controlled release dosage form leads to the release of the morphine in an immediate fashion; this might result in a fatal overdose.

Treatment of morphine overdosage:

Primary attention should be given to the establishment of a patent airway and institution of assisted or controlled ventilation.

The pure opioid antagonists are specific antidotes against the effects of opioid overdose. Other supportive measures should be employed as needed.

In the case of massive overdosage, administer naloxone 0.8 mg intravenously. Repeat at 2-3 minute intervals as necessary, or by an infusion of 2 mg in 500 ml of normal saline or 5% dextrose (0.004 mg/ml).

The infusion should be run at a rate related to the previous bolus doses administered and should be in accordance with the patient's response. However, because the duration of action of naloxone is relatively short, the patient must be carefully monitored until spontaneous respiration is reliably re-established. MXL capsules will continue to release and add to the morphine load for up to 24 hours after administration and the management of morphine overdosage should be modified accordingly.

For less severe overdosage, administer naloxone 0.2 mg intravenously followed by increments of 0.1 mg every 2 minutes if required.

Naloxone should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to morphine overdosage. Naloxone should be administered cautiously to persons who are known, or suspected, to be physically dependent on morphine. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute withdrawal syndrome.

Gastric contents may need to be emptied as this can be useful in removing unabsorbed drug, particularly when a modified release formulation has been taken.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: natural opium alkaloid

ATC code: N02A A01

Morphine acts as an agonist at opiate receptors in the CNS particularly mu and to a lesser extent kappa receptors. mu receptors are thought to mediate supraspinal analgesia, respiratory depression and euphoria and kappa receptors, spinal analgesia, miosis and sedation.

Central Nervous System

The principal actions of therapeutic value of morphine are analgesia and sedation (i.e., sleepiness and anxiolysis). Morphine produces respiratory depression by direct action on brain stem respiratory centres.

Morphine depresses the cough reflex by direct effect on the cough centre in the medulla. Antitussive effects may occur with doses lower than those usually required for analgesia.

Morphine causes miosis, even in total darkness. Pinpoint pupils are a sign of narcotic overdose but are not pathognomonic (e.g., pontine lesions of haemorrhagic or ischaemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in the setting of morphine overdose.

Gastrointestinal Tract and Other Smooth Muscle

Morphine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone is increased to the point of spasm resulting in constipation.

Morphine generally increases smooth muscle tone, especially the sphincters of the gastrointestinal and biliary tracts. Morphine may produce spasm of the sphincter of Oddi, thus raising intrabiliary pressure.

Cardiovascular System

Morphine may produce release of histamine with or without associated peripheral vasodilation. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Endocrine System

Opioids may influence the hypothalamic-pituitary-adrenal or -gonadal axes. Some changes that can be seen include an increase in serum prolactin, and decreases in plasma cortisol, oestrogen and testosterone in association with inappropriately low or normal ACTH, LH or FSH levels. Clinical symptoms may be manifest from these hormonal changes.

Other Pharmacological Effects

In vitro and animal studies indicate various effects of natural opioids, such as morphine, on components of the immune system; the clinical significance of these findings is unknown.

5.2 Pharmacokinetic Properties

Morphine is well absorbed from the capsules and, in general, peak plasma concentrations are achieved 2-6 hours following administration. The availability is complete when compared to an immediate release oral solution or MST CONTINUS tablets. The pharmacokinetics of morphine are linear across a very wide dose range. Morphine is subject to a significant first-pass effect which results in a lower bioavailability when compared to an equivalent intravenous or intramuscular dose.

The major metabolic transformation of morphine is glucuronidation to morphine-3-glucuronide and morphine-6-glucuronide which then undergo renal excretion. These metabolites are excreted in bile and may be subject to hydrolysis and subsequent reabsorption.

Because of the high inter-patient variation in morphine pharmacokinetics, and in analgesic requirements, the daily dosage in individual patients must be titrated to achieve appropriate pain control. Daily doses of up to 11.2 g have been recorded from twelve-hourly MST CONTINUS tablets. For this reason the capsules have been formulated in strengths of 30 mg, 60 mg, 90 mg, 120 mg, 150 mg and 200 mg.

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

Hydrogenated vegetable Oil BP

Macrogol 6000 Ph Eur.

Talc Ph Eur.

Magnesium stearate Ph Eur.

