Daunorubicin Hydrochloride
200mg Injection

What Daunorubicin is And What it is used for

The name of medicine is Daunorubicin 20mg Powder for I.V. Injection (called daunorubicin in this leaflet). It belongs to a group of medicines used to treat acute leukaemia.

Daunorubicin works by attacking and destroying the abnormal white blood cells which are present in a person with leukaemia.

Leukaemia is the name for a number of diseases of the white blood cells, which form part of your blood. These cells are produced in your bone marrow. In leukaemia, the white blood cells multiply in an uncontrolled and abnormal way.

The most common signs of leukaemia are:

• Increased number of white cells in the blood. This causes easy bruising and nose bleeds
• Feeling tired, faint, dizzy, having pale skin. These could be symptoms of anaemia
• Extreme tiredness (exhaustion), and headaches
• Bone and joint pain
• Severe infection and fever

Before you are given Daunorubicin

Before treatment, you should discuss the risks and benefits of this medicine with your doctor.

• You are sensitive to, or allergic to, daunorubicin or other anthracyclines or any of the other ingredients of this medicine (listed in section 6)
• Signs of an allergic reaction include: a rash, swallowing or breathing problems, swelling of your lips, face, throat or tongue
• You have chicken pox or shingles, or you have been in recent contact with anyone who has chicken pox or shingles
• You have an infection, fever or high temperature
• You have any heart problems
• You are pregnant or breast-feeding
• You have a lot of mouth ulcers

Do not have daunorubicin if any of the above applies to you. If you are not sure, talk to your doctor or nurse.

Take special care with daunorubicin
Check with your doctor or nurse before you are given daunorubicin if:

• You have had radiation treatment to the chest
• You have had any other medicines to treat leukaemia (or cancer)
• You have or have ever had gout
• You have or have ever had kidney stones or any other kidney problems
• You have any liver problems
• You are sexually active, you are advised to use effective birth control to prevent pregnancy during treatment, whether you are male or female.

If you are not sure if any of the above apply to you, talk to your doctor or nurse before being given daunorubicin.

Special care will also be taken if you are taking any of the following medicines:

other medicines that may affect your heart for example, medicines to treat cancer such as 5-fluorouracil, cyclophosphamide, cisplatin, taxanes, calcium channel blockers used to control high blood pressure, chest pain, and irregular heartbeats and if you are receiving chest radiotherapy.

other medicines that may affect the bone marrow for example, other cancer treatments, sulphonamide, chloramphenicol (used to treat infection), diphenylhydantoin (used to treat epilepsy), amidopyrine-derivative (used to relieve pain), antiretroviral agents (used to treat HIV infection) may alter the formation of blood cells

other medicines that may affect your liver e.g barbiturates (drugs used in epilepsy or sleep disorders) and rifampicin (a drug used to treat TB - Tuberculosis)

live attenuated vaccines

Do not have daunorubicin if you are pregnant, might become pregnant or think you might be pregnant as daunorubicin can be very damaging to your unborn baby (embryo). If pregnancy occurs during treatment this should be discussed with your doctor.

Both female and male patients must take special precautions in their sexual activity if there is any possibility for pregnancy to occur:

For a girl or woman of childbearing age:
You must have a negative pregnancy test before treatment and each month during treatment. This should be discussed with your doctor.

For men:
Do not have sex with a pregnant woman unless you use a condom. This will lessen the possibility for daunorubicin to be left in the woman's body.

You and your female partner must each use an effective contraceptive during the time you are taking daunorubicin and for 6 months after stopping treatment. This should be discussed with your doctor.

Men who wish to father children in the future should seek advice about freezing sperm before treatment with daunorubicin is started.

If you are a woman who is breast-feeding, you must not take daunorubicin. Discontinue breast-feeding before starting to take daunorubicin.

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You may feel and/or be sick after being given this medicine, therefore special care should be taken when driving or using machines.

There is no information available about how daunorubicin might affect your ability to drive or use machines.

