prn8099 - Number 32, February 2002

The Registration of Cosmetic Products 

The fundamental principle of the registration is consumer safety and this will allow them to make an informed choice of the products that best suit them.

On 17 July 2001, the Minister of Health announced that all local and imported cos­metics products must be registered with the National Pharmaceutical Control Bureau (NPCB) starting 1 January 2002; subsequently, the licensing shall come into force after a 2-year grace period beginning 1 January 2004. The underlying prin­ciples of cosmetic registration are:

• to make manufacturers responsible for guaran­tee product safety.

• to enable the government to maintain a vigor­ous enforcement programme.

• the consumers are provided with adequate information.

The registration process will allow the NPCB to gather adequate information for the evaluation and assessment of the quality and safety of cosmetic products.

On February 2 1998, a press statement by the Minister of Health followed a worldwide concern regarding the use of skin bleaching products containing more than two per cent hidroquinone, pre­scribed by beauticians; these products were reported to have adverse effects on the skin. Although they serve as cosmetic function in lightening skin colour, it must be stressed that these products contain drugs and have potential toxicity if used without advice from doctors. This concern has been one of the important issues that had led to cosmetic registration.

The basis for the regulatory control of cosmetic products comes from the Con­trol of Drugs and Cosmetic Regulation 1984, which defines the criteria for the manufacturing, labelling, distribution and sale of cosmetics. Under the regulation, all cosmetic products must be registered before being manufactured, distributed or imported in Malaysia; the Drug Control Authority (DCA) is the responsible au­thority for the registration and licensing. All manufacturers, importers and whole­salers of cosmetic products will accord­ingly have to be licensed by DCA starting ,1 January 2004.

Two major guidelines for cosmetic prod­ucts have been developed namely,

1. Registration guidelines (requirements for registration including those for regulation, application, labelling and licensing).
2. Good Manufacturing Practice (GMP) guide­lines (basic elements involving quality management, personnel, premises, equipment, sanitation and hygiene, production, quality control, documentation, quality audit, storage, complaints and product recall, and contract manufacturing and analysis).

One of the impacts of the registration guidelines is the mandatory ingredient list­ing whereby manufacturers are required to list all used ingredients on the product labels. Ingredients will be listed accord­ing to their International Nomenclature Cosmetic Ingredient (INCI). Compliance with the proposed GMP guidelines and the GMP status will be important pre­requisites for the licensing of locally manufactured cosmetics.

The enforcement of the cosmetic product registration is another important effort to ensure consumer safety through emphasis of the responsibilities of the industry and control by the government. 

 POISON IN THE BATHROOM - COSMETIC 

PRN CONSULT

Isoniazid (isonicotinic acid hydrazide, INH) was first introduced in 1952. It is the drug of choice for the treat­ment of tuberculosis and for prophylaxis in patients who develop a positive tuberculin skin test. There is a prevalence of use in aid's patients, Southeast Asians, Mexicans, American Indians, alcoholics and IV drug abusers. Patients with a recently positive Protein Positive Derivatives (PPD) and a normal chest x-ray are routinely put on a 6-9 months course of INH. Patients with active disease are put on a regimen of INH combined with other antituberculous medications. Due to errors in dosage or intentional overdose, life-threatening toxicity may result. Most physi­cians are aware of the use of liver function tests to detect hepatotoxicity in patients with tuberculosis who are being treated with isoniazid. However, physicians may not be aware that the acute ingestion of as little as 1.5g of this drug can be toxic. In doses of 30 mg per kg or more, isoniazid often produces seizures. If large quantities of the drug (80-150mg/kg or more) are taken intentionally or accidentally, recurrent sei­zures, profound metabolic acidosis, coma and even death can occur.

What are the mechanisms of isoniazid toxicity?

INH is rapidly and completely absorbed from the GI tract resulting in peak plasma levels within one to two hours. Half-life varies between 1 to 5 hours. Toxic effects can be seen within 30 minutes of ingestion. Isoniazid binds to pyridoxal-5-phosphate, the active form of pyridoxine (Vitamin B6), to form INH-pyridoxal hydrazones. Pyridoxal-5-phosphate is a cofactor for the enzymes glutamic acid decarboxylase and gamma-aminobutyric acid (GABA) transaminase in the GABA synthetic pathway. INH overdose results in decreased pyridoxal-5-phosphate, decreased GABA synthesis, increased cerebral excitability and seizures. Coingestion of ethanol potentiates toxicity by enhancing degradation of phosphorylated pyridoxine. INH also inhibits lactate dehydrogenase, an enzyme that converts lactate to pyruvate.

INH undergoes N-acetylation in the liver to a variety of products, including acetylhydrazine, a potent hepatotoxin.  These metabolites  are excreted in the urine. With chronic administration at therapeutic doses, INH can cause clinically significant and even fatal hepatic injury in 1% of patients and elevated liver enzymes in 10-20% of patients.