Capsule shells

Gelatin (containing sodium dodecylsulphate)

The following colours are also present:

30 mg: indigo carmine (E132), titanium dioxide (E171);

60 mg: indigo carmine (E132), titanium dioxide (E171), iron oxide (E172);

90 mg: erythrosine (E127), titanium dioxide (E171), iron oxide (E172);

120 mg: indigo carmine (E132), titanium dioxide (E171), iron oxide (E172);

150 mg: erythrosine (E127), indigo carmine (E132), titanium dioxide (E171),

iron oxide (E172);

200 mg: titanium dioxide (E171), iron oxide (E172).

Printing ink

Shellac DAB 10

Iron oxide, black (E172)

Propylene glycol

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

2 years

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

PVdC (

6.6 Special Precautions For Disposal And Other Handling

No special requirements

7. Marketing Authorisation Holder

Napp Pharmaceuticals Ltd

Cambridge Science Park

Milton Road

Cambridge CB4 0GW

8. Marketing Authorisation Number(S)

PL 16950/0042-47

9. Date Of First Authorisation/Renewal Of The Authorisation

29 March 1996/ 29 March 2006

10. Date Of Revision Of The Text

September 2009

11 Legal Category

CD (Sch 2), POM

® MXL, NAPP and the NAPP device (logo) are Registered Trade Marks.

© 2009 Napp Pharmaceuticals Ltd

Sodium Bicarbonate

Pronunciation: SO-dee-um bye-KAR-boe-nate
Generic Name: Sodium Bicarbonate
Brand Name: Generic only. No brands available.

Sodium Bicarbonate is used for:

Treating metabolic acidosis (a condition in which there is too much acid in the body) and certain drug intoxications, and replacing bicarbonate lost due to severe diarrhea. It may also be used for other conditions as determined by your doctor.

Sodium Bicarbonate is an electrolyte. It works by neutralizing excess acid in the blood. It may also replace bicarbonate when there are excess losses from the body.

Do NOT use Sodium Bicarbonate if:

• you are allergic to any ingredient in Sodium Bicarbonate


• you have alkalosis (too little acid in the body) or low blood levels of calcium or chloride


• you are vomiting

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

Before using Sodium Bicarbonate:

Some medical conditions may interact with Sodium Bicarbonate. 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 congestive heart failure, liver problems, kidney problems, a decreased amount of urine or no urine, swelling (fluid retention), or rectal bleeding of unknown cause

Some MEDICINES MAY INTERACT with Sodium Bicarbonate. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Sympathomimetics (eg, pseudoephedrine) because side effects may be increased by Sodium Bicarbonate


• Anorexiants (eg, phentermine), azole antifungals (eg, itraconazole), cephalosporins (eg, cephalexin), corticosteroids (eg, prednisone), corticotropin, lithium, or tetracyclines (eg, doxycycline) because effectiveness may be decreased by Sodium Bicarbonate

This may not be a complete list of all interactions that may occur. Ask your health care provider if Sodium Bicarbonate 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 Sodium Bicarbonate:

Use Sodium Bicarbonate as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Sodium Bicarbonate is usually administered as an injection at your doctor's office, hospital, or clinic. If you are using Sodium Bicarbonate at home, carefully follow the injection procedures taught to you by your health care provider.


• If Sodium Bicarbonate contains particles or is discolored, or if the vial is cracked or damaged in any way, do not use it.


• Keep this product, as well as syringes and needles, out of the reach of children and away from pets. Do not reuse needles, syringes, or other materials. Dispose of properly after use. Ask your doctor or pharmacist to explain local regulations for proper disposal.


• If you miss a dose of Sodium Bicarbonate, contact your doctor immediately.

Ask your health care provider any questions you may have about how to use Sodium Bicarbonate.

Important safety information:

• Tell your doctor if you begin to experience irritability or muscle rigidity.


• LAB TESTS, including blood gas monitoring and blood electrolytes, may be performed to monitor your progress or to check for side effects. Be sure to keep all doctor and lab appointments.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, discuss with your doctor the benefits and risks of using Sodium Bicarbonate during pregnancy. If you are or will be breast-feeding while you are using Sodium Bicarbonate, check with your doctor or pharmacist to discuss the risks to your baby.

Possible side effects of Sodium Bicarbonate:

All medicines may cause side effects, but many people have no, or minor, side effects. When used in small doses, no COMMON side effects have been reported with this product. Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); irritability; muscle spasms or twitching; pain, redness, or swelling at the injection site.

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: Sodium Bicarbonate 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 irritability; muscle rigidity; seizures.

Proper storage of Sodium Bicarbonate:

Store Sodium Bicarbonate at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Sodium Bicarbonate out of the reach of children and away from pets.

General information:

• If you have any questions about Sodium Bicarbonate, please talk with your doctor, pharmacist, or other health care provider.


• Sodium Bicarbonate is 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 Sodium Bicarbonate. 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.

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