How you will be given Daunorubicin

• Daunorubicin is a medicine used in hospitals
• It will be given to you by a doctor or nurse as an injection into one of your veins
• It will be given over about 20 minutes (this is called an intravenous infusion)
• It should never be given as a single injection under the skin or into a muscle
• The site of injection should not be covered or bandaged

You have any pain, swelling or warmth around the vein where daunorubicin is being injected

You notice that your face is red while the injection is being given to you. This may be a sign that the injection is being given too quickly

The exact dose will be determined by your doctor. It will depend on your age, height, weight and your general medical condition. The usual dose for a person weighing 70kg (12 stone) would be about 80mg

Your course of treatment may be altered, depending on how your body reacts to the medicine
Daunorubicin may be given alone or in combination with other medicines to treat or prevent side effects

Your condition will be closely monitored during treatment. This may involve blood, urine tests or heart monitoring (called ECG).

If you have any questions about your course of treatment ask your doctor or nurse

Possible Side Effects

Like all medicines, this medicine can cause side effects, although not everybody who is given this medicine will be affected in the same way. If you are worried about side effects you should discuss them with your doctor, who will explain the risks and benefits of your treatment.

Some of the side effects can be lessened or treated by other medicines or therapy.

• You have pain, swelling or warmth in or around the vein where daunorubicin is being injected
• You have a red face while daunorubicin is being injected. This may be a sign that the injection is being given too quickly
• You get fevers, chills or other signs of infection
• You have difficulty in breathing
• You have swelling of the feet or legs
• You have an uneven or fast heart beat
• You have black or tarry bowel motions
• You are being sick (vomiting) and bring up blood or dark brown coffee-coloured granules
• You notice any unusual bleeding or bruising

• You feel sick (nausea) or are sick (vomit)
• You have diarrhoea
• You have a skin rash
• You have sores in the mouth or on the lips

• decreased numbers of different types of blood cells (granulocytopenia, leukopenia and neutropenia, anaemia) which may cause tiredness, fever or increased risk of bleeding
• feeling very dry and thirsty (dehydration)
• inflammation of mucous membranes (mucositis), of the mouth with areas of painful erosions, ulceration and bleeding (stomatitis) and of the oesophagus (oesophagitis)
• loss of appetite
• increased pigmentation (hyperpigmentation) of skin and nails
• Daunorubicin can make your urine turn red for a couple of days after each dose
• Medicines like daunorubicin often cause temporary loss of hair. After your treatment finishes your hair should grow back

Tell your doctor or nurse if any of the side effects gets serious, lasts longer than a few days, or if you notice any side effects not listed in the leaflet.

After you have finished your course of treatment, you may still get side effects. Tell your doctor or nurse straightaway if:

• You have difficulty in breathing
• You have swelling of the feet or legs
• You get an uneven or fast heart beat

How to store Daunorubicin

• Keep this medicine out of the sight and reach of children.
• Daunorubicin should not be used after the expiry date which is stated on the carton. The expiry date refers to the last day of the month.
• The vials of powder should be kept at room temperature and protected from light.
• The daunorubicin solutions made up from the powder should be stored at between 2 - 8°C, protected from light and used within 24 hours.
• Following the injection, daunorubicin will be disposed of carefully by the doctor or nurse.
• Medicines should not be disposed of via waste water or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

Daunorubicin Hydrochloride
200mg Injection

DESCRIPTION

Daunorubicin Hydrochloride Injection consists of the hydrochloride salt of an anthracycline cytotoxic antibiotic produced by a strain of Streptomyces coeruleorubidus. It is provided as a deep red sterile liquid in vials for intravenous administration only. Each mL contains daunorubicin hydrochloride, USP equivalent to 5 mg of daunorubicin, 9 mg sodium chloride, hydrochloric acid (to adjust pH), and water for injection, q.s. It has the following structural formula which may be described with the chemical name of (1S,3S)-3-Acetyl-1,2,3,4,6,11-hexahydro-3,5,12-trihydroxy-10-methoxy-6,11-dioxo-1-naphthacenyl 3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranoside hydrochloride.

4C27H29NO10•HCl M.W. 563.99

It is a hygroscopic crystalline powder. The pH of a 5 mg/mL aqueous solution is 3 to 4.