The drug readily diffuses to all body fluids and tissues, with the largest. concentration occurring in the liver. The ingestion of 80-150mg/kg is likely to result in severe seizure activity. Blood levels are not helpful in managing an acute isoniazid overdose. Pyridoxine is a necessary cofactor for production of the neurotransmitter (GABA). Pyridoxine must be activated to produce GABA. Isoniazid combines with pyridoxine and renders the pyridoxine inactive, resulting in a depletion of GABA in the brain. This reduction in GABA levels increases the susceptibility to seizures. Thus, the neurotoxic effects of isoniazid are specifically counteracted by the administration of pyridoxine. The end result of INH overdose is the depletion of GABA, leading to supraspinal disinhibition.

The rate of acetylation of INH in the liver is race-dependent, with 60% of African-Americans and Caucasians being slow acetylators, compared with 10-20% of Asians. While slow acetylators appear more prone to INH-induced hepatitis and neuropathy with chronic use, it is unclear if the rate of acetylation affects acute toxicity. Patients of all ages may ex­perience either chronic or acute INH toxicity. Susceptibility to INH-induced hepatitis and subsequent death appear to increase with advancing age. The toxic dose of INH has been estimated as 1.5-3g (10-30mg/kg in adults.) Seizures have occurred at 30mg/kg, while the lethal dose is thought to be 10-15g.

What are the Clinical Syndrome of Isoniazid Toxicity?

Isoniazid toxicity is associated with a high mortality rate. If isoniazid is taken acutely, as little as 1.5g (five 300mg tablets) can cause toxicity. Doses larger than 30mg per kg often produce seizures. Ingestion of the drug in amounts greater than 80 to 150mg/kg can rapidly lead to death.

The first signs and symptoms of isoniazid toxicity may appear within 30 minutes to two hours after ingestion and may include nausea, vomiting, rash, fever, ataxia, slurring of speech, peripheral neuritis, dizziness and stupor. These symptoms are usually followed by grand mal seizures and coma. The seizures are often refractory to anticonvulsants, particularly phenytoin and barbiturates. Respiratory failure and death can follow.

Laboratory studies may show an elevated anion gap and metabolic acidosis, hyperglycemia, hypokalemia, glucosuria and ketonuria. The initial picture can easily be confused with diabetic ketoacidosis. The differential diagnosis of an elevated anion gap and metabolic acidosis is presented in

Table 1.

TABLE 1 Differential Diagnosis of Metabolic Acidosis and an Increased Anion Gap

Uremia/kidney failure

Alcoholic ketoacidosis

Diabetic ketoacidosis

Starvation ketoacidosis

Lactic acidosis

Drug ingestions

Direct

   Salicylates

   Paraldehyde

   Ethylene glycol

   Methanol

Indirect (via lactic acidosis)

   Cyanide

   Carbon monoxide

   Isoniazid

Adverse effects from chronic ingestion include:

• peripheral neuritis - uncommon in healthy patients but more common in diabetics, alcoholics and malnourished elderly individuals
• hepatitis - Risk factors include concomitant use of carbamazepine, phenobarbital, rifampin, and alcohol abuse.

INH is known to cause a positive antinuclear antibody (ANA) in 25% of patients and clinically apparent drug-induced lupus, characterized by fever, rash, arthralgias, arthritis and constitutional symptoms, in approximately 1% of patients. Isoniazid rarely  causes  mania,  depression, obsessive-compulsive disorder and psychosis, believed to result from its ability to act as an monoamine oxidase inhibitor (MAO) inhibitor or through depletion of pyridoxine. Rarely, an MAO inhibitor tyramine syndrome may occur following the ingestion of tyramine-containing foods (e.g., red wines, cheese). A hypersensitivity reaction is seen in 2% of patients taking INH. Signs and symptoms include fever, lymphadenopathy and skin rashes. Other adverse ef­fects from chronic use include fever, gastrointestinal upset, oliguria, ataxia, optic neuritis, paresthesias and encephalopathy.

What is the Management of Isoniazid Toxicity?

Management of the toxicity can be done in few steps:

1. Control of Life-Threatening Events

A secure airway should be established and maintained if the patient is having seizures, is comatose or is unresponsive. Intravenous ac­cess should be obtained, and fluids should be administered. Diazepam, 5-10 mg administered intravenously, is the initial approach to seizure control, with the dose repeated as necessary. Diazepam has been found to be more effective in controlling isoniazid-induced seizures than anticonvulsants such as phenytoin or barbiturates.