CLINICAL PHARMACOLOGY

Daunorubicin has antimitotic and cytotoxic activity through a number of proposed mechanisms of action. Daunorubicin forms complexes with DNA by intercalation between base pairs. It inhibits topoisomerase II activity by stabilizing the DNA-topoisomerase II complex, preventing the religation portion of the ligation-religation reaction that topoisomerase II catalyzes. Single strand and double strand DNA breaks result.

Daunorubicin hydrochloride may also inhibit polymerase activity, affect regulation of gene expression, and produce free radical damage to DNA.

Daunorubicin hydrochloride possesses an antitumor effect against a wide spectrum of animal tumors, either grafted or spontaneous.

General
Following intravenous injection of daunorubicin hydrochloride, plasma levels of daunorubicin decline rapidly, indicating rapid tissue uptake and concentration. Thereafter, plasma levels decline slowly with a half-life of 45 minutes in the initial phase and 18.5 hours in the terminal phase. By 1 hour after drug administration, the predominant plasma species is daunorubicinol, an active metabolite, which disappears with a half-life of 26.7 hours.

Distribution
Daunorubicin hydrochloride is rapidly and widely distributed in tissues, with highest levels in the spleen, kidneys, liver, lungs, and heart. The drug binds to many cellular components, particularly nucleic acids. There is no evidence that daunorubicin crosses the blood-brain barrier, but the drug apparently crosses the placenta.

Metabolism and Elimination
Daunorubicin hydrochloride is extensively metabolized in the liver and other tissues, mainly by cytoplasmic aldo-keto reductases, producing daunorubicinol, the major metabolite which has antineoplastic activity. Approximately 40% of the drug in the plasma is present as daunorubicinol within 30 minutes and 60% in 4 hours after a dose of daunorubicin. Further metabolism via reduction cleavage of the glycosidic bond, 4-O demethylation, and conjugation with both sulfate and glucuronide have been demonstrated. Simple glycosidic cleavage of daunorubicin or daunorubicinol is not a significant metabolic pathway in man. Twenty-five percent of an administered dose of daunorubicin hydrochloride is eliminated in an active form by urinary excretion and an estimated 40% by biliary excretion.

Pediatric Patients
Although appropriate studies with daunorubicin hydrochloride have not been performed in the pediatric population, cardiotoxicity may be more frequent and occur at lower cumulative doses in children.

Geriatric Patients
Although appropriate studies with daunorubicin hydrochloride have not been performed in the geriatric population, cardiotoxicity may be more frequent in the elderly. Caution should also be used in patients who have inadequate bone marrow reserves due to old age. In addition, elderly patients are more likely to have age-related renal function impairment, which may require reduction of dosage in patients receiving daunorubicin hydrochloride.

Renal and Hepatic Impairment
Doses of daunorubicin hydrochloride should be reduced in patients with hepatic and renal impairment. Patients with serum bilirubin concentrations of 1.2 to 3 mg/dL should receive 75% of the usual daily dose and patients with serum bilirubin concentrations greater than 3 mg/dL should receive 50% of the usual daily dose. Patients with serum creatinine concentrations of greater than 3 mg/dL should receive 50% of the usual daily dose.

In the treatment of adult acute nonlymphocytic leukemia, daunorubicin hydrochloride, used as a single agent, has produced complete remission rates of 40 to 50%, and in combination with cytarabine, has produced complete remission rates of 53 to 65%.

The addition of daunorubicin hydrochloride to the two-drug induction regimen of vincristine-prednisone in the treatment of childhood acute lymphocytic leukemia does not increase the rate of complete remission. In children receiving identical CNS prophylaxis and maintenance therapy (without consolidation), there is prolongation of complete remission duration (statistically significant, p < 0.02) in those children induced with the three drug (daunorubicin-vincristine-prednisone) regimen as compared to two drugs. There is no evidence of any impact of daunorubicin hydrochloride on the duration of complete remission when a consolidation (intensification) phase is employed as part of a total treatment program.

In adult acute lymphocytic leukemia, in contrast to childhood acute lymphocytic leukemia, daunorubicin hydrochloride during induction significantly increases the rate of complete remission, but not remission duration, compared to that obtained with vincristine, prednisone, and L-asparaginase alone. The use of daunorubicin hydrochloride in combination with vincristine, prednisone, and L-asparaginase has produced complete remission rates of 83% in contrast to a 47% remission in patients not receiving daunorubicin hydrochloride.

INDICATIONS AND USAGE

Daunorubicin hydrochloride injection in combination with other approved anticancer drugs is indicated for remission induction in acute nonlymphocytic leukemia (myelogenous, monocytic, erythroid) of adults and for remission induction in acute lymphocytic leukemia of children and adults.

CONTRAINDICATIONS

Daunorubicin hydrochloride is contraindicated in patients who have shown a hypersensitivity to it.

WARNINGS

Daunorubicin hydrochloride is a potent bone marrow suppressant. Suppression will occur in all patients given a therapeutic dose of this drug. Therapy with daunorubicin hydrochloride should not be started in patients with preexisting drug-induced bone marrow suppression unless the benefit from such treatment warrants the risk. Persistent, severe myelosuppression may result in superinfection or hemorrhage.

Special attention must be given to the potential cardiac toxicity of daunorubicin hydrochloride, particularly in infants and children. Preexisting heart disease and previous therapy with doxorubicin are co-factors of increased risk of daunorubicin-induced cardiac toxicity and the benefit-to-risk ratio of daunorubicin hydrochloride therapy in such patients should be weighed before starting daunorubicin hydrochloride. In adults, at total cumulative doses less than 550 mg/m2, acute congestive heart failure is seldom encountered. However, rare instances of pericarditis-myocarditis, not dose-related, have been reported.

In adults, at cumulative doses exceeding 550 mg/m2, there is an increased incidence of drug-induced congestive heart failure. Based on prior clinical experience with doxorubicin, this limit appears lower, namely 400 mg/m2, in patients who received radiation therapy that encompassed the heart.

In infants and children, there appears to be a greater susceptibility to anthracycline-induced cardiotoxicity compared to that in adults, which is more clearly dose-related. Anthracycline therapy (including daunorubicin) in pediatric patients has been reported to produce impaired left ventricular systolic performance, reduced contractility, congestive heart failure or death. These conditions may occur months to years following cessation of chemotherapy. This appears to be dose-dependent and aggravated by thoracic irradiation. Long-term periodic evaluation of cardiac function in such patients should, thus, be performed. In both children and adults, the total dose of daunorubicin hydrochloride administered should also take into account any previous or concomitant therapy with other potentially cardiotoxic agents or related compounds such as doxorubicin.

There is no absolutely reliable method of predicting the patients in whom acute congestive heart failure will develop as a result of the cardiac toxic effect of daunorubicin hydrochloride. However, certain changes in the electrocardiogram and a decrease in the systolic ejection fraction from pretreatment baseline may help to recognize those patients at greatest risk to develop congestive heart failure. On the basis of the electrocardiogram, a decrease equal to or greater than 30% in limb lead QRS voltage has been associated with a significant risk of drug-induced cardiomyopathy. Therefore, an electrocardiogram and/or determination of systolic ejection fraction should be performed before each course of daunorubicin hydrochloride. In the event that one or the other of these predictive parameters should occur, the benefit of continued therapy must be weighed against the risk of producing cardiac damage.

Early clinical diagnosis of drug-induced congestive heart failure appears to be essential for successful treatment.

Significant hepatic or renal impairment can enhance the toxicity of the recommended doses of daunorubicin hydrochloride; therefore, prior to administration, evaluation of hepatic function and renal function using conventional clinical laboratory tests is recommended.