The acidosis associated with isoniazid toxicity appears to be lactic acidosis secondary to the seizure activity. Therefore, as the seizures are controlled, the acidosis usually decreases in severity. Since sodium bicarbonate may assist in correcting severe cases of acidosis, its administration should be considered if the pH is less than 7.1. A good starting dose is 1 -3 mEq/kg, with frequent monitoring of blood gases to guide further bicarbonate administration.

2. Correction of GABA Deficiency by Pyridoxine Replacement

Pyridoxine should be administered in a dose equivalent to the suspected maximum amount of isoniazid ingested (i.e., gram-per-gram replacement). If the amount of ingested isoniazid is unknown, 5g of pyridoxine is given intravenously over 5 to 10 minutes. Repeat dosing may be needed for persistent seizure activity and may also be used to reverse deep coma. A low threshold should be used for pyridoxine administration in the setting of isoniazid toxicity Peripheral neuropathy from the use of pyridoxine in doses of up to 52g has not been reported. One study reported an absence of adverse effects with pyridox­ine doses of up to 357mg/kg.

If the intravenous form of pyridoxine is not available, the drug can be given as a slurry, using crushed tablets in a similar gram-per-gram replacement dose.

3. Supportive Care

After the initial stabilization efforts, attempts should be made to prevent the absorption of isoniazid and to hasten elimination of the drug. Gastric lavage is indicated if it can be done within one hour of isoniazid ingestion. Charcoal, if administered within one hour of the ingestion of isoniazid, has been shown to be effective in preventing absorption of the drug. Charcoal should initially be given as a slurry with sorbitol. The usual charcoal dose is 30-100g for adults (1-2g/kg) and 15-30g for children (1-2g/kg). The sorbitol dose in adults is 1-2g/kg, with a maximum dose of 150g. In children, the sorbitol dose is 1.0-1.5g/kg to a maximum dose of 50g.

If diazepam fails to control seizures or pyridoxine does not reverse coma, other interventions may be considered. Hemodialysis has been used to lower serum isoniazid levels. Thiopental has been used to treat refractory seizures that did not respond to 12g of pyridoxine.

The summary of management of isoniazid toxicity is as follows:

Many of the steps listed below can be carried out concurrently.

1. Secure the airway Remember ABC (air­way, breathing, circulation).
2. Obtain intravenous access, and administer intravenous fluids.
3. For seizures: 

6. Perform gastric lavage if within one hour of isoniazid ingestion. Remember to protect the airway: use an endotracheal tube with the cuff inflated, or place the pa­tient in the Trendelenburg and left lateral decubitus position.
7. Administer charcoal and sorbitol if within one hour of isoniazid ingestion:b. In children, give 15-30g (l-2 g/kg) of charcoal as a slurry with 1.0-1.5 g/kg of sorbitol, up to 50g. Repeat the charcoal dose only.

8. If the above methods fail to control seizures, consider hemodialysis or the administration of thiopental by an anesthesiologist.
9. If the patient remains symptomatic, obtain a complete blood count, urinalysis and measurements of electrolytes, blood urea nitrogen, creatinine, glucose, creatinine kinase and liver enzymes. If the patient has liver damage, monitor the prothrombin time or the International Normalized Ratio.

What can be done to prevent Isoniazid toxicity?

Before isoniazid is prescribed, patients should be screened for depression. If a patient with depression needs isoniazid therapy but is considered to be at high risk for misusing the drug, it may be prudent to prescribe only two weeks' worth of the drug at a time. Bimonthly tablet counts and isoniazid blood levels may also be advised. In patients without depression, isoniazid should be dispensed in a one-month supply to prevent access to large amounts of the drug. The toxic effects of isoniazid should be explained to all patients. Keeping the drug away from children must be stressed. Medical management of isoniazid poisoning is directed at seizure control with pyridoxine. Benzodiazepine administration is a temporizing measure until large doses of pyridoxine are available. The summary of drug used in management of isoniazid toxicity is found in Table 2 and 3.

Conclusion

Isoniazid toxicity should be suspected in any patient who presents with refractory seizures and metabolic acidosis. One study found that isoniazid toxicity was responsible for 5% of all cases of seizures associated with drug intoxications.

As tuberculosis increases, physicians will prescribe more isoniazid. A consequent increase in accidental and intentional ingestions of this drug should be expected. Physicians must be prepared to counteract the potentially fatal toxic effects of isoniazid. A simple step-wise approach can help.

Table 2: Drug Category: Vitamin B Complex

Table 3: Drug Category:

Notes: Standard anticonvulsants when used alone may be ineffective in controlling seizures. However, benzodiazepines should still be considered firstline agents while pyridoxine is being readied. Phenytoin should be used with caution, because INH decreases metabolism of phenytoin, placing the patient at risk of phenytoin toxicity, especially slow-acetylators. 

Clinical Updates