Daunorubicin hydrochloride may cause fetal harm when administered to a pregnant woman. An increased incidence of fetal abnormalities (parieto-occipital cranioschisis, umbilical hernias, or rachischisis) and abortions was reported in rabbits at doses of 0.05 mg/kg/day or approximately 1/100th of the highest recommended human dose on a body surface area basis. Rats showed an increased incidence of esophageal, cardiovascular and urogenital abnormalities as well as rib fusions at doses of 4 mg/kg/day or approximately 1/2 the human dose on a body surface area basis. Decreases in fetal birth weight and post-delivery growth rate were observed in mice. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

There have been reports of secondary leukemias in patients exposed to topoisomerase II inhibitors when used in combination with other antineoplastic agents or radiation therapy.

Extravasation of daunorubicin hydrochloride at the site of intravenous administration can cause severe local tissue necrosis.

PRECAUTIONS

Therapy with daunorubicin hydrochloride requires close patient observation and frequent complete blood-count determinations. Cardiac, renal, and hepatic function should be evaluated prior to each course of treatment.

Appropriate measures must be taken to control any systemic infection before beginning therapy with daunorubicin hydrochloride.

Daunorubicin hydrochloride may transiently impart a red coloration to the urine after administration, and patients should be advised to expect this.

Daunorubicin hydrochloride may induce hyperuricemia secondary to rapid lysis of leukemic cells. As a precaution, allopurinol administration is usually begun prior to initiating antileukemic therapy. Blood uric acid levels should be monitored and appropriate therapy initiated in the event that hyperuricemia develops.

Daunorubicin hydrochloride, when injected subcutaneously into mice, causes a fibrosarcomas to develop at the injection site. When administered to mice thrice weekly intraperitoneally, no carcinogenic effect was noted after 18 months of observation. In male rats administered daunorubicin thrice weekly for 6 months, at 1/70th the recommended human dose on a body surface area basis, peritoneal sarcomas were found at 18 months. A single IV dose of daunorubicin administered to rats at 1.6 fold the recommended human dose on a body surface area basis caused mammary adenocarcinomas to appear at 1 year. Daunorubicin was mutagenic in vitro (Ames assay, V79 hamster cell assay), and clastogenic in vitro (CCRFCEM human lymphoblasts) and in vivo (SCE assay in mouse bone marrow) tests.

In male dogs at a daily dose of 0.25 mg/kg administered intravenously, testicular atrophy was noted at autopsy. Histologic examination revealed total aplasia of the spermatocyte series in the seminiferous tubules with complete aspermatogenesis.

See WARNINGS section.

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 serious adverse reactions in nursing infants from daunorubicin, mothers should be advised to discontinue nursing during daunorubicin therapy.

See CLINICAL PHARMACOLOGY, Special Populations, Geriatric Patients section.

See CLINICAL PHARMACOLOGY, Special Populations, Pediatric Patients section and WARNINGS, Cardiac Effects section.

Use of daunorubicin in a patient who has previously received doxorubicin increases the risk of cardiotoxicity. Daunorubicin hydrochloride should not be used in patients who have previously received the recommended maximum cumulative doses of doxorubicin or daunorubicin hydrochloride. Cyclophosphamide used concurrently with daunorubicin hydrochloride may also result in increased cardiotoxicity.

Dosage reduction of daunorubicin hydrochloride may be required when used concurrently with other myelosuppressive agents.

Hepatotoxic medications, such as high-dose methotrexate, may impair liver function and increase the risk of toxicity.

ADVERSE REACTIONS

Dose-limiting toxicity includes myelosuppression and cardiotoxicity. Other reactions include:

Reversible alopecia occurs in most patients. Rash, contact dermatitis and urticaria have occurred rarely.

Acute nausea and vomiting occur but are usually mild. Antiemetic therapy may be of some help. Mucositis may occur 3 to 7 days after administration. Diarrhea and abdominal pain have occasionally been reported.

If extravasation occurs during administration, severe local tissue necrosis, severe cellulitis, thrombophlebitis, or painful induration can result.

Rarely, anaphylactoid reaction, fever, and chills can occur. Hyperuricemia may occur, especially in patients with leukemia, and serum uric acid levels should be monitored.

DOSAGE AND ADMINISTRATION

Parenteral drug products should be inspected visually for particulate matter prior to administration, whenever solution and container permit.

In order to eradicate the leukemic cells and induce a complete remission, a profound suppression of the bone marrow is usually required. Evaluation of both the peripheral blood and bone marrow is mandatory in the formulation of appropriate treatment plans.

It is recommended that the dosage of daunorubicin hydrochloride be reduced in instances of hepatic or renal impairment. For example, using serum bilirubin and serum creatinine as indicators of liver and kidney function, the following dose modifications are recommended:

In Combination
For patients under age 60, daunorubicin hydrochloride 45 mg/m2/day IV on days 1, 2, and 3 of the first course and on days 1, 2 of subsequent courses AND cytosine arabinoside 100 mg/m2/day IV infusion daily for 7 days for the first course and for 5 days for subsequent courses.

For patients 60 years of age and above, daunorubicin hydrochloride 30 mg/m2/day IV on days 1, 2, and 3 of the first course and on days 1, 2 of subsequent courses AND cytosine arabinoside 100 mg/m2/day IV infusion daily for 7 days for the first course and for 5 days for subsequent courses. This daunorubicin hydrochloride dose-reduction is based on a single study and may not be appropriate if optimal supportive care is available.

The attainment of a normal-appearing bone marrow may require up to three courses of induction therapy. Evaluation of the bone marrow following recovery from the previous course of induction therapy determines whether a further course of induction treatment is required.

In Combination
Daunorubicin hydrochloride 25 mg/m2 IV on day 1 every week, vincristine 1.5 mg/m2 IV on day 1 every week, prednisone 40 mg/m2 PO daily. Generally, a complete remission will be obtained within four such courses of therapy; however, if after four courses the patient is in partial remission, an additional one or, if necessary, two courses may be given in an effort to obtain a complete remission.

In children less than 2 years of age or below 0.5 m2 body surface area, it has been recommended that the daunorubicin hydrochloride dosage calculation should be based on weight (1 mg/kg) instead of body surface area.

In Combination
Daunorubicin hydrochloride 45 mg/m2/day IV on days 1, 2, and 3 AND vincristine 2 mg IV on days 1, 8, and 15; prednisone 40 mg/m2/day PO on days 1 through 22, then tapered between days 22 to 29; L-asparaginase 500 IU/kg/day X 10 days IV on days 22 through 32.

The sterile 4 mL vial contents provide 20 mg of daunorubicin with 5 mg of daunorubicin per mL. The desired dose is withdrawn into a syringe containing 10 mL to 15 mL of 0.9% sodium chloride injection, USP and then injected into the tubing or sidearm in a rapidly flowing IV infusion of 5% dextrose injection, USP or 0.9% sodium chloride injection, USP. Daunorubicin hydrochloride should not be administered mixed with other drugs or heparin.

Storage and Handling

Store unopened vials in refrigerator, 2° to 8°C (36° to 46°F). Store prepared solution for infusion at room temperature, 20° to 25°C (68° to 77°F) for up to 24 hours. Contains no preservative. Discard unused portion. Protect from light. Retain in carton until time of use.

If daunorubicin hydrochloride contacts the skin or mucosae, the area should be washed thoroughly with soap and water. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

HOW SUPPLIED

Daunorubicin Hydrochloride Injection, 5 mg (base)/mL, is available as follows:

The 20 mg base/4 mL vials are packaged in tens.

REFERENCES

1. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH Publication No. 83-2621. For Sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, D.C. 20402.
2. AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. JAMA. 253 (11): 1590–1592, 1985.
3. National Study Commission on Cytotoxic Exposure—Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, Sc.D., Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115.
4. Clinical Oncological Society of Australia: Guidelines and recommendations for safe handling of antineoplastic agents. Med J Australia 1:426–428, 1983.
5. Jones RB, et al.: Safe handling of chemotherapeutic agents: A report from the Mount Sinai Medical Center, Ca – A Cancer Journal for Clinicians Sept/Oct, 258–263, 1983.
6. American Society of Hospital Pharmacists technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm 47:1033–1049, 1990.
7. OSHA Work Practice Guidelines for Personnel Dealing with Cyotoxic (Antineoplastic) Drugs. AM J Hosp Pharm 43:1193–1204, 1986.